Composition for precise cancer treatment and precise cancer treatment method

Abstract

Disclosed herein are compositions comprising one or more anti-tumor ketones, and methods of using these compositions for treating and / or preventing cancer, extending survival in a subject, and preventing and / or reducing cancer metastasis. The method further comprises obtaining a biological sample from the subject before and / or after performing the precise cancer treatment and performing free cell DNA (cfDNA) analysis on the biological sample, the analysis comprising next generation sequencing of one or more cancer-related genes, wherein sequencing the one or more cancer-related genes comprises determining one or more genomic aberrations, including mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, or any combination thereof, and then diagnosing the subject in need of a precise cancer treatment.

Description

[0001] I. Cross-reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 396,104, filed on August 8, 2022, the entire contents of which are incorporated herein by reference. II. Background Technology

[0003] Cancer is daunting in its breadth and scope of diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Increasingly powerful experimental and computational tools and techniques are providing vast amounts of "big data" about the diverse clinical manifestations of the disease encompassed by cancer. The integrative concepts embodied by the hallmarks of cancer are helping to distill this complexity into an increasingly coherent science, and the provisional new dimensions proposed in this Perspective may add value to this effort, leading to a more complete understanding of the mechanisms of cancer development and malignant progression and the application of this knowledge to cancer medicine.

[0004] Cancer is one of the leading causes of death worldwide. In 2018, there were 18.1 million new cases and 9.5 million cancer-related deaths worldwide. By 2040, the number of new cancer cases and cancer-related deaths is projected to rise to 29.5 million per year, and 16.4 million per year. Generally speaking, cancer incidence is highest in countries with the highest life expectancy, education levels, and living standards. However, for some cancer types, such as cervical cancer, the opposite is true, with the highest incidence occurring in countries with lower population rankings in these indicators.

[0005] Despite advances in care, there remains an unmet medical need for developing precision cancer treatments for patients with cancer, such as those with terminal cancer.

[0006] III. Brief Description of the Drawings

[0007] Figure 1 Kaplan-Meier survival curves are shown for all evaluable patients with terminal cancer who did or did not receive AS.

[0008] Figure 2 Kaplan-Meier survival curves are shown for evaluable terminal cancer patients diagnosed with head and neck, kidney, ovarian, pancreatic, or prostate cancer (eg, common cancers other than BE, CL, and LU) who did or did not receive AS.

[0009] Figure 3 Shown are Kaplan-Meier survival curves for evaluable patients with terminal cancer who were diagnosed with a rare cancer and who did or did not undergo AS. Patients with multiple diagnoses are listed only once.

[0010] Figure 4 Figure 3 shows the variant allele frequency of ctDNA-detected mutations in an individual patient who responded to AS therapy and was diagnosed with invasive ductal carcinoma, ER + PR - HER-2 + , with liver metastasis (stage IV). Due to successful treatment, as of November 1, 2017, the mutated genes PIK3CA and FGFR2 no longer exist.

[0011] Figure 5 Figure 3 shows the variant allele frequency of ctDNA-detected mutations in an individual patient who responded to AS therapy and was diagnosed with invasive ductal carcinoma with extensive DCIS, ER - PR - HER-2 + , with lymph node and skin metastases (stage IV). Due to successful treatment, the mutated genes TP53, ERBB2, and SMAD4 were no longer seen in the Guardant test results on September 13, 2018 and January 16, 2019.

[0012] Figure 6 Figure 2 shows the variant allele frequency of ctDNA-detected mutations in an individual patient who responded to AS therapy and was diagnosed with invasive ductal carcinoma, ER + PR + HER-2 - , with extensive metastasis to the bones (stage IV). Due to successful treatment, the mutated gene PIK3CA no longer exists on October 2, 2018.

[0013] Figure 7 Figure 2 shows the variant allele frequency of ctDNA-detected mutations in an individual patient who responded to AS therapy and was diagnosed with invasive ductal carcinoma, ER + PR + HER-2 - , with multiple metastases to the lymph nodes, bones, and brain (stage IV). Thanks to successful treatment, on April 8, 2019, the mutated genes MYC, BRCA2, PIK3CA, APC, BRCA1, FGFR3, RAF1, and ARAF no longer existed.

[0014] Figure 8 Figure 2 shows the variant allele frequency of ctDNA-detected mutations in an individual patient who responded to AS therapy and was diagnosed with invasive ductal carcinoma of the left breast, ER + PR - HER-2 +The patient had extensive metastases to the brain, bones, liver, and lungs, with epidural involvement at T6-T12 (stage IV). Due to successful treatment, the mutated genes EGFR, ERBB2, and PIK3CA were no longer present as of December 30, 2019.

[0015] Figure 9 A plot showing the variant allele frequencies of ctDNA-detected mutations in an individual patient diagnosed with breast adenocarcinoma, ER + PR - HER-2 + , with metastases to the lymph nodes, brain, lungs, pleura, bones, peritoneum, and ovaries. Due to successful treatment, the mutated genes CCND1, CDK6, ERBB2, FGFR1, PIK3CA, PTEN, ARID1A, and PDGFRA no longer exist on January 6, 2020.

[0016] Figure 10 Figure 2 shows the variant allele frequency of ctDNA-detected mutations in an individual patient who responded to AS therapy and was diagnosed with highly invasive urothelial bladder carcinoma with lymph node, lung, bone, and brain metastases (stage IV). Mutant EGFR was no longer present on November 5, 2019, BRAF was no longer present on April 16, 2020, and concentrations of mutant TERT, TP53, and ERBB2 decreased on April 16, 2020.

[0017] Figure 11 Shown are survival analyses of patients with common cancers treated with AS and A10 (ANP).

[0018] Figure 12 Shown is a survival analysis of patients with rare cancers treated with AS and A10 (ANP). IV. Summary of the Invention

[0019] Disclosed herein are compositions comprising one or more antineoplastons.

[0020] Disclosed herein is a pharmaceutical formulation comprising one or more antineoplastons and one or more pharmaceutically acceptable carriers.

[0021] Disclosed herein is a method of treating and / or preventing cancer, comprising administering a precision cancer therapy to a subject in need thereof, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy.

[0022] Disclosed herein is a method of treating cancer, comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy.

[0023] Disclosed herein is a method for treating cancer, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as being in need of precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; administering the precision cancer therapy to the subject; and measuring the subject's tumor response and / or the subject's molecular response.

[0024] Disclosed herein is a method of treating cancer, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; wherein, if the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample, diagnosing the subject as being in need of precision cancer therapy; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy.

[0025] Disclosed herein is a method of extending survival in a subject, the method comprising administering a precision cancer therapy to a subject in need thereof, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0026] Disclosed herein is a method for extending survival in a subject, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0027] Disclosed herein is a method for extending survival in a subject, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; administering the precision cancer therapy to the subject; and, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0028] Disclosed herein is a method for extending survival of a subject, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; wherein, if the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample, diagnosing the subject as being in need of precision cancer therapy; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0029] Disclosed herein is a method of preventing and / or reducing metastasis, the method comprising administering a precision cancer therapy to a subject in need thereof, wherein the subject exhibits a tumor response and / or molecular response to the precision cancer therapy, and metastasis is prevented and / or reduced.

[0030] Disclosed herein is a method for preventing and / or reducing metastasis, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or molecular response to the precision cancer therapy, and metastasis is prevented and / or reduced.

[0031] Disclosed herein is a method for preventing and / or reducing metastasis, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; administering the precision cancer therapy to the subject; and wherein the subject exhibits a tumor response and / or molecular response to the precision cancer therapy, and metastasis is prevented and / or reduced.

[0032] Disclosed herein is a method for preventing and / or reducing metastasis, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; wherein, if the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample, diagnosing the subject as needing precision cancer therapy; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or molecular response to the precision cancer therapy, and metastasis is prevented and / or reduced.

[0033] V. Detailed description

[0034] The present disclosure describes formulations, composite compositions, test kits, capsules, containers and / or methods thereof. It should be understood that, unless otherwise stated, aspects of the invention are not limited to specific synthetic methods, nor to specific reactants, as these can certainly vary. It should also be understood that the terms used herein are intended only to describe specific aspects and are not restrictive. Although any methods and materials similar or equivalent to the methods and materials described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.

[0035] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials associated with the cited publications. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publications by virtue of prior invention.

[0036] A. Definition

[0037] Before disclosing and describing the present compounds, compositions, articles, systems, devices and / or methods, it should be understood that they are not limited to specific synthetic methods (unless otherwise specified) nor to specific reactants (unless otherwise specified), as these can of course vary. It should also be understood that the terminology used herein is intended to describe specific aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.

[0038] This disclosure describes the inventive concept with reference to specific embodiments. However, it is intended to cover all modifications, equivalents, and substitutes of the inventive concept consistent with this disclosure.

[0039] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0040] The phrase "consisting essentially of" limits the scope of a claim to the recited components of a composition or recited steps of a method, as well as those components or steps that do not materially affect the basic and novel characteristics of the claimed composition or method. The phrase "consisting of" excludes any component, step, or element not recited in the claim. The phrase "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended. "Comprising" does not exclude additional, unrecited components or steps.

[0041] As used herein, when referring to any numerical value, the term "about" refers to a value that falls within ±10% of the stated value.

[0042] Ranges herein may be expressed as from "about" a particular value, and / or to "about" another particular value. When such a range is expressed, another aspect includes from that particular value and / or to that other particular value. Similarly, when a value is expressed as an approximation, by using the preposition "about," it is understood that that particular value constitutes another aspect. It will be further understood that each endpoint of the range is distinct from and independent of the other endpoint. Furthermore, it will be understood that a number of values ​​are disclosed herein, and each value is disclosed herein as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It will also be understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0043] References in the specification and subsequent claims to parts by weight of a particular element or component in a composition refer to the weight relationship of that element or component to any other elements or components in the composition or article expressed in parts by weight. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, regardless of the presence of other components in the compound.

[0044] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. In one aspect, the disclosed method may optionally include one or more additional steps, such as, for example, repeating an administration step or changing an administration step, etc.

[0045] As used herein, the term "subject" refers to the target of administration, such as humans. The term "subject" also includes domesticated animals (such as cats, dogs, etc.), livestock (such as cattle, horses, pigs, sheep, goats, etc.) and laboratory animals (such as mice, rabbits, rats, guinea pigs, fruit flies, etc.). Therefore, the subject of the disclosed methods herein can be a vertebrate, such as a mammal, fish, bird, reptile or amphibian. Alternatively, the subject of the disclosed methods herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cattle, cat, guinea pig or rodent. The term does not represent a specific age or sex, therefore, it is intended to cover adult and young subjects and fetuses, whether male or female. In one aspect, the subject can be a human patient. In one aspect, the subject can suffer from cancer, be suspected of having cancer or have a risk of suffering from cancer.

[0046] As used herein, the term "diagnosed" means that a person has been examined by a skilled person (e.g., a physician) and found to have a condition that can be diagnosed or treated with one or more disclosed antineoplastons, disclosed pharmaceutical preparations, or any combination thereof, or with one or more disclosed methods. For example, "diagnosed with a disease or condition" means that a person has been examined by a skilled person (e.g., a physician) and found to have a condition that can be treated with one or more disclosed antineoplastons, disclosed pharmaceutical preparations, or any combination thereof, or with one or more disclosed methods (e.g., cancer). For example, "suspected of having a disease or condition" may mean that a person has been examined by a skilled person (e.g., a physician) and found to have a condition that may be treated with one or more disclosed antineoplastons, disclosed pharmaceutical preparations, or any combination thereof, or with one or more disclosed methods (e.g., cancer). In one aspect, the examination may be a physical examination, which may involve various tests (e.g., blood tests, genotyping, biopsy, etc.), scans (e.g., CT scans, PET scans, etc.), and analyses (e.g., enzyme analyses), or a combination thereof.

[0047] "Patient" refers to a subject having a disease or condition (e.g., cancer, terminal cancer, metastatic cancer). In one aspect, a patient may refer to a subject diagnosed with or suspected of having a disease or condition (such as cancer). In one aspect, a patient may refer to a subject diagnosed with or suspected of having a disease or condition and who is seeking treatment for or receiving treatment for a disease or condition (such as cancer).

[0048] As used herein, "identifying a need for treatment of a disease or condition" and the like refers to selecting a subject based on the need for treatment of the disease or condition. For example, a subject may be identified as needing treatment for a disease or condition (e.g., cancer) based on an earlier diagnosis by a technician, and then treated for the cancer. In one aspect, the identification may be made by a person other than the person making the diagnosis. In one aspect, the administration may be performed by the person making the diagnosis.

[0049] As used herein, "inhibit, inhibiting, inhibition" refers to weakening or reducing activity, level, response, condition, severity, disease, or other biological parameters. This may include, but is not limited to, complete ablation of activity, level, response, condition, severity, disease, or other biological parameters (such as, for example, one or more genomic aberrations, etc.). For example, this may also include 10% inhibition or reduction of activity, level, response, condition, severity, disease, or other biological parameters (such as, for example, one or more genomic aberrations, etc.) compared to native or control levels (e.g., subjects who have not received a disclosed antineoplastic, a disclosed pharmaceutical formulation, or any combination thereof). Thus, in one aspect, inhibition or reduction may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any reduction therebetween, compared to native or control levels. In one aspect, compared to native or control levels (e.g., a subject not receiving disclosed antineoplastons, disclosed pharmaceutical preparations, or any combination thereof), inhibition or reduction can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In one aspect, compared to native or control levels, inhibition or reduction can be 0-25%, 25-50%, 50-75%, or 75-100%. In one aspect, native or control levels can be levels before disease or illness (e.g., precancerous state).

[0050] The term "treat, treat, or treatment" includes palliative treatment, i.e., treatment that is intended to relieve symptoms rather than cure a disease, pathological condition, or disorder; preventive treatment, i.e., treatment that is intended to minimize or partially or completely inhibit the development of a related disease, pathological condition, or disorder; and supportive treatment, i.e., treatment that is used to supplement another specific therapy that is intended to improve a related disease, pathological condition, or disorder. In one aspect, the term encompasses any treatment of a subject (including a mammal, such as a human), and includes (i) preventing undesirable physiological changes, diseases, pathological conditions, or disorders from occurring in a subject who is susceptible to the disease but has not yet been diagnosed with the disease; (ii) inhibiting physiological changes, diseases, pathological conditions, or disorders, i.e., preventing their development; or (iii) alleviating physiological changes, diseases, pathological conditions, or disorders, i.e., causing regression of the disease. For example, in one aspect, treating a disease or disorder can reduce the severity of the disease or disorder that the subject has suffered from by 1%-100%, compared to a control (such as, for example, an individual who does not have cancer). In one aspect, treatment can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% reduction in severity of a disease or condition (such as cancer). For example, treating a disease or condition can reduce one or more symptoms of a subject's disease or condition by 1%-100%, compared to a control (such as an individual not suffering from cancer, etc.). In one aspect, treatment can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% reduction in one or more symptoms of an established disease or condition. It will be understood that treatment does not necessarily refer to a cure or complete ablation or eradication of a disease or condition. However, in one aspect, treatment may refer to cure or complete ablation or eradication of a disease or disorder (eg, cancer).

[0051] As used herein, the term "prevent\preventing\prevention" refers to excluding, preventing, avoiding, pre-empting, interrupting or hindering something from happening, especially by taking action in advance. It will be understood that when reducing, inhibiting or preventing is used herein, unless otherwise specified, the use of the other two words is also explicitly disclosed. In one aspect, it is intended to prevent a disease or condition with chromatin deregulation and / or chromatin dysregulation. The word "prevention" also refers to preventive or preventative measures for protecting or excluding a subject (such as an individual) who does not suffer from a given disease or condition (such as cancer) or related complications from developing the complication. In one aspect, it is intended to prevent metastasis.

[0052] As used herein, the term "administering" refers to any method of providing one or more disclosed antineoplastons, disclosed pharmaceutical formulations, or any combination thereof to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, nasal administration, topical administration, intrauterine administration, intratumoral administration, intrahepatic administration, intravaginal administration, intraocular administration, intraauricular administration, ear administration, intracerebral administration, rectal administration, sublingual administration, oral administration, and parenteral administration, including parenteral administration, such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration may also include intrahepatic artery administration or administration through the hepatic portal vein (HPV). Administration of the disclosed composition, disclosed pharmaceutical composition, disclosed therapeutic agent, disclosed immunomodulator, disclosed proteasome inhibitor, disclosed small molecule, disclosed endonuclease, disclosed oligonucleotide, disclosed RNA therapeutic agent, or any combination thereof may include administration directly into the central nervous system or prostate system. Administration may be continuous or intermittent. Administration may include a combination of one or more routes. In one aspect, administration can include dose titration of a disclosed composition, a disclosed pharmaceutical composition, a disclosed therapeutic agent, a disclosed immunomodulator, a disclosed proteasome inhibitor, a disclosed small molecule, a disclosed endonuclease, a disclosed oligonucleotide, a disclosed RNA therapeutic, or any combination thereof to identify an effective dose and / or to identify an effective dose that causes only minor adverse reactions and / or side effects.

[0053] As known in the art, disclosed small molecules can include any non-polymeric organic or inorganic material. As known in the art, disclosed small molecules can exclude macromolecules, such as large proteins (such as proteins with a molecular weight exceeding 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000), large nucleic acids (such as nucleic acids with a molecular weight exceeding 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000), or large polysaccharides (such as polysaccharides with a molecular weight exceeding 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000). In one aspect, a "small molecule", for example, can be a drug that easily enters a cell due to its low molecular weight. In one aspect, small molecules can be used with the disclosed compositions or disclosed formulations in the disclosed methods.

[0054] In one aspect, a skilled artisan can determine an effective dosage, effective schedule, and effective route of administration of a disclosed antineoplastic, a disclosed pharmaceutical formulation, or any combination thereof to treat or prevent a disease or condition (e.g., cancer). In one aspect, a skilled artisan can also change, alter, or modify an aspect of the administration step to improve the efficacy of a disclosed antineoplastic, a disclosed pharmaceutical formulation, or any combination thereof.

[0055] "Determining the amount" refers to the absolute quantification of a particular analyte (e.g., a cancer biomarker) or the determination of the relative abundance of a particular analyte (e.g., a cancer biomarker). The phrase includes direct or indirect abundance measurements, or both.

[0056] As used herein, "modifying a method" may include modifying or changing one or more features or aspects of one or more steps of a disclosed method for treating and / or preventing cancer. In one aspect, the method can be modified by changing the amount of a disclosed precision cancer treatment, a disclosed antineoplastons, a disclosed pharmaceutical formulation, a disclosed antichemokine, a disclosed anticancer agent, a disclosed chemotherapeutic agent, or a combination thereof administered to a subject, or by changing the frequency of administration of a disclosed precision cancer treatment, a disclosed antineoplastons, a disclosed pharmaceutical formulation, a disclosed antichemokine, a disclosed anticancer agent, a disclosed chemotherapeutic agent, or a combination thereof to a subject, by changing the duration of administration of a disclosed precision cancer treatment, a disclosed antineoplastons, a disclosed pharmaceutical formulation, a disclosed antichemokine, a disclosed anticancer agent, a disclosed chemotherapeutic agent, or a combination thereof to a subject, or by replacing one or more disclosed ingredients and / or reagents with similar or equivalent ingredients and / or reagents. This also applies to all disclosed precision cancer treatments, disclosed antineoplastons, disclosed pharmaceutical formulations, disclosed antichemokines, disclosed anticancer agents, disclosed chemotherapeutic agents, or a combination thereof.

[0057] As used herein, the term "pharmaceutically acceptable carrier" refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In one aspect, the pharmaceutical carrier used can be solid, liquid or gas. In one aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. In one aspect, examples of liquid carriers can include syrup, peanut oil, olive oil and water. In one aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. When preparing the disclosed oral dosage form compositions, any convenient pharmaceutical medium can be used. For example, water, glycol, oils, alcohols, flavorings, preservatives, colorants, and the like can be used to form oral liquid formulations such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used to form oral solid formulations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units using solid pharmaceutical carriers due to their ease of administration. Alternatively, tablets can be coated using standard aqueous or nonaqueous techniques. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the desired particle size in dispersions, and using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Protection against microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride. The absorption time of injectable formulations can be prolonged by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable depot dosage forms are prepared by forming a drug microcapsule matrix in a biodegradable polymer such as polylactic acid-polyglycolate, polyorthoesters, and polyanhydrides. Depot injection formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues. The release rate of the drug can be controlled based on the ratio of drug to polymer and the properties of the specific polymer used. The injectable formulation can be sterilized, for example, by filtering through a bacteria-retaining filter, or by adding a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection media before use. Suitable inert carriers may include sugars such as lactose. Desirably, at least 95% of the active ingredient particles, by weight, have an effective particle size between 0.01 and 10 microns.

[0058] As used herein, the term "excipient" refers to an inert substance commonly used as a diluent, carrier, preservative, binder or stabilizer, including but not limited to proteins (such as serum albumin, etc.), amino acids (such as aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (such as alkyl sulfonates, octanoate, etc.), surfactants (such as SDS, polysorbate, nonionic surfactants, etc.), sugars (such as sucrose, maltose, trehalose, etc.), and polyols (such as mannitol, sorbitol, etc.). For reference, see also Remington's Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., the entire contents of which are incorporated herein by reference. In one aspect, acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations used herein and may include buffers such as, but not limited to, phosphates, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethylammonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol, etc.); low molecular weight (less than about 10 residues) polypeptides; proteins, Such as serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (such as zinc protein complexes); and / or non-ionic surfactants such as Tween, Pluronics, or polyethylene glycol (PEG).

[0059] As used herein, "simultaneously" means (1) at the same time, or (2) at different times during a common treatment plan.

[0060] As used herein, the term "contact" refers to contacting one or more disclosed precision cancer treatments, disclosed antineoplastons, disclosed pharmaceutical preparations, disclosed antichemokines, disclosed anticancer agents, disclosed chemotherapeutic agents, or a combination thereof with a target area or a predetermined target area, so that the disclosed precision cancer treatments, disclosed antineoplastons, disclosed pharmaceutical preparations, disclosed antichemokines, disclosed anticancer agents, disclosed chemotherapeutic agents, or a combination thereof can directly or indirectly act on a predetermined target or target area. The target area or predetermined target area can be one or more organs of the subject that carry cancer cells (e.g., lungs, heart, liver, kidneys, brain, etc.). In one aspect, the target area or predetermined target area can be any cell or any organ infected by a disease or condition (such as cancer, etc.). In one aspect, the target area or predetermined target area can be any organ, tissue, or cell affected by a disease or condition (such as cancer, etc.).

[0061] As used herein, "determining" can refer to measuring or ascertaining the presence and severity of a disease or condition (such as, for example, cancer, etc.). Methods and techniques for determining the presence and / or severity of a disease or condition (such as, for example, cancer, etc.) are generally well known in the medical arts. For example, methods for confirming and / or diagnosing the presence, severity, or both of a disease or condition (such as, for example, cancer, etc.) are familiar in the art.

[0062] As used herein, "effective amount", "effective amount" may refer to an amount sufficient to achieve the desired effect, such as, for example, an amount to treat and / or prevent a disease or condition (such as cancer) or a suspected disease or condition. As used herein, "effective amount" may refer to an amount sufficient to achieve the desired therapeutic effect on an undesirable condition (such as cancer). For example, a "therapeutically effective amount" refers to an amount sufficient to achieve the desired therapeutic effect or to produce an effect on an undesirable symptom but generally not sufficient to cause an adverse reaction. In one aspect, a "therapeutically effective amount" refers to an amount of a disclosed precision cancer treatment, a disclosed antineoplastons, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosed anticancer agent, a disclosed chemotherapeutic agent, or a combination thereof, which (i) treats a specific disease, condition, or condition (such as cancer), (ii) alleviates, improves, or eliminates one or more symptoms of a specific disease, condition, or condition (such as cancer) described herein, or (iii) delays the occurrence of one or more symptoms of a specific disease, condition, or condition (such as cancer) described herein. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including the condition being treated and the severity of the condition; the disclosed precision cancer therapy, disclosed antineoplastons, disclosed pharmaceutical formulations, disclosed antichemokines, disclosed anticancer agents, disclosed chemotherapeutic agents, or a combination thereof being used; the disclosed method being used; the patient's age, weight, general health, sex, and diet; the time of administration; the route of administration; the rate of excretion of the disclosed precision cancer therapy, disclosed antineoplastons, disclosed pharmaceutical formulations, disclosed antichemokines, disclosed anticancer agents, disclosed chemotherapeutic agents, or a combination thereof being used; the duration of treatment; drugs used in combination or concurrently with the disclosed precision cancer therapy, disclosed antineoplastons, disclosed pharmaceutical formulations, disclosed antichemokines, disclosed anticancer agents, disclosed chemotherapeutic agents, or a combination thereof being used, and other similar factors well known in the medical arts. For example, a person skilled in the art can start the dosage of the disclosed precision cancer treatment, the disclosed antineoplastons, the disclosed pharmaceutical preparations, the disclosed antichemokines, the disclosed anticancer agents, the disclosed chemotherapeutic agents, or a combination thereof from a dosage lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. If necessary, the effective daily dose can be divided into multiple administrations. Therefore, a single dose of the disclosed precision cancer treatment, the disclosed antineoplastons, the disclosed pharmaceutical preparations, the disclosed antichemokines, the disclosed anticancer agents, the disclosed chemotherapeutic agents, or a combination thereof can contain such an amount or its submultiples to constitute a daily dose. In the event of any contraindications, the dosage can be adjusted by an individual physician. The dosage can vary and can be administered once or multiple times a day, for one or several consecutive days. Guidance on appropriate dosages for a given class of drugs can be found in the literature.In further aspects, the formulation can be administered in a "prophylactically effective amount"; that is, an amount effective to prevent a disease or condition, such as, for example, a disease or condition caused by the absence, deficiency, and / or mutation of a protein or enzyme, etc.

[0063] As used herein, "monoclonal antibody" refers to a homologous antibody group that participates in highly specific recognition and binding to a single antigenic determinant or epitope. This is different from polyclonal antibodies, which typically include different antibodies directed against different antigenic determinants. The term "monoclonal antibody" includes complete and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv, etc.), single-chain (scFv) mutants, fusion proteins comprising antibody portions, and any other modified immunoglobulin molecules comprising an antigen recognition site. In addition, "monoclonal antibody" refers to an antibody made in any manner, including but not limited to hybridomas, phage selection, recombinant expression, and transgenic animals.

[0064] As used herein, the term "humanized antibody" refers to the form of non-human (e.g., mouse) antibodies, which are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof containing minimal non-human sequences. Typically, a humanized antibody is a human immunoglobulin in which the residues of its complementary determining region (CDR) are replaced by residues of non-human species (e.g., mouse, rat, rabbit, hamster, etc.) CDRs with desired specificity, affinity, and performance. In some cases, the Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding residues in non-human species antibodies with desired specificity, affinity, and performance. Humanized antibodies can be further modified by replacing additional residues in the Fv framework region and / or in the replaced non-human residues to improve and optimize the specificity, affinity, and / or performance of the antibody. In general, a humanized antibody will substantially comprise at least one, typically all of two or three variable domains, the variable domains comprising all or substantially all of the CDR regions corresponding to the non-human immunoglobulin, and all or substantially all of the FR regions being those of the human immunoglobulin consensus sequence. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.

[0065] By "selectively binding" or "specifically binding" an antibody to an epitope or receptor is meant that the antibody reacts or binds to the epitope or receptor more frequently, more rapidly, for a longer period of time, with a higher affinity, or with some combination thereof, than to an alternative substance comprising an unrelated protein. "Selectively binding" or "specifically binding" means, for example, that the antibody binds to the protein with a KD of about 0.1 mM or less, more typically about 1 μM or less. "Selectively binding" or "specifically binding" sometimes refers to binding of the antibody to the protein with a KD of about 0.1 mM or less, sometimes about 1 μM or less, sometimes about 0.1 μM or less, sometimes about 0.01 μM or less, and sometimes about 1 nM or less. It will be understood that in certain aspects, an antibody or binding portion that specifically binds to a first target may specifically or non-specifically bind to a second target. Thus, "specific binding" does not necessarily require (although it can include) exclusive binding, e.g., binding to a single target.

[0066] Polyclonal antibodies can be prepared by any known method. Polyclonal antibodies are produced by multiple subcutaneous or intraperitoneal injections of relevant antigens (purified peptide fragments, full-length recombinant proteins, fusion proteins, etc.) to immunize animals (such as rabbits, rats, mice, donkeys, goats, etc.). These antigens are optionally combined with keyhole limpet hemocyanin (KLH), serum albumin, etc. diluted in sterile saline, and combined with adjuvants (such as complete or incomplete Freund's adjuvant) to form a stable emulsion. Polyclonal antibodies are then recovered from the blood, ascites, etc. of the immunized animals. The collected blood is coagulated, the serum is poured out, centrifuged and clarified, and the antibody titer is measured. Polyclonal antibodies can be purified from serum or ascites according to standard methods in the art including affinity chromatography, ion exchange chromatography, gel electrophoresis, and dialysis.

[0067] As used herein, "precision medicine" methods and "precision cancer treatment" can be used interchangeably and refer to methods for administering cancer treatment (such as ANP therapy) to a subject after measuring the subject's molecular markers to assess the likelihood of a response or non-response to a specific cancer treatment. In one aspect, for example, precision cancer treatment may include ANP and one or more other therapeutic agents (determined using disclosed genomic analysis). For cancer treatment, precision medicine means measuring the subject's molecular markers to select the treatment most likely to help the subject while avoiding the subject from receiving treatment that is unlikely to be helpful. In one aspect, the molecular markers disclosed herein can be used to confirm one or more precision cancer treatments to be administered to a subject herein, and / or can be determined by assessing the genetic expression of one or more cancer-related genes. In one aspect, the molecular markers disclosed herein can be used to confirm one or more precision cancer treatments to be administered to a subject herein, and compared to healthy subjects who do not have or are suspected of having cancer, it can be an increase in the expression of one or more cancer-related genes. In one aspect, the molecular markers disclosed herein can be used to confirm that one or more precision cancer treatments to be administered to a subject herein, compared to healthy subjects who do not have or are suspected of having cancer, the expression of one or more cancer-related genes can be reduced. In one aspect, the molecular markers disclosed herein can be used to identify one or more precision cancer treatments to be administered to a subject herein, and can be base mutations and / or variations in one or more cancer-related gene sequences compared to healthy subjects who do not have or are suspected of having cancer.

[0068] As used herein, the terms "cancer / carcinoma" and "cancerous" refer to or describe the physiological condition of a mammal in which a cell population is characterized by unregulated cell growth. Examples of cancer include, but are not limited to, epithelial cancers, lymphomas, blastomas, sarcomas, and leukemias. More specific examples of cancer include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, peritoneal cancer, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine epithelial cancer, salivary gland epithelial cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, various types of head and neck cancer, various types of brain tumors, or any combination thereof.

[0069] The terms "proliferative disorder" and "proliferative disease" refer to disorders associated with abnormal cell proliferation, such as cancer.

[0070] As used herein, "tumor" and "neoplasm" refer to any mass of tissue formed by excessive growth or proliferation of cells, which can be benign (non-cancerous) or malignant (cancerous), including precancerous lesions. As used herein, "metastasis" refers to the process by which cancer spreads or metastasizes from its primary site to other parts of the body and forms similar cancerous lesions in the new location. A "metastatic" or "metastatic" cell is a cell that has lost adhesive contacts with neighboring cells and has migrated from the primary disease site to adjacent body structures via the blood or lymph.

[0071] The terms "cancer stem cell" or "tumor stem cell" or "solid tumor stem cell" are used interchangeably herein to refer to a population of cells from solid tumors that (1) possess extensive proliferative capacity; (2) are capable of asymmetric cell division to produce one or more differentiated progeny with reduced proliferative or developmental potential; and (3) are capable of symmetric cell division and self-renewal or self-sustaining. In contrast to most tumor cells that are unable to form tumors, these properties of "cancer stem cells" or "tumor stem cells" or "solid tumor stem cells" enable these cancer stem cells to form frank tumors after serial transplantation into immunocompromised mice. Cancer stem cells self-renew and differentiate in a promiscuous manner, forming tumors with abnormal cell types that mutate over time.

[0072] The terms "cancer cells" or "tumor cells" and grammatical equivalents refer to the total cell population from a tumor, including non-tumorigenic cells and tumorigenic stem cells (cancer) that make up the bulk of the tumor cell population.

[0073] As used herein, "tumorigenicity" refers to the functional characteristics of solid tumor stem cells, including the properties of self-renewal (producing more tumorigenic cancer stem cells) and proliferation to give rise to all other tumor cells (producing differentiated, and therefore non-tumorigenic, tumor cells), which enable solid tumor stem cells to form tumors.

[0074] As used herein, tumor "tumorigenicity" refers to the ability of random samples of tumor cells to form palpable tumors following serial transplantation into immunocompromised mice.

[0075] As used herein, "immunomodulation" refers to the ability of a disclosed isolated nucleic acid molecule, a disclosed precision cancer treatment, a disclosed pharmaceutical formulation, or a disclosed agent to alter (modulate) one or more aspects of the immune system. The immune system protects the body from infection and foreign antigens through cellular and humoral mechanisms involving lymphocytes, macrophages, and other antigen-presenting cells, which regulate each other through various cell-cell interactions and through the production of soluble factors (including lymphokines and antibodies), thereby producing autocrine, paracrine, and endocrine effects on immune cells.

[0076] As used herein, "immunomodulator" refers to an agent that can adjust a specific immune response to a desired level (such as immune enhancement, immunosuppression, or induction of immune tolerance). Examples of immunomodulators include, but are not limited to, disclosed immunomodulators, which may include aspirin, azathioprine, belimumab, betamethasone dipropionate, betamethasone valerate, bortezomib, brevillin, cyclothiopurine, cyclophosphamide, cyclosporine, deoxyspergualin, tunicain B, fluocinolone acetonide, folinic acid, ibuprofen, IL6 inhibitors (such as salinomycin, etc.), indomethacin, inebilizumab, intravenous immunoglobulin (IVIG), methotrexate, methylprednisolone, mycophenolate mofetil, naproxen, prednisolone, prednisone, prednisolone indomethacin (prednisolone), and the like. In one aspect, the disclosed immunomodulators may include bortezomib or SVP-rapamycin. In one aspect, the immunomodulator can be administered by any suitable route of administration, including but not limited to intrauterine, intraCSF, intrathecal, intravenous, subcutaneous, transdermal, intradermal, intramuscular, oral, transdermal, intraperitoneal (IP) or intravaginal. In one aspect, the disclosed immunomodulator can be administered using a combination of routes. Administration can also include intrahepatic arterial administration or administration via the hepatic portal vein (HPV). Administration of the immunomodulator can be continuous or intermittent, and administration can include a combination of one or more routes.

[0077] As used herein, the term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0078] As used herein, the term "in combination" includes the use of more than one therapy (e.g., drug therapy) in the context of administering other therapies (e.g., other agents). Administration "in combination with" one or more further therapeutic agents includes simultaneous (e.g., concurrent) and sequential administration in any order. The use of the term "in combination" does not limit the order of administration to a subject. As a non-limiting example, a first therapy (e.g., a disclosed precision cancer therapy, a disclosed antineoplastons, a disclosed pharmaceutical formulation, a disclosed antichemokine, a disclosed anticancer agent, a disclosed chemotherapeutic agent, or a combination thereof) can be administered prior to (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 4 hours, 5 minutes ... or 12 weeks or longer), concurrently with or subsequent to (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks) administering to a subject having or diagnosed with cancer.

[0079] Disclosed are components for preparing the disclosed isolated nucleic acid molecules, disclosed precision cancer treatments, or disclosed pharmaceutical formulations, as well as the use of the disclosed isolated nucleic acid molecules, disclosed precision cancer treatments, or disclosed pharmaceutical formulations in the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed, while not every distinct individual and collective combination and permutation of these compounds is explicitly disclosed, each combination and permutation is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed, and various modifications that can be made to various molecules including that compound are discussed, then unless explicitly stated to the contrary, every combination and permutation of that compound and possible modifications are specifically contemplated. Thus, if a class of molecules A, B, and C is disclosed, and a class of molecules D, E, and F is disclosed, and an example of a combination molecule AD is disclosed, then each molecule is individually and collectively contemplated, even if not individually recited, meaning that the combination of AE, AF, BD, BE, BF, CD, CE, and CF is considered disclosed. Similarly, any subset or combination of these is also disclosed. Thus, for example, the subgroups of AE, BF, and CE would be considered disclosed. This concept applies to all aspects of this application, including, but not limited to, method steps for making and using the compositions of the present invention. Thus, if various additional steps can be performed, it is understood that each of these additional steps can be performed by any specific disclosed method or disclosed aspect, or combination of disclosed methods or disclosed aspects.

[0080] B. Compositions for Use in the Disclosed Methods

[0081] 1. Antineoplastons

[0082] Disclosed herein are compositions comprising one or more antineoplastons.Antineoplaston (ANP) is a peptide, amino acid derivative, and carboxylic acid originally isolated from the blood and urine of healthy subjects.

[0083] Atengenal (A10) may contain synthetic phenylacetylglutaminate sodium (PG) and phenylacetylisoglutaminate sodium (iso-PG) in a 4:1 ratio. PG has a molecular weight of 286.26 and an empirical formula of C 13 H 15N2NaO4. PG can be synthesized by reacting phenylacetyl chloride with L-glutamine in an aqueous solution containing sodium bicarbonate. PG is a hygroscopic white powder with a melting point of approximately 102°C and is highly soluble in water. The structural formula of PG is:

[0084]

[0085] The molecular weight of iso-PG is 286.26 and its empirical formula is C 13 H 15 N2NaO4. Iso-PG can be synthesized by reacting phenylacetyl chloride with L-glutamine in an aqueous solution containing sodium bicarbonate to form PG, which is then heated at 160°C under vacuum to form A10C (3-phenylacetamido-2,6-piperidinedione). When A10C is treated with sodium hydroxide, a 4:1 mixture of PG and iso-PG is produced. Iso-PG is a white powder with a melting point of approximately 175-176°C and is readily soluble in water. The structural formula of iso-PG is:

[0086]

[0087] Astugenal (AS2-1) can contain phenylacetate (PN) and PG in a 4:1 ratio. PN is characterized by a molecular weight of 158.63 and an empirical formula of C8H8NaO2. PN can be synthesized by refluxing benzyl cyanide with dilute sulfuric acid or hydrochloric acid. The melting point of solid PN is approximately 76.5°C. The structural formula of PN is:

[0088]

[0089] As used herein, "antineoplastic (ANP) therapy" may refer to administering an "ANP therapeutic composition" or a disclosed composition or pharmaceutical formulation comprising one or more antineoplastons (e.g., a therapeutically effective amount of Atengenal (A10), Astugenal (AS2-1), or any combination thereof) to a subject or patient by any route of administration.

[0090] In one aspect, the disclosed ANP therapies can be used as pan-tumor therapies.

[0091] 2. Recipe

[0092] Disclosed herein is a pharmaceutical formulation comprising one or more antineoplastons and one or more pharmaceutically acceptable carriers.

[0093] In one aspect of the disclosed pharmaceutical formulation, the disclosed antineoplastons can include phenylacetate, phenylacetylglutamine, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or any combination thereof.

[0094] In one aspect of the disclosed pharmaceutical formulation, the disclosed one or more antineoplastons may include sodium phenylacetylglutamine (PG) and sodium phenylacetylisoglutamine (iso-PG). In one aspect of the disclosed pharmaceutical formulation, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect of the disclosed pharmaceutical formulation, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may range from about 10:1 to about 1:10. In one aspect of the disclosed pharmaceutical formulation, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 4:1. In one aspect, a therapeutically effective amount of the disclosed pharmaceutical formulation may include about 0.1 g / kg / day to about 20 g / kg / day.

[0095] In one aspect of the disclosed pharmaceutical formulation, the disclosed one or more antineoplastons may include phenylacetate (PN) and phenylacetylglutamine (PG). In one aspect of the disclosed pharmaceutical formulation, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) may be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect of the disclosed pharmaceutical formulation, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) may range from about 10:1 to about 1:10. In one aspect of the disclosed pharmaceutical formulation, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) may be about 4:1. In one aspect, a therapeutically effective amount of the disclosed pharmaceutical formulation may include about 0.08 g / kg / day to about 0.6 g / kg / day.

[0096] In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can include bevacizumab, pazopanib, sorafenib, dasatinib, everolimus, or any combination thereof. For example, in one aspect, pazopanib and / or sorafenib can be orally administered to a subject at a dose of about 1 mg / kg / day to about 12 mg / kg / day or 2 mg / kg / day to about 6 mg / kg / day. In one aspect, the disclosed optimal dose of pazopanib and / or sorafenib can be about 3 mg / kg / day. In one aspect, dasatinib can be orally administered to a subject at a dose of about 0.3 mg / kg / day to about 2.0 mg / kg / day or about 0.7 mg / kg / day to about 1.4 mg / kg / day. In one aspect, the disclosed optimal dose of dasatinib can be about 0.7 mg / kg / day. In one aspect, everolimus can be orally administered to a subject at a dose of about 0.03 mg / kg / day to about 0.15 mg / kg / day or about 0.03 mg / kg / day to about 0.10 mg / kg / day. In one aspect, the disclosed optimal dose of everolimus can be about 0.07 mg / kg / day.

[0097] In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can reduce and / or eliminate the number and / or types of genomic aberrations. For example, in one aspect, if a subject initially has X genomic aberrations, then after administration of the disclosed pharmaceutical formulation, the subject has fewer than X genomic aberrations. In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can prevent or reduce metastasis. In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can prolong a subject's survival. In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can increase a subject's survival rate. In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can increase a subject's survival rate, increase the time to metastasis, reduce the likelihood of surgical intervention, reduce the need for administration of one or more additional therapeutic agents or treatment regimens, reduce the size of one or more tumors in a subject, eliminate one or more tumors in a subject, reduce and / or eliminate the prevalence of one or more genomic aberrations, restore normal metabolism in one or more organ systems in a subject, restore one or more aspects of cellular homeostasis and / or cellular function, and / or metabolic dysregulation; or any combination thereof.

[0098] In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can protect a subject from metastasis. In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can reduce the risk of developing metastasis.

[0099] In one aspect, one or more aspects of restoring cellular homeostasis and / or cellular function may include one or more of the following: (i) correcting cellular starvation of one or more cell types (such as, for example, liver cells and muscle cells); (ii) normalizing the autophagy pathway (such as, for example, correcting, preventing, reducing and / or improving autophagy); (iii) improving, enhancing, restoring and / or protecting mitochondrial functionality and / or structural integrity; (iv) improving, enhancing, restoring and / or protecting organelle functionality and / or structural integrity; (v) preventing, slowing and / or eliminating hypoglycemia, ketosis and / or other liver abnormalities; (vi) correcting liver enzyme imbalances; (vii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor metastasis; (viii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor growth and / or cancer spread, or (ix) any combination of the above. In one aspect, one or more aspects of restoring cellular homeostasis may include one or more aspects of improving, enhancing, restoring and / or maintaining cellular structural and / or functional integrity in, for example, an organ or system that has been affected by cancer.

[0100] In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons may comprise one or more chemotherapeutic agents. In one aspect, the disclosed chemotherapeutic agents may comprise anthracyclines, vinca alkaloids, alkylating agents, immune cell antibodies, antimetabolites, TNFR glucocorticoid-induced TNFR-related protein (GITR) agonists, proteasome inhibitors, immunomodulators, or any combination thereof. In one aspect, the disclosed chemotherapeutic agents may include 5-fluorouracil (Adrucil, Efudex), 6-mercaptopurine (Purinethol), 6-thioguanine, aclarubicin or aclarubicin A, alemtuzamab (Lemtrada), anastrozole (Arimidex), bicalutamide (Casodex), bleomycin sulfate (bleomycin sulfate) (Blenoxane), bortezomib (Velcade), busulfan (Myleran), busulfan injection (Busulfex), capecitabine (Xeloda), carboplatin (Paraplatin), carmustine (BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), dactinomycin (Cosmegan), cyclophosphamide (Cytoxan or Neosar), cyclophosphamide, cytarabine liposomal injection (DepoCyt), cytarabine, cytosine arabinoside (Cytosar-U), dacarbazine (DTIC-Dome), dactinomycin (Cosmegen), daunorubicin citrate liposomal injection (DaunoXome), daunorubicin hydrochloride (C erubidine), dexamethasone, docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin, Rubex), etoposide (Vepesid), fludarabine phosphate (Fludara), flutamide (Eulexin), folic acid antagonists, gemcitabine (difluorodeoxycytidine), gemtuzumab, gliotoxin, hydroxyurea (Hydrea), idarubicin (Idamycin), ifosfamide (IFEX), irinotecan (Camptosar), L-asparaginase (ELSPAR), lenalidomide), leucovorin, melphalan (Alkeran), melphalan, methotrexate (Folex),Mitoxantrone (Novantrone), gemtuzumab tuzumab (mylotarg), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, nab-paclitaxel (Abraxane), paclitaxel (Taxol), pentostatin, phoenix (yttrium 90 / MX-DTPA), polyphenylpropenol 20 and carmustine membrane implant (Gliadel), purine analogs and adenosine deaminase inhibitors (fludarabine), pyrimidine analogs, rituximab , tamoxifen citrate (Nolvadex), temozolomide, teniposide (Vumon), tezacitibine, thalidomide or a thalidomide derivative, thiotepa, tirapazamine (Tirazone), topotecan hydrochloride for injection (Hycamptin), tositumomab, vinblastine (Velban), vinblastine, vincristine (Oncovin), vindesine, vinorelbine (Navelbine), or any combination thereof.

[0101] In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons may include an anti-chemokine therapy that enhances the formation of resident memory T cells in tumor-free tissue. In one aspect, the disclosed anti-chemokine therapy may include one or more antibodies against CCL1, CCL2, CCL4, CCL17, CCL19, CCL21, CCL22, CCL25, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CCR2, CCR5, CCR7, CCR8, CCR9, CXCR3, CXCR4, CXCR5, CX3CL1, CX3CR1, or any combination thereof.

[0102] In one aspect, the disclosed pharmaceutical formulations comprising one or more antineoplastons can be prepared for systemic administration or direct administration. In one aspect, the disclosed pharmaceutical formulations can be prepared for oral administration, intravenous administration, intratumoral administration, or intraperitoneal administration, or any combination thereof. In one aspect, the disclosed pharmaceutical formulations can be prepared for any method of administration disclosed herein. In one aspect, the disclosed pharmaceutical formulations can be prepared for simultaneous or sequential administration via a variety of routes. For example, in one aspect, the disclosed pharmaceutical formulations can be administered intratumorally first, followed by intravenous administration. In one aspect, the disclosed pharmaceutical formulations can be administered intratumorally first, followed by oral administration. A skilled clinician can determine the best route of administration for a subject within a given timeframe.

[0103] In one aspect, the disclosed pharmaceutical formulations comprising one or more disclosed antineoplastons can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) combinations thereof. In one aspect, the disclosed pharmaceutical formulations can comprise one or more immunomodulators. In one aspect, the disclosed pharmaceutical formulations can comprise one or more proteasome inhibitors. In one aspect, the disclosed pharmaceutical formulations can comprise one or more immunosuppressive substances or immunosuppressants. In one aspect, the immunosuppressant can be antithymocyte globulin (ATG), cyclosporine (CSP), mycophenolate mofetil (MMF), or a combination thereof. In one aspect, the disclosed pharmaceutical formulations can comprise a non-resistance agent (such as, for example, a C7 compound such as triheptanoin or MCT).

[0104] In one aspect, the disclosed pharmaceutically acceptable carriers can include any disclosed carrier. In one aspect, the disclosed pharmaceutically acceptable carriers can include any disclosed excipient.

[0105] In one aspect, the disclosed pharmaceutical formulations can be packaged in unit dosage form, such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

[0106] In one aspect, the disclosed pharmaceutical formulations can be used as pan-tumor therapies.

[0107] C. Methods of treating and / or preventing cancer

[0108] Disclosed herein is a method of treating and / or preventing cancer, comprising administering a precision cancer therapy to a subject in need thereof, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy.

[0109] Disclosed herein is a method of treating cancer, comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy.

[0110] Disclosed herein is a method of treating cancer, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as being in need of precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; administering the precision cancer therapy to the subject; and measuring the subject's tumor response and / or the subject's molecular response.

[0111] Disclosed herein is a method for treating cancer, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; wherein, if the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample, diagnosing the subject as needing precision cancer therapy; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy.

[0112] In one aspect, the disclosed precision cancer treatments may include one or more antineoplastons, or may include compositions comprising one or more antineoplastons. In one aspect, the disclosed antineoplastons may include phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or any combination thereof. In one aspect, the disclosed compositions comprising one or more antineoplastons may include phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or any combination thereof.

[0113] In one aspect, the disclosed compositions comprising one or more antineoplastons may comprise a pharmaceutically acceptable carrier. In one aspect, the disclosed one or more antineoplastons may comprise sodium phenylacetylglutamine (PG) and sodium phenylacetylisoglutamine (iso-PG). In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may range from about 10:1 to about 1:10. In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 4:1. In one aspect, the disclosed dosage of the one or more antineoplastons may comprise about 0.1 g / kg / day to about 20 g / kg / day. In one aspect, the disclosed therapeutically effective dose of one or more antineoplastons may comprise about 0.1 g / kg / day to about 20 g / kg / day. In one aspect, the disclosed doses of sodium phenylacetylglutamine (PG) may comprise about 0.4 g / kg / day to about 16 g / kg / day, and the disclosed doses of sodium phenylacetylisoglutamine (iso-PG) may comprise about 0.1 g / kg / day to about 4 g / kg / day. In one aspect, the disclosed therapeutically effective amounts of sodium phenylacetylglutamine (PG) may comprise about 0.4 g / kg / day to about 16 g / kg / day. In one aspect, the disclosed therapeutically effective amounts of sodium phenylacetylglutamine (iso-PG) may comprise about 0.1 g / kg / day to about 4 g / kg / day.

[0114] In one aspect, the disclosed one or more antineoplastons can include phenylacetate (PN) and phenylacetylglutamine (PG). In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can range from about 10:1 to about 1:10. In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can be about 4:1. In one aspect, the disclosed dosage of the one or more antineoplastons can include about 0.08 g / kg / day to about 0.6 g / kg / day. In one aspect, the disclosed therapeutically effective dosage of the one or more antineoplastons can include about 0.08 g / kg / day to about 0.6 g / kg / day. In one aspect, the disclosed dosage of phenylacetate (PN) may comprise about 0.064 g / kg / day to about 0.48 g / kg / day, and the disclosed dosage of phenylacetamine (PG) may comprise about 0.016 g / kg / day to about 0.12 g / kg / day. In one aspect, the therapeutically effective dosage of phenylacetate (PN) may comprise about 0.064 g / kg / day to about 0.48 g / kg / day, and the therapeutically effective dosage of phenylacetamine (PG) may comprise about 0.016 g / kg / day to about 0.12 g / kg / day.

[0115] In one aspect of the disclosed method for treating and / or preventing cancer, administering the disclosed precision cancer therapy may comprise intravenous administration. In one aspect, the disclosed precision cancer therapy can be administered intravenously to a subject using, for example, a dual-channel infusion pump or two single-channel pumps and a central venous catheter. In one aspect, the disclosed precision cancer therapy can be administered once every four hours at an IV infusion rate of about 50 ml / hour to about 250 ml / hour (e.g., about 50, 75, 100, 125, 150, 175, 200, 225, 250 ml / hour), depending on the age and condition / tolerance of the subject.

[0116] In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed precision cancer therapy. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of A10, AS2-1, or a combination thereof. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed compositions, disclosed pharmaceutical compositions, disclosed therapeutic agents, disclosed immunomodulators, disclosed proteasome inhibitors, disclosed small molecules, disclosed endonucleases, disclosed oligonucleotides, disclosed RNA therapeutics, or any combination thereof to confirm an effective dose and / or to confirm an effective dose that causes only minor adverse reactions and / or side effects.

[0117] In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed precision cancer therapy in a specific or disclosed subject. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of A10, AS2-1, or a combination thereof in a specific or disclosed subject. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed composition, the disclosed pharmaceutical composition, the disclosed therapeutic agent, the disclosed immunomodulator, the disclosed proteasome inhibitor, the disclosed small molecule, the disclosed endonuclease, the disclosed oligonucleotide, the disclosed RNA therapeutic agent, or any combination thereof to confirm an effective dose for a specific or disclosed subject and / or to confirm an effective dose that causes only mild adverse reactions and / or side effects to the subject.

[0118] In one aspect, administering comprises administering to the subject a maximum tolerated dose of A10, AS2-1, or both. In one aspect, administering comprises administering to the subject less than the maximum tolerated dose of A10, AS2-1, or both.

[0119] In one aspect, IV administration of the disclosed precision cancer treatments can include an outpatient setting. In one aspect, A10 can be administered before, concurrently, or after AS2-1. In one aspect, AS2-1 can be administered before, concurrently, or after A10. In one aspect, the order in which one or more antineoplastons are administered can be altered during a treatment regimen.

[0120] In one aspect, the disclosed method for treating and / or preventing cancer may further include obtaining a biological sample from the subject before administering the disclosed precision cancer treatment. In one aspect, the disclosed method for treating and / or preventing cancer may further include obtaining a biological sample from the subject after administering the disclosed precision cancer treatment. In one aspect, the disclosed method for treating and / or preventing cancer may further include performing cell-free DNA (cfDNA) analysis on the biological sample. cfDNA analysis is known to those skilled in the art. In one aspect, the disclosed cfDNA analysis can be repeated one or more times. In one aspect, the disclosed acquisition step can be repeated one or more times.

[0121] In one aspect of the disclosed methods for treating and / or preventing cancer, the disclosed cfDNA analysis may include next generation sequencing. In one aspect, next generation sequencing (NGS) may include the use of one or more commercially available platforms. Commercially available NGS sequencing platforms may include, for example, Guardant 360CDx (Guardant Health), Foundation OneCDx (F1CDx) (Foundation Medicine), or TempusxT (Tempus).

[0122] In one aspect of the disclosed method for treating and / or preventing cancer, the disclosed cancer-related genes may include ABL1, ABL2, ACO2, ACTB, ACVR1B, AKT, AKT1 AKT2, AKT3, ALK, AMER11, APC, AR, ARAF, ARFRP1, ARID1A, ARID1B, ARID2, ASK, ASPM, ASXL1, ATF1, ATF3, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXL, BAD, BAGE, BAGE2, BAP1, BARD1, BAX, BCL2, BCL2L1, BCL2L2, BCL6, BCMA, BCOR, BCORL1, BDNF, BLM, BMPR1A, BRAF, B RCA1, BRCA2, BRD4, BRIP1, BTG1, BTK, BUB1, C10ORF54, CAGE1, CARD11, CASP5, CBFB, CBL, CCL1, CCL11, CCL13, CCL14, CCL15, CCL16 , CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL7, CCL8, CCNA 2. CCNB 1. CCNB 2. CCND, CCND1, CCND2, CCND3, CCNE1, CCNE2, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD123, CD19, CD20, CD25, CD274, CD276 , CD30, CD33, CD4, CD79A, CD79B, CD8, CD80, CD86, CDC, CDC2, CDC20, CDC25A, CDC25B, CDC25C, CDC42, CDC6, CDC6; CDC7, CDC73, CDCA8, CDH1, CDK12 , CDK2, CDK3, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CEA, CEBPA, CFS1, CHD2, CHD4, CHEK1, CHEK2, CHK-1, CIC, CLDND1, CNE2, CREBBP, CRKL, CRLF2, CSF1, CSF1R, CSF3, CTAG1, CTAG1B, CTAG2, CTAG4, CTAG5, CTAG6, CTAG9, CTCF, CTLA4, CTNNA1, CTNNB1, CUL3, CXCL1, CXCL10,CXCL11、CXCL12、CXCL13、CXCL14、CXCL16、CXCL17、CXCL2、CXCL3、CXCL5、CX CL6、CXCL9、CXCR1、CXCR2、CXCR3、CXCR5、CXCR6、CYLD、DAXX、DCC、DDR2、DEP TOR、DICER1、DLD、DLST、DNMT3A、DOT1L、DUSP1、DUSP6、E2F1、EBNA1、EBNA2、 EGFR、EMSY、ENOX2、EP300、EPCAM、EPHA3、EPHA5、EPHA7、EPHB1、ERBB2、ERBB3 、ERBB4、ERCC1、EREG、ERG、ERK、ERRFI1、ESR1、EWSR1、EZH2、FAM46C、FANCA、 FANCC、FANCD2、FANCE、FANCF、FANCG、FANCL、FAS、FAT1、FBXW7、FGF10、FGF14 、FGF19、FGF23、FGF3、FGF4、FGF6、FGFR、FGFR1、FGFR2、FGFR3、FGFR4、FH、FL CN、FLI1、FLT1、FLT3、FLT4、FOLH1、FOLR1、FOXL2、FOXP1、FRS2、FUBP1、GABRA 6、GADD45A、GAGE1、GAGE10、GAGE12D、GAGE12F、GAGE12J、GAGE13、GAGE2A、G AGE2B、GAGE2C、GAGE2D、GAGE2E、GAGE4、GART、GATA1、GATA2、GATA3、GATA4、G ATA6、GID4、GLI1、GNA、GNA11、GNA13、GNAQ、GNAS、GPNMB、GPR124、GRIN2A、G RM3、GSK3B、H3F3A、HAVCR2、HDAC、HDAC1、HDAC5、HGF、HHLA2、HIF1、HIF1A、HI ST1H1D、HNF1A、HRAS、HSD3B1、HSP90AA1、ICOSLG、IDH1、IDH2、IDH3A、IDH3B、IDO、IGF1R、IGF2、IKBKE、IKZF1、IL1、IL15、IL1A、IL1B、IL6、IL7R、IL8、INH BA、INPP4B、IRF2、IRF4、IRS2、JAK1、JAK2、JAK3、JUN、KDM5A、KDM5C、KDM6A、 KDR、KEAP、KEL、KIT、KLHL6、KLK3、KRAS、LAG1、LAG3、LMO1、LMP1、LRP1B、LYN、LZTR1、MAD2L1、MAGEA1、MAGEA10、MAGEA12、MAGEA2、MAGEA3、MAGEA4、MAGEA5、MAGEA6、MAGEA7、MAGEA8、MAGEA9、MAGEB1、MAGEB10、MAGEB16、MAGEB18、MAGEB2、MAGEB3、MAGEB4、MAGEB6、MAGEC1、MAGEC2、MAGEC3、MAGED1、MAGED2、MAGED4、MAGED4B、MAGEE1、MAGEE2、MAGEF1、MAGEH1、MAGEL2、MAGI2、MAP2K1、MAP2K2、MAP2K4、MAP3K1、MAP3K6、MAPK、MCL1、MCM、MCM2、MCM3、MCM4、MCM5、MCM6、MCM7、MDH1、MDM2、MDM4、MED12、MEF26、MEF2B、MEN1、MET、MITF、MLH1、MLL、MLL2、MLL3、MPL、MRE11A、MSH2、MSH6、MTOR、MUC1、MUTYH、MYC、MYCL、MYCN、MYD88、MYH、MYST3、NCR3LG1、Netrin、NF1、NF2、NFE2L2、NFKB、NFKB1A、NGF、NKX2-1、NOTCH1、NOTCH2、NOTCH3、NPM1、NRAS、NSD1、NTRK1、NTRK2、NTRK3、NUP93、OGDH、ORC、ORC1、ORC1L、ORC1L;、ORC6L、ORCL、ORCLPCNA、PAK3、PALB2、PAPPA、PARK2、PAX、PAX3、PBRM1、PCNA、PDCD1、PDCD1LG2、PDGFRA、PDGFRB、PDHA1、PDK1、PGR、PIK3C2B、PIK3CA、PIK3CB、PIK3CG、PIK3R1、PIK3R2、PIK3RI、PKMYT、PKMYT1、PLCG2、PLK1、PMS2、POLD1、POLE、PPM1A、PPP2R1A、PREX2、PRKAR1A、PRKC1、PRKDC、PRSS8、PTCH1、PTEN、PTPN1、PTPN11、PTPRR、PTTG、PTTG1、PTTG2、PTTG3、QK1、RAC1、RAD50、RAD51、RAF1、RANBP1、RARA、RAS、RB1、RBL1、RBM10、RET、RICTOR、RIT1、RNF43、ROS1、RPTOR、RUNX1、RUNX1T1、SDHA、SDHB, SDHC, SDHD, SETD2, SF3B1, SKP2, SLAMF7, SLIT2, SMAD2, SMAD3, SMAD4, SMARCA4, SMARCB1, SMC1A, SMC1L1, SMO, SNCAIP, SOCS1, SOX10, SOX2, SOX9, SPAG1, SPAG11A, SPAG11B, SPAG16, SPAG17, SP AG4, SPAG5, SPAG6, SPAG7, SPAG8, SPAG9, SPEN, SPOP, SPTA1, SRC, SRSF2, STAG2, STAT3, STAT4, STAT5, STAT5B, STK11, SUCLG1, SUCLG2, SUFU, SYK, T(BRACHYURY), TAF1, TBC1D8, TBX3, TERC, TERT, TERT promoter, TET2, TFDP1, TGFRB2, TNFAIP3, TNFRSF14, TOP1, TOP2A, TOP2B, TP53, TRIB3, TSC1, TSC2, TSHR, TUBB3, TYMP, TYMS, U2AF1, UNC5A, UNC5B, VEGFA, VHL, VTCN1, WEE1, WISP3, WT1, XAGE1D, XAGE2, XAGE3, XAGE5, XCL1, XCL2, XCR1, XPO1, ZBTB2, ZNF217, ZNF703, or any combination thereof.

[0123] In one aspect, the disclosed cancer-associated genes may include one or more genomic aberrations. In one aspect, the subject may have one or more genomic aberrations in the disclosed cancer-associated genes.

[0124] In one aspect, the disclosed ALK gene can encode an ALK protein having an I1461L or N1544K mutation. In one aspect, the disclosed ARID2 gene can encode an ARID2 protein having an N127fs18 mutation. In one aspect, the disclosed AKT1 gene can encode an AKT1 protein having an E17K or R346H mutation. In one aspect, the disclosed APC gene can encode an APC protein having G29G, K445K, V2716L, E918E, Q1378*, S457*, I1304fs, E888fs, R230C, Q1090Q, S1360P mutations. In one aspect, the disclosed gene can encode an AR protein having an A356EM887V or S510R mutation. In one aspect, the disclosed ARAF gene can encode an ARAF protein having a Y495Y mutation. In one aspect, the disclosed ARID1A gene may encode an ARID1A protein having an S1798L, S1167F, G246V, R1889W, or Q802fs mutation. In one aspect, the disclosed ARID2 gene may encode an ARID2 protein having an N127fs18 mutation. In one aspect, the disclosed ARTX gene may have an S850fs*2 or N179fs*26 mutation. In one aspect, the disclosed ASXL1 gene may have an R1273f*s mutation. In one aspect, the disclosed BRAF gene may encode a BRAF protein having an E264 or V600E mutation. In one aspect, the disclosed BRCA1 gene may encode a BRAC1 protein having an H662Q or R1443* mutation. In one aspect, the disclosed BRCA2 gene may encode a BRCA2 protein having a D237N or I2040V mutation. In one aspect, the disclosed CCND1 gene may encode a CCND1 protein having an R291W mutation. In one aspect, the disclosed CCNE1 gene may encode a CCNE1 protein having a P268P or R95Q mutation. In one aspect, the disclosed CDKN1B gene may encode a CDKN1B protein having a K59fs* mutation. In one aspect, the disclosed CDKN2A gene may encode a CDKN2A protein having a D74N mutation. In one aspect, the disclosed CTNNB1 gene may encode a CTNNB1 protein having a T41A mutation. In one aspect, the disclosed DDR2 gene may encode a DDR2 protein having an L749L mutation. In one aspect, the disclosed EGFR gene may encode an EGFR protein having a P753L, V524I, D321D, or V7421 mutation. In one aspect, the disclosed ERBB2 gene may encode an ERBB2 protein having a C584G or V797del (exon 20 deletion) mutation. In one aspect, the disclosed EWSR1 gene can encode an EWSR1 protein with a FLI1 fusion.In one aspect, the disclosed FBXW7 gene can encode an FBXW7 protein having a Y545C or R658* mutation. In one aspect, the disclosed FGFR gene can encode an FGFR protein having a T320T, S726F, H791H, P47P, S430fs, or R179H mutation. In one aspect, the disclosed FGFR1 gene can encode an FGFR1 protein having an S726F mutation. In one aspect, the disclosed FGFR2 gene can encode an FGFR2 protein having a KCNH7 fusion. In one aspect, the disclosed FGFR3 gene can encode an FGFR3 protein having an H290Y mutation. In one aspect, the disclosed GATA3 gene can encode a GATA3 protein having a P433fs43, P409fs, PS405fs, D336fs, S430fs, or c.1213_1214del mutation. In one aspect, the disclosed GNA11 gene can encode a GNA11 protein having an N244S mutation. In one aspect, the disclosed GNAS gene can encode a GNAS protein having an R201H* mutation. In one aspect, the disclosed HIST1H1D gene can encode a HIST1H1D protein having a K185-A186>T mutation. In one aspect, the disclosed H3F3A gene can encode an H3F3A protein having a K28N or K27 mutation. In one aspect, the disclosed IDH1 gene can encode an IDH1 protein having an R132H mutation. In one aspect, the disclosed JAK2 gene can encode a JAK2 protein having a V617 mutation. In one aspect, the disclosed KIT gene has Q 775fs (exon 16 deletion). In one aspect, the disclosed ARID1A gene can encode an ARID1A protein having an S1798L, S1167F, G246V, R1889W, or Q802fs mutation. In one aspect, the disclosed KRAS gene can encode a KRAS protein having a G12V, G12D, G12S, G13D, or p.AG11GD mutation. In one aspect, the disclosed MAP2K1 gene can encode a MAP2K1 protein having a K57E mutation. In one aspect, the disclosed MAP2K4 gene has a deletion of exon 2. In one aspect, the disclosed MAP3K1 gene can encode a MAP3K1 protein having an S398 mutation. In one aspect, the disclosed MAP3K6 gene can encode a MAP3K6 protein having a P646L mutation. The disclosed MET gene can encode a MET protein having a C385Y, T895M, T7591, or M391 mutation. In one aspect, the disclosed MPL gene can encode an MPL protein having a Y591D mutation. In one aspect, the disclosed MYC gene can encode a MYC protein having an S244S mutation.In one aspect, the disclosed NF1 gene has splice site 480-11_4801del11, splice site SNV, c.6655>T, p.D2219Y, V2378fs*8, or can encode A2617A, F710C, I1719T, or K583R mutations. In one aspect, the disclosed NOTCH1 gene can encode a NOTCH1 protein having an A465V, V220M, D1681H, or S223N mutation. In one aspect, the disclosed NOTCH2 gene can encode a NOTCH2 protein having an S2379F mutation. In one aspect, the disclosed NTRK1 gene can encode an NTRK1 protein having a P387L or R766Q mutation. In one aspect, the disclosed PDGFRA gene can encode a PDGFRA protein having an E86A or V299G mutation. In one aspect, the disclosed PIK3CA gene can encode a PIK3CA protein having a Q546H, Q546K, Q546R, Q597H, E542K, E545K, E726K, E39K, E453K, R4-P18del, H1047L, H104R, K567E, I1543I, p.E545K, or G1049R mutation. In one aspect, the disclosed PIK3R1 gene can encode a PIK3R1 protein having a S399Y408del splice site 917-1G>A mutation. In one aspect, the disclosed PTCH1 has a p.M17 start loss-LOF. In one aspect, the disclosed PTEN gene can encode a PTEN protein having H196_1203DEL, R55fs, N323fs*23, Y27C, R130*, C136Y, D252Y, or exon 4-7 deletion mutations. In one aspect, the disclosed RAF1 gene can encode a RAF1 protein having a P63P mutation. In one aspect, the disclosed RB1 gene can encode an RB1 protein having a Q217*, Y173fs*, or H673fs mutation. In one aspect, the disclosed RUNX1 gene can encode a RUNX1 protein having an R107C mutation. In one aspect, the disclosed SMAD4 gene can encode a SMAD4 protein having a P511L, D537V, Q450H, L495R, A451P, or A406T mutation. In one aspect, the disclosed SPEN gene can encode a SPEN protein having an A2510V mutation. In one aspect, the disclosed SRSF2 gene can encode an SRSF2 protein having a P95H mutation. In one aspect, the disclosed STAT5B gene can encode a STAT5B protein having an R110H mutation. In one aspect, the disclosed TET2 gene can encode a TET2 protein having a C1875G mutation.In one aspect, the disclosed TP53 gene can encode a TP53 gene having V73fs, R175G, R196, R249T, C176F, G187D, R282W, E287*, E285K, S241del, c.97-2899del, Y126D, R273H, C176W, K320*, T253A, splice site 37G-1G>AA, Q104, P151 H, H179Y, R273C, R248W, R176H, R209fscer, N235-Y236del, R248Qer, R306*, C176Y, S241F, L252-1254del, L145P, R158H, R213*, Y220C, R110P, V274G, or c.376-4_384del mutated TP53 protein.

[0125] For the Guardant 360 platform, genomic aberrations in disclosed cancer-associated genes can include single nucleotide variations. For example, in one aspect, the disclosed single nucleotide variations can be identified in AKT1, ALK, APC, AR, ARAF, ATM, BRAF, BRCA1, BRCA2, CCND1, CDH1, CDK4, CDK6, CDK12, CDKN2A, CTNNB1, EGFR, ERBB2, ESR1, FGFR1, FGFR2, FGFR3, GATA3, GNA11, GNAQ, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MAP2K2, MET, MLH1, MTOR, MYC, NF1, NFE2L2, NRAS, NTRK1, NTRK3, PDGFRA, PIK3CA, PTEN, RAF1, RET, RHEB, ROS1, SMAD4, SMO, STK11, TERT, TSC1, VHL, or any combination thereof. For the Guardant 360 platform, the genomic aberrations in the disclosed cancer-related genes may include insertions and / or deletions. For example, in one aspect, the disclosed insertions and deletions (Indels) can be confirmed in the following genes: AKT1, ALK, APC, ATM, BRAF, BRCA1, BRCA2, CDH1, CDK12, CDKN2A, EGFR, ERBB2, ESR1, FGFR2, GATA3, HNF1A, HRAS, KIT, KRAS, MET, MLH1, NF1, PDGFRA, PIK3CA, PTEN, RET, ROS1, STK11, TSC1, VHL, or any combination thereof. For the Guardant 360 platform, in one aspect, the genomic aberrations in the disclosed cancer-related genes may include copy number amplification (CNA). For example, in one aspect, the disclosed CNA can be confirmed in the following genes: ERBB2 and / or MET. For the Guardant 360 platform, in one aspect, the disclosed fusions can include ALK, NTRK1, RET, ROS1, or any combination thereof.

[0126] For the Foundation platform, in one aspect, the genomic aberrations in the disclosed cancer-related genes can include substitutions, indels, or copy number amplifications. For example, in one aspect, the disclosed substitutions, disclosed indels, or disclosed CNAs can be confirmed in the following genes: ABL1, ACVR1B, AKT1, AKT2, AKT3, ALK, ALOX12B, AMER1 (FAM723B), APC, AR, ARAF, ARFRP1, ARID1A, ASXL1, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXL, BAP1, BARD1, BCL2, BCL2L1, BCL2L2, BCL6, BCOR, BCORL1, BRAF, BRCA1, BRCA2, BRD4, BR IP1, BTG1, BTG2, BTK, C11ORF30(EMSY), CALR, CARD11, CASP8, CBFB, CBL, CCND1, CCND2, CCND3, CCNE1, CD22, CD274(PD-L7), CD70, CD79A, CD79B , CDC73, CDH1, CDK12, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CEBPA, CHEK7, CHEK2, CIC, CREBBP, CRKL, CSFIR, CSF3R, CTCF , CTNNA1, CTNNB1, CUL3, CUL4A, CXCR4, CYP17A1, DAXX, DDR1, DDR2, DIS3, DNMT3A, DOT1L, EED, EGFR, EP300, EPHA3, EPHB1, EPHB4, ERBB2, ERBB3 , ERBB4, ERCC4, ERG, ERRFI1, ESR1, EZH2, FAM46C, FANCA, FANCC, FANCG, FANCL, FAS, FBXW7, FGF10, FGF12, FGF14, FGF19, FGF23, FGF3, FGF4, FGF 6. FGFR1, FGFR2, FGFR3, FGFR4, FH, FLCN, FLT1, FLT3, FOXL2, FUBP1, GABRA6, GATA3, GATA4, GATA6, GID4(C17ORF39), GNA11, GNA13, GNAQ, GNAS, GRM3, GSK3B, H3F3A, HDAC1, HGF, HNF1A, HRAS, HSD3B1, ID3, IDH1, IDH2, IGF1R, IKBKE, IKZF1, INPP4B, IRF2, IRF4, IRS2, JAK1, JAK2, JAK3, JUN,KDM5A、KDM5C、KDM6A、KDR、KEAP1、KEL、KIT、KLHL6、KMT2A(MLL)、KMT2D( MLL2)、KRAS、LTK、LYN、MAF、MAP2K1(MEK1)、MAP2K2(MEK2)、MAP2K4、MAP 3K1、MAP3K13、MAPK1、MCL1、MDM2、MDM4、MED12、MEF2B、MEN1、MERTK、MET 、MITF、MKNK1、MLH1、MPL、MRE11A、MSH2、MSH3、MSH6、MST1R、MTAP、MTOR、 MUTYH、MYC、MYCL(MYCL1)、MYCN、MYD88、NBN、NF1、NF2、NFE2L2、NFKBIA、 NKX2-1、NOTCH1、NOTCH2、NOTCH3、NPM1、NRAS、NT5C2、NTRK1、NTRK2、NTR K3、P2RY8、PALB2、PARK2、PARP1、PARP2、PARP3、PAX5、PBRM1、PDCD1(PD- 1)、PDCD1LG2(PD-L2)、PDGFRA、PDGFRB、PDK1、PIK3C2B、PIK3C2G、PIK3CA 、PIK3CB、PIK3R1、PIM1、PMS2、POLD1、POLE、PPARG、PP2R1A、PPP2R2A、PR DM1、PRKAR1A、PRKCI、PTCH1、PTEN、PTPN11、PTPRO、OKI、RAC1、RAD21、RA D51、RAD51B、RAD51C、RAD51D、RAD52、RAD54L、RAF1、RARA、RB1、RBM10、R EL、RET、RICTOR、RNF43、ROS1、RPTOR、SDHA、SDHB、SDHC、SDHD、SETD2、SF 3B1、SGK1、SMAD2、SMAD4、SMARCA4、SMARCB1、SMO、SNCAIP、SOCS1、SOX2、 SOX9、SPEN、SPOP、SRC、STAG2、STAT3、STK11、SUFU、SYK、TBX3、TEK、TET2 、TGFBR2、TIPARP、TNFAIP3、TNFRSF14、TP53、TSC1、TSC2、TYRO3、U2AF1、 VEGFA、VHL、WHSC1(MMSET)、WHSC1L1、WT1、XPO1、XRCC2、ZNF217、ZNF703、Or any combination thereof. For the Foundation platform, the disclosed genomic aberrations of cancer-related genes may include rearrangements. For example, in one aspect, the disclosed rearrangements may be confirmed in the following genes: ALK, BCL2, BCR, BRAF, BRCA1, BRCA2, CD74, EGFR, ETV4, ETVs, ETV6, EWSRI, EZR, FGFR1, FGFR2, FGFR3, KIT, KMT2A (MLL), MSH2, MYB, MYC, NOTCH2, NTRKI NTRK2 NUTMI, PDGFRA, RAFT, RARA, RET, ROS1, RSPO2 SDC4, SLC34A2TERC (ncRNA), TERT (promoter only), TMPRSS2, or any combination thereof. ,

[0127] For the Tempus platform, in one aspect, the disclosed genomic aberrations of cancer-related genes can include rearrangements. For example, in one aspect, the disclosed rearrangements can be confirmed in the following genes: ABL1, ALK, BCR, BRAF, EGFR, ETV6, EWSR1, FGFR2, FGFR3, MYB, NRG1, NTRK1, NTRK2, NTRK3, PAX8, PDGFRA, PML, RARA, RET, ROS1, TFE3, TMPRSS2, or any combination thereof. For the Tempus platform, in one aspect, the disclosed genomic aberrations of cancer-related genes can include single nucleotide variations, indels, or copy number amplifications. For example, in one aspect, a disclosed single nucleotide variation, a disclosed indel, or a disclosed CNA can be identified in the following genes: ABCB1, ABCC3, ABL1, ABL2, ABRAXAS1, ACTA2, ACVR1, (ALK2), ACVR1B, AGO1, AJUBA, AKT1, AKT2, AKT3, ALK, AMER1, APC, APLNR, APOB, AR, ARAF, ARHGAP26, ARHGAP35, ARID1A, ARID1B, ARID2, ARID5B, ASNS, ASPSCR1, ASXL1, ATIC, ATM, ATP7B, ATR, ATRX, AURKA, AURKB, AXIN1, AXIN2, AXL, B2M , BAP1, BARD1, BCL10, BCL11B, BCL2, BCL2L1, BCL2L11, BCL6, BCL7A, BCLAF1, BCOR, BCORL1, BCR, BIRC3, BLM, BMPR1A , BRAF, BRCA1, BRCA2, BRD4, BRIP1, BTG1, BTK, BUB1B, C11orf65, C3orf70, C8orf34, CALR, CARD11, CARM1, CASP8, C ASR, CBFB, CBL, CBLB, CBLC, CBR3, CCDC6, CCND1, CCND2, CCND3, CCNE1, CD19, CD22, CD274, (PD-L1), CD40, CD70, CD7 9A, CD79B, CDC73, CDH1, CDK12, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2B, CDKN2C, CEBPA, CEP57 , CFTR, CHD2, CHD4, CHD7, CHEK1, CHEK2, CIC, CIITA, CKS1B, CREBBP, CRKL, CRLF2, CSF1R, CSF3R, CTC1, CTCF, CTLA4,CTNNA1, CTNNB1, CTRC, CUL1, CUL3, CUL4A, CUL4B, CUX1, CXCR4, CYLD, CYP1B 1. CYP2D6, CYP3A5, CYSLTR2, DAXX, DDB2, DDR2, DDX3X, DICER1, DIRC2, DIS3 DIS3L2, DKC1, DNM2, DNMT3A, DOT1L, DPYD, DYN, C2H1, EBF1, ECT2L, EGF, EG FR EGLN1 EIF1AX ELF3 ELOC (TCEB1) EMSY ENG EP300 EPCAM EPHA2 EP HA7, EPHB1, EPHB2, EPOR, ERBB2, (HER2), ERBB3, ERBB4, ERCC1, ERCC2, ERCC 3. ERCC4, ERCC5, ERCC6, ERG, ERRFI1, ESR1, ETS1, ETS2, ETV1, ETV4, ETV5, E TV6, EWSR1, EZH2, FAM46C, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FAN CG, FANCI, FANCL, FANCM, FAS, FAT1, FBXO11, FBXW7, FCGR2A, FCGR3A, FDPS, F GF1, FGF10, FGF14, FGF2, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9 FGFR1, FGFR2, FGFR3, FGFR4, FH, FHIT, FLCN, FLT1, FLT3, FLT4, FNTB, FOXA1 FOXL2, FOXO1, FOXO3, FOX, P1, FOXQ1, FRS2, FUBP1, FUSG6PD, GABRA6, GALN T12、GATA1、GATA2、GATA3、GATA4、GATA6、GEN1、GLI1、GLI2、GNA11、GNA13、GN AQ, GNAS, GPC3, GPS2, GREM1, GRIN2A, GRM3, GSTP1, H19, H3F3A, HAS3, HAVCR 2. HDAC1, HDAC2, HDAC4, HGF, HIF1A, HIST1H1E, HIST1H3B, HIST1H4E, HLA-A 、SON-B、SON-C、SON-DMA、SON-DMB、SON-DOA、SON-DOB、SON-DPA1、SON-DPB1 HLA-DPB2、HLA-DQA1、HLA-DQA2、HLA-DQB1、HLA-DQB2、HLA-DRA、HLA-DRB1HLA-DRB5、HLA-DRB6、HLA-E、HLA-F、HLA-G、HNF1A、HNF1B、HOXA11、HOXB13、 HRAS、HSD11B2、HSD3B1、HSD3B2、HSP90AA1、HSPH1、IDH1、IDH2、IDO1、IFIT1 、IFIT2、IFIT3、IFNAR1、IFNAR2、IFNGR1、IFNGR2、IFNL3、IKBKE、IKZF1、IL1 0RA、IL15、IL2RA、IL6R、IL7R、ING1、INPP4B、IRF1、IRF2、IRF4、IRS2、ITPKB、 JAK1、JAK2、JAK3、JUN、KAT6A、KDM5A、KDM5C、KDM5D、KDM6A、KDR、KEAP1、KEL、KIF1B、KIT、KLF4、KLHL6、KLLN、KMT2A、KMT2B、KMT2C、KMT2D、KRAS、L2HGDH、 LAG3、LATS1、LCK、LDLR、LEF1、LMNA、LMO1、LRP1B、LYN、LZTR1、MAD2L2、MAF、 MAFB、MAGI2、MALT1、MAP2K1、MAP2K2、MAP2K4、MAP3K1、MAP3K7、MAPK1、MAX、M C1R、MCL1、MDM2、MDM4、MED12、MEF2B、MEN1、MET、MGMT、MIB1、MITF、MKI67、MLH1、MLH3、MLLT3、MN1、MPL、MRE11、MS4A1、MSH2、MSH3、MSH6、MTAP、MTHFD2、M THFR、MTOR、MTRR、MUTYH、MYB、MYC、MYCL、MYCN、MYD88、MYH11、NBN、NCOR1、N COR2、NF1、NF2、NFE2L2、NFKBIA、NHP2、NKX2-1、NOP10、NOTCH1、NOTCH2、NOTC H3、NOTCH4、NPM1、NQO1、NRAS、NRG1、NSD1、NSD2、NT5C2、NTH、L1、NTRK1、NTRK2、NTRK3、NUDT15、NUP98、OLIG2、P2RY8、PAK1、PALB2、PALLD、PAX3、PAX5、PA X7,PAX8,PBRM1,PCBP1,PDCD1,PDCD1LG2,PDGFRA,PDGFRB,PDK1,PHF6,PHG DH、PHLPP1、PHLPP2、PHOX2B、PIAS4、PIK3C2B、PI、K3、CA、PIK3CB、PI、K3、CD、PIK3CG, PI, K3, R1, PIK3R2, PIM1, PLCG1, PLCG2, PML, PMS1, PMS2, POLD1, POLE, POLH, POLQ, POT1, POU2F2, PPARA, PPARD, PPARG, PPM1D, PPP1R15A, PPP2R1A, PPP2R2A, PPP6C, PRCC, PRDM1, PREX2, PRKAR1A, PRKDC, PRKN, PRSS1, PTC, H, 1, PTCH2, PTEN, PTPN11, PTPN13, PTPN22, PTPRD, PTPRT, QKI, RAC1, RAD21, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, RAF1, RANBP2, RARA, RASA1, RB1, RBM10, RECQL4, RET, RHEB, RHOA, RICTOR, RINT1, RIT1, RNF139, RNF43, ROS1, RPL5, RPS15, RPS6KB1, RPTOR, RRM1, RSF1, RUNX1, RUNX1T1, RXRA, SCG5, SDHA, SDHAF2, SDHB, SDHC, SDHD, SEC23B, SEMA3C, SETBP1, SETD2, SF3B1, SGK1, SH2B3, SHH, SLC26A3, SLC47A2, SLC9A3R1, SLIT2, SLX4, SM, AD2, SMAD3, SMAD4, SMARCA1, SMARCA4, SMARCB1, SMARCE1, SMC1A, SMC3, SMO, SOCS1, SOD2, SOX10, SOX2, SOX9, SPEN, SPINK1, SPOP, SPRED1, SRC, SRSF2, STAG2, STAT3, STAT4, STAT5A, STAT5B, STAT6, STK11, SUFU, SUZ12, SYK, SYNE1, TAF1, TANC1, TAP1, TAP2, TARBP2, TBC1D12, TBL1XR1, TBX3, TCF3, TCF7L2, TCL1A, TERT (promoter), TET2, TFE3, TFEB, TFEC, TGFBR1, TGFBR2, TIGIT, TMEM127, TMEM173, TMPRSS2, TNF, TNFAIP3, TNFRSF14, TNFRSF17, TNFRSF9, TOP1, TOP2A, TP53, TP63, TPM1, TPMT, TRAF3, TRAF7, TSC1, TSC2, TSHR, TUSC3, TYMS, U2AF1UBE2T, UGT1A1, UGT1A9, UMPS, VEGFA, VEGFB, VHL, VSIR, WEE1, WNK1, WNK2, WRN, WT1, XPA, XPC, XPO1, XRCC1, XRCC2, XRCC3, YEATS4, ZFHX3, ZMYM3, ZNF217, ZNF471, ZNF620, ZNF750, ZNRF3, ZRSR2, or any combination thereof.

[0128] For the Tempus platform, the following apply: APC (APC-related conditions), ATM (ataxia-telangiectasia, breast cancer susceptibility, pancreatic cancer susceptibility), AXIN2 (oligodontia-colorectal cancer syndrome), BAP1 (BAP1 tumor predisposition syndrome), BARD1 (breast cancer susceptibility), BLM (Bloom syndrome), BMPR1A (juvenile polyposis), BRCA1 (hereditary breast and ovarian cancer), BRCA2 (hereditary breast and ovarian cancer, Fanconi anemia), BRIP1 (ovarian cancer susceptibility, Fanconi anemia), CDH1 (hereditary diffuse gastric cancer, breast cancer susceptibility), CDK4 (melanoma susceptibility), CDKN2A (melanoma-pancreatic cancer syndrome), CEBPA (acute myeloid leukemia), leukemia susceptibility), CHEK2 (breast cancer susceptibility, colon cancer susceptibility), DICER1 (DICER1 tumor predisposition syndrome), EGFR (lung cancer susceptibility, TKI resistance), EPCAM (Lynch syndrome), ETV6 (leukemia susceptibility, thrombocytopenia susceptibility), FH (hereditary leiomyomatosis and renal cell carcinoma), FLCN (Butter-Hoag-Dubé syndrome), GATA2 (GATA2 deficiency and susceptibility to myeloid malignancies), KIT (familial gastrointestinal stromal tumor), MAX (hereditary paraganglioma-pheochromocytoma syndrome), MEN1 (multiple endocrine neoplasia type 1), MET (hereditary papillary renal cell carcinoma), MLH1 (Lynch syndrome, constitutive mismatch repair deficiency), MSH2 (Lynch syndrome,Constitutive mismatch repair deficiency), MSH3 (MSH3-associated polyposis), MSH6 (Lynch syndrome, constitutive mismatch repair deficiency), MUTYH (MUTYH-associated polyposis), NBN (Nijmegen breakage syndrome, breast cancer susceptibility), NF1 (neurofibromatosis type 1), NF2 (neurofibromatosis type 2), NTHL1 (NTHL1 tumor syndrome, NTHL1-associated polyposis), PALB2 (breast cancer susceptibility, pancreatic cancer susceptibility, ovarian cancer susceptibility, Fanconi anemia), PDGFRA (familial gastrointestinal stromal tumor, GIST-plus syndrome syndrome), PHOX2B (neuroblastoma susceptibility), PMS2 (Lynch syndrome, constitutive mismatch repair deficiency), POLD1 (polymerase proofreading-associated polyposis), POLE (polymerase proofreading-associated polyposis), PRKAR1A (Carney complex), PTCH1 (Gorlin syndrome, basal cell nevus syndrome), PTEN (PTEN hamartoma syndrome), RAD51C (ovarian cancer susceptibility, breast cancer susceptibility, Fahr's syndrome), RAD51C (ovarian cancer susceptibility, breast cancer susceptibility, Fanconi anemia), RAD5 1D (ovarian cancer susceptibility, breast cancer susceptibility), RB1 (retinoblastoma), RET (multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma), RUNX1 (acute myeloid leukemia susceptibility), SDHA (hereditary paraganglioma-pheochromocytoma syndrome), SDHAF2 (hereditary paraganglioma-pheochromocytoma syndrome), SDHB (hereditary paraganglioma-pheochromocytoma syndrome), SDHC (hereditary paraganglioma-pheochromocytoma syndrome), SDHD (hereditary paraganglioma-pheochromocytoma syndrome), SMAD4 (juvenile dysplasia susceptibility), Sarcoidosis, hereditary hemorrhagic telangiectasia, SMARCA4 (rhabdoid tumor predisposition syndrome), SMARCB1 (rhabdoid tumor predisposition syndrome, schwannomatosis), STK11 (Poitz-Jegger syndrome), SUFU (Gorlin syndrome, basal cell nevus syndrome), TMEM127 (hereditary paraganglioma-pheochromocytoma syndrome), TP53 (Li-Fraumeni syndrome), TSC1 (tuberous sclerosis complex), TSC2 (tuberous sclerosis complex), VHL (von Hippel-Lindau syndrome), and WT1 (WT1-related Wilms tumor).

[0129] In one aspect of the disclosed method for treating and / or preventing cancer, next generation sequencing may include sequencing one or more cancer-related genes. In one aspect of the disclosed method for treating and / or preventing cancer, sequencing one or more cancer-related genes may include confirming one or more genomic aberrations. In one aspect, the one or more genomic aberrations may include somatic genomic aberrations. In one aspect, the disclosed one or more somatic genomic aberrations may include mutations, insertions, deletions, chromosome rearrangements, copy number aberrations, or any combination thereof.

[0130] In one aspect of the disclosed method for treating and / or preventing cancer, the disclosed cfDNA analysis may include quantification of one or more cancer-related genes. In one aspect, if the expression and / or quantity and / or presence of one or more genomic aberrations disclosed in the biological sample before treatment is higher than the expression and / or quantity and / or presence of the same one or more genomic aberrations in the control sample, the disclosed method for treating and / or preventing cancer may include diagnosing that the subject needs precision cancer treatment. In one aspect, the disclosed control sample can be a sample obtained from a subject who does not have cancer. In one aspect, the disclosed control sample can be a pooled sample obtained from multiple subjects who do not have cancer.

[0131] In one aspect, if the expression and / or amount and / or presence of one or more genomic aberrations disclosed in a biological sample after treatment is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in the sample before treatment, then the disclosed methods of treating and / or preventing cancer may comprise continuing to administer a disclosed precision cancer therapy to the subject. In one aspect, if the expression and / or amount and / or presence of one or more genomic aberrations disclosed in a biological sample after treatment is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in the sample after the previous treatment, then the disclosed methods of treating and / or preventing cancer may comprise continuing to administer a disclosed precision cancer therapy to the subject.

[0132] In one aspect, the disclosed methods of treating and / or preventing cancer may further comprise measuring a subject's tumor response to the precision cancer therapy. In one aspect, a subject's tumor response may comprise a partial response or a complete response. In one aspect, a disclosed partial response may comprise a decrease in tumor size or a decrease in one or more tumors by 25% or more compared to the size of the same tumor or the same tumor(s) before treatment. In one aspect, a disclosed partial response may comprise a decrease in tumor size or a decrease in one or more tumors by 50% or more compared to the size of the same tumor or the same tumor(s) before treatment. In one aspect, a disclosed partial response may comprise a decrease in tumor size or a decrease in one or more tumors by about 100% or more compared to the size of the same tumor or the same tumor(s) before treatment.

[0133] In one aspect, the disclosed methods for treating and / or preventing cancer may further comprise measuring a subject's molecular response to the disclosed precision cancer therapy. In one aspect, the disclosed molecular response may comprise a reduction in the number of somatic genomic aberrations in a biological sample obtained from a subject. In one aspect, the disclosed somatic genomic aberrations may comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, fusions, or any combination thereof. In one aspect, the disclosed methods for treating and / or preventing cancer may further comprise administering one or more additional therapeutic agents to the subject.

[0134] In one aspect, the disclosed additional therapeutic agents can include chemotherapeutic agents, monoclonal antibodies, cell cycle inhibitors, small molecules, or any combination thereof.

[0135] Monoclonal antibodies are known to those skilled in the art. Monoclonal antibodies may include, but are not limited to, adotrastuzumab, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, cemiplimab, cetuximab, daratumumab, denosumab, dinutuximab, durvalumab, elotuzumab, gemtuzumab, and selegiline. umab, ibritumomab, inotuzumab, ipilimumab, necitumumab, nivolumab, obinutuzumab, ofatumumab, olaratumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab, trastuzumab, or any combination thereof.

[0136] Small molecules are known to those skilled in the art. Small molecules may include, but are not limited to, abemaciclib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, gilteritinib, and selenobutaline. nib), cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, dasatini, duvelisib, encorafenib, entrectinib, erdafitinib, erlotinib, gefitinib, Ibrance ibrutinib, imatinib, ivosidenib, lapatinib, larotrectinib, lenvatinib, lorlatinib, marizomib, neratinib, nilotinib, niraparib, olaparib, osimertinib ), palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sorafenib, sunitinib, talazoparib, trametinib, vandetanib, vemurafenib, or any combination thereof. In one aspect, additional therapeutic agent can include bevacizumab, pazopanib, sorafenib, dasatinib, everolimus, or any combination thereof.

[0137] For example, in one aspect, pazopanib and / or sorafenib can be orally administered to a subject at a dosage of about 1 mg / kg / day to about 12 mg / kg / day or 2 mg / kg / day to about 6 mg / kg / day. In one aspect, the disclosed optimal dose of pazopanib and / or sorafenib can be about 3 mg / kg / day. In one aspect, dasatinib can be orally administered to a subject at a dosage of about 0.3 mg / kg / day to about 2.0 mg / kg / day or about 0.7 mg / kg / day to about 1.4 mg / kg / day. In one aspect, the disclosed optimal dose of dasatinib can be about 0.7 mg / kg / day. In one aspect, everolimus can be orally administered to a subject at a dosage of about 0.03 mg / kg / day to about 0.15 mg / kg / day or about 0.03 mg / kg / day to about 0.10 mg / kg / day. In one aspect, the disclosed optimal dose of everolimus can be about 0.07 mg / kg / day. In one aspect, bevacizumab can be administered intravenously to a subject at a dose of about 2 mg / kg / day to about 15 mg / kg / day every 1 to 3 weeks or administered to a patient at a dose of about 5 mg / kg / day to about 12 mg / kg / day every 1 to 3 weeks. In one aspect, the disclosed optimal dose of bevacizumab can be administered intravenously to a subject once every 2 weeks, with an optimal dose of about 10 mg / kg / day.

[0138] In one aspect, the disclosed molecular markers can be measured from a sample by high-density expression arrays, DNA microarrays, polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), real-time quantitative reverse transcription PCR (qRT-PCR), serial analysis of gene expression (SAGE), spotted cDNA arrays, gene chips, spotted oligonucleotide arrays, microbead arrays, RNA sequencing, tiling arrays, Northern blots, hybridization microarrays, in situ hybridization, whole exome sequencing, whole genome sequencing, liquid biopsy, next generation sequencing, or any combination thereof, which can determine one or more appropriate precision cancer treatments in one or more of the disclosed methods.

[0139] In one aspect, the disclosed molecular markers for one or more suitable precision cancer treatments in the disclosed methods for treating and / or preventing cancer can be determined based on the nucleic acid sequence of at least one of circulating DNA and / or RNA. In one aspect, the disclosed molecular markers can be assessed from circulating tumor DNA and / or RNA (ctDNA and / or ctRNA); circulating cell-free DNA and / or RNA (cfDNA, cfRNA); or any combination thereof. ctDNA / ctRNA refers to DNA fragments in the blood that are not associated with cells and are derived from tumors. cfDNA / cfRNA refers to DNA that circulates freely in the bloodstream, but is not necessarily derived from tumors. In one aspect, cfDNA / ctDNA may include any complete or fragmented genomic DNA or mitochondrial DNA, and / or cfRNA / ctRNA may include mRNA, tRNA, microRNA, small interfering RNA, long non-coding RNA (lncRNA). In one aspect, cfRNA and / or ctRNA may be fragmented DNA having a length of at least about 50 base pairs (bp), about 100 bp, about 200 bp, about 500 bp, or about 1 kbp. In one aspect, cfDNA / ctDNA can be the full length or fragment of mRNA (e.g., at least 70% of the full length, at least 50% of the full length, at least 30% of the full length, etc.). In one aspect, the disclosed molecular markers can be directed against any cancer-related gene disclosed herein.

[0140] In one aspect, the disclosed methods may further comprise surgically removing one or more tumors from the subject. In one aspect, the disclosed methods may further comprise repeating one or more disclosed steps of the disclosed methods.

[0141] For example, in one aspect, repeating one or more disclosed steps of the disclosed methods can comprise repeatedly administering a precision cancer therapy to a subject, repeatedly measuring a tumor response in a subject, repeatedly obtaining a biological sample from a subject, repeatedly performing cfDNA analysis on a biological sample, repeatedly administering one or more additional therapeutic agents, or any combination thereof.

[0142] In one aspect, the disclosed molecular markers can be detected, quantified and / or analyzed over time (at different time points) to determine the effectiveness of the disclosed precision cancer treatment (such as AS therapy) on the subject and / or determine the response of the subject or the subject's tumor to the precision cancer treatment (such as the development of drug resistance, susceptibility, etc.). In one aspect, the disclosed method may include obtaining multiple measurements from the same subject over time, and the same sample can be quantified at a single time point or over time. In one aspect, the treatment of the disclosed treatment regimen (e.g., the disclosed precision cancer treatment comprising one or more antineoplastons) can be designed and / or determined based on the cancer status and / or the change / type of one or more molecular markers. In one aspect, the likelihood of success of the disclosed precision cancer treatment can be determined based on the cancer status and the type / quantity of one or more molecular markers.

[0143] In one aspect, the disclosed molecular markers can be derived from genes expressed in one or more cells of a tumor or in immune cells and can indicate an immunosuppressive tumor microenvironment, the development of cancer severity, the occurrence of metastasis, the cancer state, or any combination thereof. In one aspect, the disclosed molecular markers can be proteins or peptides encoded by the genes from which the molecular markers are derived and can be targeted by antagonists or any other type of binding molecules to inhibit the function of the polypeptide.

[0144] Thus, in one aspect, increased expression of the disclosed molecular markers derived from the disclosed genes associated with an immunosuppressive tumor microenvironment (e.g., above a predetermined threshold) may indicate the presence of an immunosuppressive tumor microenvironment, and may also indicate that antagonists of peptides encoded by genes associated with an immunosuppressive tumor microenvironment are likely to inhibit the progression of cancer by suppressing the immunosuppressive tumor microenvironment and further promoting the activity of immune cells against tumor cells in such a microenvironment. In one aspect, once a molecular marker has been identified, any suitable antagonist targeting a gene or protein may be used. For example, in one aspect, a kinase inhibitor may target a specific kinase, a synthetic ligand may target a specific signaling receptor, or a synthetic antagonist or antibody may target a specific checkpoint receptor, etc. In one aspect, the target molecule antagonists disclosed herein may be administered before, after, or in combination with AS treatment.

[0145] In one aspect, the subject can be a human patient. In one aspect, the subject can be of any age (e.g., elderly, adult, youth, adolescent, child, puberty, child, toddler, infant, or newborn), male or female, of any nationality, of any ethnicity, and / or of any race. In one aspect, the subject can have terminal cancer.

[0146] In one aspect, the subject has not received treatment prior to administering the disclosed precision cancer treatment to the disclosed subject. In one aspect, the subject has received treatment prior to administering the disclosed precision cancer treatment to the disclosed subject. In one aspect of the disclosed method, the subject has received surgery, antibody therapy, chemotherapy, radiation therapy, immunotherapy, or any combination thereof prior to administering the disclosed precision cancer treatment. In one aspect of the disclosed method, the subject in need has been diagnosed with cancer, or the subject in need is suspected of having cancer.

[0147] In one aspect, the disclosed cancers may be refractory cancers or refractory diseases. In one aspect, "refractory" refers to a cancer and / or tumor that is unresponsive to treatment and / or develops resistance. In one aspect, the subject may have a recurrent disease. In one aspect, "relapse" or "recurrent" refers to the return or development of a tumor after improvement (e.g., a partial or complete response) with treatment. In one aspect, the disclosed cancers may include solid tumors. In one aspect, the disclosed cancers may include metastatic cancers. In one aspect, the disclosed cancers may include terminal cancers.

[0148] In one aspect, the disclosed cancers may include adenocarcinoma (including appendix and cervix), adenoid cystic epithelial carcinoma, adult T-cell leukemia, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, astrocytoma, basal cell carcinoma, B-cell carcinoma, benign and malignant lymphoma, biliary tract-cholangiocarcinoma, intestinal cancer, brain cancer (including anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, brainstem anaplastic astrocytoma, brainstem glioma, diffuse astrocytoma, DIPG H3K27 mutation, ganglioglioma, glioblastoma multiforme, medulloblastoma, pilocytic astrocytoma, brainstem glioma), breast cancer, breast cancer, breast cancer, and ovarian cancer. carcinoma), Burkitt lymphoma, bladder cancer and urothelial carcinoma, epithelial carcinoma of unknown primary site, carcinosarcoma, cervical cancer, cholangiocarcinoma, chronic atypical myeloid leukemia, chronic atypical myeloid leukemia, colon cancer, colorectal cancer, diffuse astrocytoma, diffuse intrinsic pontine glioma (DIPG), endometrial cancer, endometrial epithelial carcinoma, ependymoma, esophageal cancer and esophageal epithelial carcinoma, Uveal sarcoma, ganglioglioma, ganglioneuroma Glioblastoma, Gastrointestinal Stromal Tumor (GIST), Glioblastoma, Glioma, Head and Neck Cancer and Head and Neck Epithelial Cancer, Angiosarcoma, Hepatocellular Carcinoma, Renal Cell Carcinoma, Hodgkin's Disease, Kaposi's Sarcoma, Kidney Cancer and Renal Epithelial Cancer, Large B-Cell Lymphoma, Leptomeningeal Carcinomatosis, Leukemia, Liposarcoma, Hepatocellular Carcinoma, Lung Cancer (Non-Small Cell and Small Cell), Medulloblastoma, Melanoma, Meningeal Sarcoma, Meningioma, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative Disorders Diseases, myositis, neuroblastoma, neuroendocrine epithelial cancer, neurofibroma, non-Hodgkin's lymphoma, oligodendroglioma, osteosarcoma, ovarian cancer and ovarian epithelial cancer, pancreatic cancer and pancreatic epithelial cancer, peripheral neuroepithelial tumor, peripheral T-cell lymphoma, Philadelphia chromosome positive and positive CML, pilocytic astrocytoma, pineal cell tumor, pleomorphic sarcoma, pre-B lymphoma, primitive neuroectodermal tumor (PNET), prostate cancer and prostatic epithelial cancer, Refractory anemia, salivary gland epithelial cancer, sarcoma, Schwannoma, skin cancer and skin epithelial cancer, squamous cell epithelial cancer, gastric cancer and gastric epithelial cancer, synovial sarcoma, testicular cancer, thyroid cancer and thyroid epithelial cancer, T-line acute lymphoblastic leukemia (T-ALL), T-line lymphocytic lymphoma (T-LL), urinary tract cancer and urinary tract high-grade epithelial cancer, uterine, cervical, vulvar and / or endometrial epithelial cancer, Wilms' tumor or teratoma, or any combination thereof.

[0149] In one aspect, the disclosed cancers can include breast cancer, colorectal cancer, head and neck cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, brain cancer, adenoid cystic carcinoma, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, brain stem glioma, diffuse astrocytoma, diffuse intrinsic pontine glioma (DIPG), ganglioglioma, medulloblastoma, pilocytic astrocytoma, bile duct cancer, chronic atypical myeloid leukemia, endometrial epithelial carcinoma, esophageal cancer, Ewing sarcoma, gastrointestinal stromal tumor (GIST), leptomeningeal carcinomatosis, multiple myeloma, myelodysplastic syndrome, neuroendocrine epithelial cancer, non-Hodgkin lymphoma, pleomorphic sarcoma, primitive neuroectodermal tumor (PNET), refractory anemia, salivary gland epithelial cancer, skin cancer, gastric cancer, thyroid cancer, urinary tract cancer, or any combination thereof.

[0150] In one aspect, the disclosed method may further include monitoring the subject for adverse reactions (e.g., liver damage, blood toxicity, nervous system toxicity, skin toxicity, gastrointestinal toxicity, or any combination thereof). In one aspect, in the absence of adverse reactions, the disclosed method may further include continuing to administer the disclosed precision cancer treatment to the subject. In one aspect, in the presence of adverse reactions, the disclosed method may further include modifying one or more disclosed steps of the disclosed method. In one aspect, the disclosed method may further include treating one or more adverse reactions.

[0151] In one aspect, the disclosed methods can include modifying the disclosed administering steps. In one aspect, modifying the disclosed administering steps can include changing the amount of one or more antineoplastons or compositions comprising one or more antineoplastons administered to a subject, changing the frequency of administering one or more antineoplastons or compositions comprising one or more antineoplastons to a subject, changing the duration of administering one or more antineoplastons or compositions comprising one or more antineoplastons to a subject, changing the route of administration of one or more antineoplastons or compositions comprising one or more antineoplastons to a subject, or any combination thereof.

[0152] In one aspect, the disclosed method may further include obtaining a tissue biopsy from the subject. In one aspect, the disclosed tissue biopsy may be subjected to next generation sequencing. In one aspect, the disclosed method may include subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known in the art. In one aspect, the disclosed non-invasive diagnostic assessments may include X-rays, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasound, positron emission tomography (PET), or any combination thereof. In one aspect, the disclosed invasive diagnostic assessments may include tissue biopsy or exploratory surgery.

[0153] In one aspect, the disclosed methods can improve the life expectancy of a subject. In one aspect, the life expectancy of a subject is compared to the life expectancy of a control. In one aspect, the control is a subject that has not received precision cancer therapy. In one aspect, the control is a pool of subjects that have not received precision cancer therapy. In one aspect, the control is one or more subjects with the same cancer type and the same cancer stage as the subject. In one aspect of the disclosed methods of extending the survival of a subject, the subject's cancer is treated.

[0154] In one aspect, the method can increase life expectancy compared to the cancer life expectancy of an untreated subject with the same or nearly the same disease condition and the same or nearly the same predicted outcome. As used herein, "life expectancy" is defined as the time at which 50% of subjects survive and 50% of subjects die. In one aspect, following treatment using the disclosed methods, a patient's life expectancy may be indeterminate. In one aspect, a patient's life expectancy can be increased by at least about 5% or more to at least about 100%, at least about 10% or more to at least about 95% or more, at least about 20% or more to at least about 80% or more, at least about 40% or more to at least about 60% or more, compared to an untreated subject with the same or nearly the same disease condition and the same or nearly the same predicted outcome.

[0155] In one aspect, life expectancy can be increased by at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 25% or more, at least about 30% or more, at least about 35% or more, at least about 40% or more, at least about 45% or more, at least about 50% or more, at least about 55% or more, at least about 60% or more, at least about 65% or more, at least about 70% or more, at least about 75% or more, at least about 80% or more, at least about 85% or more, at least about 90% or more, at least about 95% or more, at least about 100% compared to an untreated subject with the same or approximately the same disease condition and the same or approximately the same predicted outcome. In one aspect, life expectancy can be increased by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 50% or more to at least about 57% or more, at least about 58% or more to at least about 59% or more, at least about 60% or more to at least about 61% or more, at least about 62% or more to at least about 63% or more, at least about 64% or more to at least about 66% or more, at least about 67% or more to at least about 68% or more, at least about 69% or more to at least about 70% or more, at least about 71% or more to at least about 72% or more, at least about 73% or more to at least about 74% or more, at least about 75% or more to at least about 76% or more, at least about 77% or more to at least about 78% or more, at least about 79% or more to at least about 80% or more, at least about 81% or more to at least about 82% or more, at least about 83% or more to at least about 84% or more, at least about 85% or more to at least about 86% or more, at least about From at least about 45% or more to at least about 50% or more, at least about 50% or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100%.

[0156] In one aspect, the disclosed methods may include protecting a subject from metastasis. In one aspect, the disclosed methods may include reducing the risk of metastasis. In one aspect of the disclosed methods, treating cancer may include improving the survivability of a subject, increasing the length of time before metastasis, reducing the likelihood of surgical intervention, reducing the need to administer one or more additional therapeutic agents or treatment regimens, reducing the size of one or more tumors in a subject, eliminating one or more tumors in a subject, reducing or eliminating the prevalence of one or more genomic aberrations, restoring normal metabolism in one or more organ systems in a subject, restoring one or more aspects of cellular homeostasis and / or cellular function, and / or metabolic dysregulation; or any combination thereof.

[0157] In one aspect of the disclosed methods, one or more aspects of restoring cellular homeostasis and / or cellular function may include one or more of the following: (i) correcting cellular starvation of one or more cell types (such as, for example, liver cells and muscle cells, etc.); (ii) normalizing the autophagy pathway (such as, for example, correcting, preventing, reducing and / or improving autophagy, etc.); (iii) improving, enhancing, restoring and / or protecting mitochondrial function and / or structural integrity; (iv) improving, enhancing, restoring and / or protecting organelle function and / or structural integrity; (v) preventing, slowing and / or eliminating hypoglycemia, ketosis and / or other liver abnormalities; vi) correcting liver enzyme dysregulation; (vii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor metastasis; (viii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor growth and / or cancer spread, or (ix) any combination of the foregoing. In one aspect, one or more aspects of restoring cellular homeostasis may include one or more aspects of improving, enhancing, restoring and / or maintaining cellular structural and / or functional integrity in, for example, an organ or system that has been affected by cancer.

[0158] For example, in one aspect, tumor growth can be attenuated by at least about 5% or more to at least about 100%, at least about 10% or more to at least about 95% or more, at least about 20% or more to at least about 80% or more, at least about 40% or more to at least about 60% or more, compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome. In one aspect, the growth of one or more tumors in a subject treated using the disclosed methods can be reduced by at least 5% (or more as described above) compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome.

[0159] In one aspect, tumor growth can be impaired by at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 25% or more, at least about 30% or more, at least about 35% or more, at least about 40% or more, at least about 45% or more, at least about 50% or more, at least about 55% or more, at least about 60% or more, at least about 65% or more, at least about 70% or more, at least about 75% or more, at least about 80% or more, at least about 85% or more, at least about 90% or more, at least about 95% or more, at least about 100% as compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome.

[0160] In one aspect, tumor growth can be attenuated by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 50% or more to at least about 56% or more, at least about 57% or more to at least about 58% or more, at least about 59% or more to at least about 60% or more, at least about 61% or more to at least about 62% or more, at least about 63% or more to at least about 64% or more, at least about 65% or more to at least about 66% or more, at least about 67% or more to at least about 68% or more, at least about 69% or more to at least about 70% or more, at least about 71% or more to at least about 72% or more, at least about 73% or more to at least about 74% or more, at least about 75% or more to at least about 76% or more, at least about 77% or more to at least about 78% or more, at least about 79% or more to at least about 80% or more, at least about 81% or more to at least about 82% or more, at least about 83% or more to at least about 84% or more, at least about 85% or more to at least about 86% or more, at least about From at least about 45% or more to at least about 50% or more, at least about 50% or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100%.

[0161] In one aspect, treating a tumor according to the methods disclosed herein (e.g., AS therapy) can reduce the tumor relative to its starting size. In one aspect, the tumor is reduced by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 45% or more to at least about 50% or more, at least about 50% or more, or at least about 50% or more, as compared to its starting size. % or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100% (referring to complete disappearance of the tumor after treatment).

[0162] In one aspect, the disclosed subject may present with one or more cancerous solid tumors, metastatic nodules, or any combination thereof. In any aspect, the subject herein may have a cancerous tumor cell of origin, which may be less than about 0.2 cm 3 to at least about 20cm 3 or larger, at least about 2 cm 3 to at least about 18cm 3 or larger, at least about 3cm 3 to at least about 15cm 3 or larger, at least about 4cm 3 to at least about 12 cm 3 or larger, at least about 5cm 3 to at least about 10 cm 3 or larger, or at least about 6cm 3 to at least about 8cm 3 or larger.

[0163] In one aspect, the disclosed methods of treating and / or preventing cancer can include a pan-tumor approach, such as, for example, administering the disclosed ANP therapies.

[0164] D. Methods to prolong survival

[0165] Disclosed herein is a method of extending survival in a subject, the method comprising administering a precision cancer therapy to a subject in need thereof, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0166] Disclosed herein is a method for extending survival in a subject, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0167] Disclosed herein is a method for extending survival in a subject, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as needing precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; administering the precision cancer therapy to the subject; and wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0168] Disclosed herein is a method for extending survival in a subject, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; wherein, if the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample, diagnosing the subject as being in need of precision cancer therapy; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein the subject's life expectancy is extended.

[0169] In one aspect, the life expectancy of a subject is compared to the life expectancy of a control. In one aspect, the control is a subject who has not received the precision cancer treatment. In one aspect, the control is a pool of subjects who have not received the precision cancer treatment. In one aspect, the control is one or more subjects with the same cancer type and the same cancer stage as the subject. In one aspect of the disclosed method of extending the survival of a subject, the subject is treated for cancer.

[0170] In one aspect, the disclosed precision cancer treatments may include one or more antineoplastons, or may include compositions comprising one or more antineoplastons. In one aspect, the disclosed antineoplastons may include phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or any combination thereof. In one aspect, the disclosed compositions comprising one or more antineoplastons may include phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or any combination thereof.

[0171] In one aspect, the disclosed compositions comprising one or more antineoplastons may comprise a pharmaceutically acceptable carrier. In one aspect, the disclosed one or more antineoplastons may comprise sodium phenylacetylglutamine (PG) and sodium phenylacetylisoglutamine (iso-PG). In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may range from about 10:1 to about 1:10. In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 4:1. In one aspect, the disclosed dosage of the one or more antineoplastons may comprise about 0.1 g / kg / day to about 20 g / kg / day. In one aspect, the disclosed therapeutically effective doses of one or more antineoplastons may include about 0.1 g / kg / day to about 20 g / kg / day. In one aspect, the disclosed doses of sodium phenylacetylglutamine (PG) may include about 0.4 g / kg / day to about 16 g / kg / day, and the disclosed doses of sodium phenylacetylisoglutamine (iso-PG) may include about 0.1 g / kg / day to about 4 g / kg / day. In one aspect, the disclosed therapeutically effective amounts of sodium phenylacetylglutamine (PG) may include about 0.4 g / kg / day to about 16 g / kg / day, and the disclosed therapeutically effective amounts of sodium phenylacetylisoglutamine (iso-PG) may include about 0.1 g / kg / day to about 4 g / kg / day.

[0172] In one aspect, the disclosed one or more antineoplastons can include phenylacetate (PN) and phenylacetylglutamine (PG). In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can range from about 10:1 to about 1:10. In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can be about 4:1. In one aspect, the disclosed dosage of the one or more antineoplastons can include about 0.08 g / kg / day to about 0.6 g / kg / day. In one aspect, the disclosed therapeutically effective dosage of the one or more antineoplastons can include about 0.08 g / kg / day to about 0.6 g / kg / day. In one aspect, the disclosed dosage of phenylacetate (PN) may include about 0.064 g / kg / day to about 0.48 g / kg / day, and the disclosed dosage of phenylacetamine (PG) may include about 0.016 g / kg / day to about 0.12 g / kg / day. In one aspect, the disclosed therapeutically effective dosage of phenylacetate (PN) may include about 0.064 g / kg / day to about 0.48 g / kg / day, and the disclosed therapeutically effective dosage of phenylacetamine (PG) may include about 0.016 g / kg / day to about 0.12 g / kg / day.

[0173] In one aspect of the disclosed method of extending the survival of a subject, administering the disclosed precision cancer treatment may comprise intravenous administration. In one aspect, the disclosed precision cancer treatment may be administered intravenously to a subject using, for example, a dual-channel infusion pump or two single-channel pumps and a central venous catheter. In one aspect, the disclosed precision cancer treatment may be administered once every four hours at an IV infusion rate of about 50 ml / hour to about 250 ml / hour (e.g., about 50, 75, 100, 125, 150, 175, 200, 225, 250 ml / hour), depending on the age and condition / tolerance of the subject.

[0174] In one aspect, the disclosed methods for extending the survival of a subject may comprise titrating the dose of the disclosed precision cancer therapy. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of A10, AS2-1, or a combination thereof. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed compositions, disclosed pharmaceutical compositions, disclosed therapeutic agents, disclosed immunomodulators, disclosed proteasome inhibitors, disclosed small molecules, disclosed endonucleases, disclosed oligonucleotides, disclosed RNA therapeutics, or any combination thereof to confirm an effective dose and / or to confirm an effective dose that causes only minor adverse reactions and / or side effects.

[0175] In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed precision cancer therapy in a specific or disclosed subject. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of A10, AS2-1, or a combination thereof in a specific or disclosed subject. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed composition, the disclosed pharmaceutical composition, the disclosed therapeutic agent, the disclosed immunomodulator, the disclosed proteasome inhibitor, the disclosed small molecule, the disclosed endonuclease, the disclosed oligonucleotide, the disclosed RNA therapeutic agent, or any combination thereof to confirm an effective dose for a specific or disclosed subject and / or to confirm an effective dose that causes only mild adverse reactions and / or side effects to the subject.

[0176] In one aspect, administering comprises administering to the subject a maximum tolerated dose of A10, AS2-1, or both. In one aspect, administering comprises administering to the subject less than the maximum tolerated dose of A10, AS2-1, or both.

[0177] In one aspect, IV administration of the disclosed precision cancer treatments can include an outpatient setting. In one aspect, A10 can be administered before, concurrently, or after AS2-1. In one aspect, AS2-1 can be administered before, concurrently, or after A10. In one aspect, the order in which one or more antineoplastons are administered can be altered during a treatment regimen.

[0178] In one aspect, the disclosed method for extending the survival of a subject may further include obtaining a biological sample from the subject before administering the disclosed precision cancer treatment. In one aspect, the disclosed method for extending the survival of a subject may further include obtaining a biological sample from the subject after administering the disclosed precision cancer treatment. In one aspect, the disclosed method for extending the survival of a subject may further include performing cell-free DNA (cfDNA) analysis on the biological sample. cfDNA analysis is known to those skilled in the art. In one aspect, the disclosed cfDNA analysis can be repeated one or more times. In one aspect, the disclosed acquisition step can be repeated one or more times.

[0179] In one aspect of the disclosed method for extending subject survival, the disclosed cfDNA analysis may include next generation sequencing. In one aspect, next generation sequencing (NGS) may include the use of one or more commercially available platforms. Commercially available NGS sequencing platforms may include, for example, Guardant 360CDx (Guardant Health), Foundation OneCDx (F1CDx) (Foundation Medicine), or TempusxT (Tempus).

[0180] In one aspect of the disclosed method for extending the survival of a subject, the disclosed cancer-related genes may include ABL1, ABL2, ACO2, ACTB, ACVR1B, AKT, AKT1 AKT2, AKT3, ALK, AMER11, APC, AR, ARAF, ARFRP1, ARID1A, ARID1B, ARID2, ASK, ASPM, ASXL1, ATF1, ATF3, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXL, BAD, BAGE, BAGE2, BAP1, BARD1, BAX, BCL2, BCL2L1, BCL2L2, BCL6, BCMA, BCOR, BCORL1, BDNF, BLM, BMPR1A, BRAF, B RCA1, BRCA2, BRD4, BRIP1, BTG1, BTK, BUB1, C10ORF54, CAGE1, CARD11, CASP5, CBFB, CBL, CCL1, CCL11, CCL13, CCL14, CCL15, CCL16 , CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL7, CCL8, CCNA 2. CCNB 1. CCNB 2. CCND, CCND1, CCND2, CCND3, CCNE1, CCNE2, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD123, CD19, CD20, CD25, CD274, CD276, CD30, CD33, CD4, CD79A, CD79B, CD8, CD80, CD86, CDC, CDC2, CDC20, CDC25A, CDC25B, CDC25C, CDC42, CDC6, CDC6; CDC7, CDC73, CDCA8, CDH1, CDK12, CD K2, CDK3, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CEA, CEBPA, CFS1, CHD2, CHD4, CHEK1, CHEK2, CHK-1, CIC, CLDND1, CNE2, CREBB P, CRKL, CRLF2, CSF1, CSF1R, CSF3, CTAG1, CTAG1B, CTAG2, CTAG4, CTAG5, CTAG6, CTAG9, CTCF, CTLA4, CTNNA1, CTNNB1, CUL3, CXCL1, CXCL10, CXCL11,CXCL12、CXCL13、CXCL14、CXCL16、CXCL17、CXCL2、CXCL3、CXCL5、CXCL6、CXC L9、CXCR1、CXCR2、CXCR3、CXCR5、CXCR6、CYLD、DAXX、DCC、DDR2、DEPTOR、DIC ER1、DLD、DLST、DNMT3A、DOT1L、DUSP1、DUSP6、E2F1、EBNA1、EBNA2、EGFR、EM SY、ENOX2、EP300、EPCAM、EPHA3、EPHA5、EPHA7、EPHB1、ERBB2、ERBB3、ERBB4、 ERCC1、EREG、ERG、ERK、ERRFI1、ESR1、EWSR1、EZH2、FAM46C、FANCA、FANCC、F ANCD2、FANCE、FANCF、FANCG、FANCL、FAS、FAT1、FBXW7、FGF10、FGF14、FGF19、 FGF23、FGF3、FGF4、FGF6、FGFR、FGFR1、FGFR2、FGFR3、FGFR4、FH、FLCN、FLI1 、FLT1、FLT3、FLT4、FOLH1、FOLR1、FOXL2、FOXP1、FRS2、FUBP1、GABRA6、GADD4 5A、GAGE1、GAGE10、GAGE12D、GAGE12F、GAGE12J、GAGE13、GAGE2A、GAGE2B、GAGE2C、GAGE2D、GAGE2E、GAGE4、GART、GATA1、GATA2、GATA3、GATA4、GATA6、G ID4、GLI1、GNA、GNA11、GNA13、GNAQ、GNAS、GPNMB、GPR124、GRIN2A、GRM3、GS K3B、H3F3A、HAVCR2、HDAC、HDAC1、HDAC5、HGF、HHLA2、HIF1、HIF1A、HIST1H1D 、HNF1A、HRAS、HSD3B1、HSP90AA1、ICOSLG、IDH1、IDH2、IDH3A、IDH3B、IDO、I GF1R、IGF2、IKBKE、IKZF1、IL1、IL15、IL1A、IL1B、IL6、IL7R、IL8、INHBA、INP P4B、IRF2、IRF4、IRS2、JAK1、JAK2、JAK3、JUN、KDM5A、KDM5C、KDM6A、KDR、KE AP、KEL、KIT、KLHL6、KLK3、KRAS、LAG1、LAG3、LMO1、LMP1、LRP1B、LYN、LZTR1、MAD2L1、MAGEA1、MAGEA10、MAGEA12、MAGEA2、MAGEA3、MAGEA4、MAGEA5、MAGEA6、MAGEA7、MAGEA8、MAGEA9、MAGEB1、MAGEB10、MAGEB16、MAGEB18、MAGEB2、MAGEB3、MAGEB4、MAGEB6、MAGEC1、MAGEC2、MAGEC3、MAGED1、MAGED2、MAGED4、MAGED4B、MAGEE1、MAGEE2、MAGEF1、MAGEH1、MAGEL2、MAGI2、MAP2K1、MAP2K2、MAP2K4、MAP3K1、MAP3K6、MAPK、MCL1、MCM、MCM2、MCM3、MCM4、MCM5、MCM6、MCM7、MDH1、MDM2、MDM4、MED12、MEF26、MEF2B、MEN1、MET、MITF、MLH1、MLL、MLL2、MLL3、MPL、MRE11A、MSH2、MSH6、MTOR、MUC1、MUTYH、MYC、MYCL、MYCN、MYD88、MYH、MYST3、NCR3LG1、Netrin、NF1、NF2、NFE2L2、NFKB、NFKB1A、NGF、NKX2-1、NOTCH1、NOTCH2、NOTCH3、NPM1、NRAS、NSD1、NTRK1、NTRK2、NTRK3、NUP93、OGDH、ORC、ORC1、ORC1L、ORC1L;、ORC6L、ORCL、ORCLPCNA、PAK3、PALB2、PAPPA、PARK2、PAX、PAX3、PBRM1、PCNA、PDCD1、PDCD1LG2、PDGFRA、PDGFRB、PDHA1、PDK1、PGR、PIK3C2B、PIK3CA、PIK3CB、PIK3CG、PIK3R1、PIK3R2、PIK3RI、PKMYT、PKMYT1、PLCG2、PLK1、PMS2、POLD1、POLE、PPM1A、PPP2R1A、PREX2、PRKAR1A、PRKC1、PRKDC、PRSS8、PTCH1、PTEN、PTPN1、PTPN11、PTPRR、PTTG、PTTG1、PTTG2、PTTG3、QK1、RAC1、RAD50、RAD51、RAF1、RANBP1、RARA、RAS、RB1、RBL1、RBM10、RET、RICTOR、RIT1、RNF43、ROS1、RPTOR、RUNX1、RUNX1T1、SDHA、SDHB、SDHC, SDHD, SETD2, SF3B1, SKP2, SLAMF7, SLIT2, SMAD2, SMAD3, SMAD4, SMARCA4, SMARCB1, SMC1A, SMC1L1, SMO, SNCAIP, SOCS1, SOX10, SOX2, SOX9, SPAG1, SPAG11A, SPAG11B, SPAG16, SPAG17, SPAG4 , SPAG5, SPAG6, SPAG7, SPAG8, SPAG9, SPEN, SPOP, SPTA1, SRC, SRSF2, STAG2, STAT3, STAT4, STAT5, STAT5B, STK11, SUCLG1, SUCLG2, SUFU, SYK, T(BRACHYURY), TAF1, TBC1D8, TBX3, TERC, TERT, TERT promoter, TET2, TFDP1, TGFRB2, TNFAIP3, TNFRSF14, TOP1, TOP2A, TOP2B, TP53, TRIB3, TSC1, TSC2, TSHR, TUBB3, TYMP, TYMS, U2AF1, UNC5A, UNC5B, VEGFA, VHL, VTCN1, WEE1, WISP3, WT1, XAGE1D, XAGE2, XAGE3, XAGE5, XCL1, XCL2, XCR1, XPO1, ZBTB2, ZNF217, ZNF703, or any combination thereof.

[0181] In one aspect, the disclosed cancer-associated genes may include one or more genomic aberrations. In one aspect, the subject may have one or more genomic aberrations in the disclosed cancer-associated genes.

[0182] In one aspect, the disclosed ALK gene can encode an ALK protein having an I1461L or N1544K mutation. In one aspect, the disclosed ARID2 gene can encode an ARID2 protein having an N127fs18 mutation. In one aspect, the disclosed AKT1 gene can encode an AKT1 protein having an E17K or R346H mutation. In one aspect, the disclosed APC gene can encode an APC protein having G29G, K445K, V2716L, E918E, Q1378*, S457*, I1304fs, E888fs, R230C, Q1090Q, S1360P mutations. In one aspect, the disclosed gene can encode an AR protein having an A356EM887V or S510R mutation. In one aspect, the disclosed ARAF gene can encode an ARAF protein having a Y495Y mutation. In one aspect, the disclosed ARID1A gene may encode an ARID1A protein having an S1798L, S1167F, G246V, R1889W, or Q802fs mutation. In one aspect, the disclosed ARID2 gene may encode an ARID2 protein having an N127fs18 mutation. In one aspect, the disclosed ARTX gene may have an S850fs*2 or N179fs*26 mutation. In one aspect, the disclosed ASXL1 gene may have an R1273f*s mutation. In one aspect, the disclosed BRAF gene may encode a BRAF protein having an E264 or V600E mutation. In one aspect, the disclosed BRCA1 gene may encode a BRAC1 protein having an H662Q or R1443* mutation. In one aspect, the disclosed BRCA2 gene may encode a BRCA2 protein having a D237N or I2040V mutation. In one aspect, the disclosed CCND1 gene may encode a CCND1 protein having an R291W mutation. In one aspect, the disclosed CCNE1 gene may encode a CCNE1 protein having a P268P or R95Q mutation. In one aspect, the disclosed CDKN1B gene may encode a CDKN1B protein having a K59fs* mutation. In one aspect, the disclosed CDKN2A gene may encode a CDKN2A protein having a D74N mutation. In one aspect, the disclosed CTNNB1 gene may encode a CTNNB1 protein having a T41A mutation. In one aspect, the disclosed DDR2 gene may encode a DDR2 protein having an L749L mutation. In one aspect, the disclosed EGFR gene may encode an EGFR protein having a P753L, V524I, D321D, or V7421 mutation. In one aspect, the disclosed ERBB2 gene may encode an ERBB2 protein having a C584G or V797del (exon 20 deletion) mutation. In one aspect, the disclosed EWSR1 gene can encode an EWSR1 protein with a FLI1 fusion.In one aspect, the disclosed FBXW7 gene can encode an FBXW7 protein having a Y545C or R658* mutation. In one aspect, the disclosed FGFR gene can encode an FGFR protein having a T320T, S726F, H791H, P47P, S430fs, or R179H mutation. In one aspect, the disclosed FGFR1 gene can encode an FGFR1 protein having an S726F mutation. In one aspect, the disclosed FGFR2 gene can encode an FGFR2 protein having a KCNH7 fusion. In one aspect, the disclosed FGFR3 gene can encode an FGFR3 protein having an H290Y mutation. In one aspect, the disclosed GATA3 gene can encode a GATA3 protein having a P433fs43, P409fs, PS405fs, D336fs, S430fs, or c.1213_1214del mutation. In one aspect, the disclosed GNA11 gene can encode a GNA11 protein having an N244S mutation. In one aspect, the disclosed GNAS gene can encode a GNAS protein having an R201H* mutation. In one aspect, the disclosed HIST1H1D gene can encode a HIST1H1D protein having a K185-A186>T mutation. In one aspect, the disclosed H3F3A gene can encode an H3F3A protein having a K28N or K27 mutation. In one aspect, the disclosed IDH1 gene can encode an IDH1 protein having an R132H mutation. In one aspect, the disclosed JAK2 gene can encode a JAK2 protein having a V617 mutation. In one aspect, the disclosed KIT gene has Q 775fs (exon 16 deletion). In one aspect, the disclosed ARID1A gene can encode an ARID1A protein having an S1798L, S1167F, G246V, R1889W, or Q802fs mutation. In one aspect, the disclosed KRAS gene can encode a KRAS protein having a G12V, G12D, G12S, G13D, or p.AG11GD mutation. In one aspect, the disclosed MAP2K1 gene can encode a MAP2K1 protein having a K57E mutation. In one aspect, the disclosed MAP2K4 gene has a deletion of exon 2. In one aspect, the disclosed MAP3K1 gene can encode a MAP3K1 protein having an S398 mutation. In one aspect, the disclosed MAP3K6 gene can encode a MAP3K6 protein having a P646L mutation. The disclosed MET gene can encode a MET protein having a C385Y, T895M, T7591, or M391 mutation. In one aspect, the disclosed MPL gene can encode an MPL protein having a Y591D mutation. In one aspect, the disclosed MYC gene can encode a MYC protein having an S244S mutation.In one aspect, the disclosed NF1 gene has splice site 480-11_4801del11, splice site SNV, c.6655>T, p.D2219Y, V2378fs*8, or can encode A2617A, F710C, I1719T, or K583R mutations. In one aspect, the disclosed NOTCH1 gene can encode a NOTCH1 protein having an A465V, V220M, D1681H, or S223N mutation. In one aspect, the disclosed NOTCH2 gene can encode a NOTCH2 protein having an S2379F mutation. In one aspect, the disclosed NTRK1 gene can encode an NTRK1 protein having a P387L or R766Q mutation. In one aspect, the disclosed PDGFRA gene can encode a PDGFRA protein having an E86A or V299G mutation. In one aspect, the disclosed PIK3CA gene can encode a PIK3CA protein having a Q546H, Q546K, Q546R, Q597H, E542K, E545K, E726K, E39K, E453K, R4-P18del, H1047L, H104R, K567E, I1543I, p.E545K, or G1049R mutation. In one aspect, the disclosed PIK3R1 gene can encode a PIK3R1 protein having a S399Y408del splice site 917-1G>A mutation. In one aspect, the disclosed PTCH1 has a p.M17 start loss-LOF. In one aspect, the disclosed PTEN gene can encode a PTEN protein having H196_1203DEL, R55fs, N323fs*23, Y27C, R130*, C136Y, D252Y, or exon 4-7 deletion mutations. In one aspect, the disclosed RAF1 gene can encode a RAF1 protein having a P63P mutation. In one aspect, the disclosed RB1 gene can encode an RB1 protein having a Q217*, Y173fs*, or H673fs mutation. In one aspect, the disclosed RUNX1 gene can encode a RUNX1 protein having an R107C mutation. In one aspect, the disclosed SMAD4 gene can encode a SMAD4 protein having a P511L, D537V, Q450H, L495R, A451P, or A406T mutation. In one aspect, the disclosed SPEN gene can encode a SPEN protein having an A2510V mutation. In one aspect, the disclosed SRSF2 gene can encode an SRSF2 protein having a P95H mutation. In one aspect, the disclosed STAT5B gene can encode a STAT5B protein having an R110H mutation. In one aspect, the disclosed TET2 gene can encode a TET2 protein having a C1875G mutation.In one aspect, the disclosed TP53 gene can encode a TP53 gene having V73fs, R175G, R196, R249T, C176F, G187D, R282W, E287*, E285K, S241del, c.97-2899del, Y126D, R273H, C176W, K320*, T253A, splice site 37G-1G>AA, Q104, P151 H, H179Y, R273C, R248W, R176H, R209fscer, N235-Y236del, R248Qer, R306*, C176Y, S241F, L252-1254del, L145P, R158H, R213*, Y220C, R110P, V274G, or c.376-4_384del mutated TP53 protein.

[0183] For the Guardant 360 platform, genomic aberrations in disclosed cancer-associated genes can include single nucleotide variations. For example, in one aspect, the disclosed single nucleotide variations can be identified in AKT1, ALK, APC, AR, ARAF, ATM, BRAF, BRCA1, BRCA2, CCND1, CDH1, CDK4, CDK6, CDK12, CDKN2A, CTNNB1, EGFR, ERBB2, ESR1, FGFR1, FGFR2, FGFR3, GATA3, GNA11, GNAQ, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MAP2K2, MET, MLH1, MTOR, MYC, NF1, NFE2L2, NRAS, NTRK1, NTRK3, PDGFRA, PIK3CA, PTEN, RAF1, RET, RHEB, ROS1, SMAD4, SMO, STK11, TERT, TSC1, VHL, or any combination thereof. For the Guardant 360 platform, the genomic aberrations in the disclosed cancer-related genes may include insertions and / or deletions. For example, in one aspect, the disclosed insertions and deletions (Indels) can be confirmed in the following genes: AKT1, ALK, APC, ATM, BRAF, BRCA1, BRCA2, CDH1, CDK12, CDKN2A, EGFR, ERBB2, ESR1, FGFR2, GATA3, HNF1A, HRAS, KIT, KRAS, MET, MLH1, NF1, PDGFRA, PIK3CA, PTEN, RET, ROS1, STK11, TSC1, VHL, or any combination thereof. For the Guardant 360 platform, in one aspect, the genomic aberrations in the disclosed cancer-related genes may include copy number amplification (CNA). For example, in one aspect, the disclosed CNA can be confirmed in the following genes: ERBB2 and / or MET. For the Guardant 360 platform, in one aspect, the disclosed fusions can include ALK, NTRK1, RET, ROS1, or any combination thereof.

[0184] For the Foundation platform, in one aspect, the genomic aberrations in the disclosed cancer-related genes can include substitutions, indels, or copy number amplifications. For example, in one aspect, the disclosed substitutions, disclosed indels, or disclosed CNAs can be confirmed in the following genes: ABL1, ACVR1B, AKT1, AKT2, AKT3, ALK, ALOX12B, AMER1 (FAM723B), APC, AR, ARAF, ARFRP1, ARID1A, ASXL1, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXL, BAP1, BARD1, BCL2, BCL2L1, BCL2L2, BCL6, BCOR, BCORL1, BRAF, BRCA1, BRCA2, BRD4, BR IP1, BTG1, BTG2, BTK, C11ORF30(EMSY), CALR, CARD11, CASP8, CBFB, CBL, CCND1, CCND2, CCND3, CCNE1, CD22, CD274(PD-L7), CD70, CD79A, CD79B , CDC73, CDH1, CDK12, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CEBPA, CHEK7, CHEK2, CIC, CREBBP, CRKL, CSFIR, CSF3R, CTCF , CTNNA1, CTNNB1, CUL3, CUL4A, CXCR4, CYP17A1, DAXX, DDR1, DDR2, DIS3, DNMT3A, DOT1L, EED, EGFR, EP300, EPHA3, EPHB1, EPHB4, ERBB2, ERBB3 , ERBB4, ERCC4, ERG, ERRFI1, ESR1, EZH2, FAM46C, FANCA, FANCC, FANCG, FANCL, FAS, FBXW7, FGF10, FGF12, FGF14, FGF19, FGF23, FGF3, FGF4, FGF 6. FGFR1, FGFR2, FGFR3, FGFR4, FH, FLCN, FLT1, FLT3, FOXL2, FUBP1, GABRA6, GATA3, GATA4, GATA6, GID4(C17ORF39), GNA11, GNA13, GNAQ, GNAS, GRM3, GSK3B, H3F3A, HDAC1, HGF, HNF1A, HRAS, HSD3B1, ID3, IDH1, IDH2, IGF1R, IKBKE, IKZF1, INPP4B, IRF2, IRF4, IRS2, JAK1, JAK2, JAK3, JUN,KDM5A、KDM5C、KDM6A、KDR、KEAP1、KEL、KIT、KLHL6、KMT2A(MLL)、KMT2D( MLL2)、KRAS、LTK、LYN、MAF、MAP2K1(MEK1)、MAP2K2(MEK2)、MAP2K4、MAP 3K1、MAP3K13、MAPK1、MCL1、MDM2、MDM4、MED12、MEF2B、MEN1、MERTK、MET 、MITF、MKNK1、MLH1、MPL、MRE11A、MSH2、MSH3、MSH6、MST1R、MTAP、MTOR、 MUTYH、MYC、MYCL(MYCL1)、MYCN、MYD88、NBN、NF1、NF2、NFE2L2、NFKBIA、 NKX2-1、NOTCH1、NOTCH2、NOTCH3、NPM1、NRAS、NT5C2、NTRK1、NTRK2、NTR K3、P2RY8、PALB2、PARK2、PARP1、PARP2、PARP3、PAX5、PBRM1、PDCD1(PD- 1)、PDCD1LG2(PD-L2)、PDGFRA、PDGFRB、PDK1、PIK3C2B、PIK3C2G、PIK3CA 、PIK3CB、PIK3R1、PIM1、PMS2、POLD1、POLE、PPARG、PP2R1A、PPP2R2A、PR DM1、PRKAR1A、PRKCI、PTCH1、PTEN、PTPN11、PTPRO、OKI、RAC1、RAD21、RA D51、RAD51B、RAD51C、RAD51D、RAD52、RAD54L、RAF1、RARA、RB1、RBM10、R EL、RET、RICTOR、RNF43、ROS1、RPTOR、SDHA、SDHB、SDHC、SDHD、SETD2、SF 3B1、SGK1、SMAD2、SMAD4、SMARCA4、SMARCB1、SMO、SNCAIP、SOCS1、SOX2、 SOX9、SPEN、SPOP、SRC、STAG2、STAT3、STK11、SUFU、SYK、TBX3、TEK、TET2 、TGFBR2、TIPARP、TNFAIP3、TNFRSF14、TP53、TSC1、TSC2、TYRO3、U2AF1、 VEGFA、VHL、WHSC1(MMSET)、WHSC1L1、WT1、XPO1、XRCC2、ZNF217、ZNF703、Or any combination thereof. For the Foundation platform, the disclosed genomic aberrations of cancer-related genes may include rearrangements. For example, in one aspect, the disclosed rearrangements may be confirmed in the following genes: ALK, BCL2, BCR, BRAF, BRCA1, BRCA2, CD74, EGFR, ETV4, ETVs, ETV6, EWSRI, EZR, FGFR1, FGFR2, FGFR3, KIT, KMT2A (MLL), MSH2, MYB, MYC, NOTCH2, NTRKI NTRK2 NUTMI, PDGFRA, RAFT, RARA, RET, ROS1, RSPO2 SDC4, SLC34A2TERC (ncRNA), TERT (promoter only), TMPRSS2, or any combination thereof. ,

[0185] For the Tempus platform, in one aspect, the disclosed genomic aberrations of cancer-related genes can include rearrangements. For example, in one aspect, the disclosed rearrangements can be confirmed in the following genes: ABL1, ALK, BCR, BRAF, EGFR, ETV6, EWSR1, FGFR2, FGFR3, MYB, NRG1, NTRK1, NTRK2, NTRK3, PAX8, PDGFRA, PML, RARA, RET, ROS1, TFE3, TMPRSS2, or any combination thereof. For the Tempus platform, in one aspect, the disclosed genomic aberrations of cancer-related genes can include single nucleotide variations, indels, or copy number amplifications. For example, in one aspect, a disclosed single nucleotide variation, a disclosed indel, or a disclosed CNA can be identified in the following genes: ABCB1, ABCC3, ABL1, ABL2, ABRAXAS1, ACTA2, ACVR1, (ALK2), ACVR1B, AGO1, AJUBA, AKT1, AKT2, AKT3, ALK, AMER1, APC, APLNR, APOB, AR, ARAF, ARHGAP26, ARHGAP35, ARID1A, ARID1B, ARID2, ARID5B, ASNS, ASPSCR1, ASXL1, ATIC, ATM, ATP7B, ATR, ATRX, AURKA, AURKB, AXIN1, AXIN2, AXL, B2M , BAP1, BARD1, BCL10, BCL11B, BCL2, BCL2L1, BCL2L11, BCL6, BCL7A, BCLAF1, BCOR, BCORL1, BCR, BIRC3, BLM, BMPR1A , BRAF, BRCA1, BRCA2, BRD4, BRIP1, BTG1, BTK, BUB1B, C11orf65, C3orf70, C8orf34, CALR, CARD11, CARM1, CASP8, C ASR, CBFB, CBL, CBLB, CBLC, CBR3, CCDC6, CCND1, CCND2, CCND3, CCNE1, CD19, CD22, CD274, (PD-L1), CD40, CD70, CD7 9A, CD79B, CDC73, CDH1, CDK12, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2B, CDKN2C, CEBPA, CEP57 , CFTR, CHD2, CHD4, CHD7, CHEK1, CHEK2, CIC, CIITA, CKS1B, CREBBP, CRKL, CRLF2, CSF1R, CSF3R, CTC1, CTCF, CTLA4,CTNNA1, CTNNB1, CTRC, CUL1, CUL3, CUL4A, CUL4B, CUX1, CXCR4, CYLD, CYP1B 1. CYP2D6, CYP3A5, CYSLTR2, DAXX, DDB2, DDR2, DDX3X, DICER1, DIRC2, DIS3 DIS3L2, DKC1, DNM2, DNMT3A, DOT1L, DPYD, DYN, C2H1, EBF1, ECT2L, EGF, EG FR EGLN1 EIF1AX ELF3 ELOC (TCEB1) EMSY ENG EP300 EPCAM EPHA2 EP HA7, EPHB1, EPHB2, EPOR, ERBB2, (HER2), ERBB3, ERBB4, ERCC1, ERCC2, ERCC 3. ERCC4, ERCC5, ERCC6, ERG, ERRFI1, ESR1, ETS1, ETS2, ETV1, ETV4, ETV5, E TV6, EWSR1, EZH2, FAM46C, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FAN CG, FANCI, FANCL, FANCM, FAS, FAT1, FBXO11, FBXW7, FCGR2A, FCGR3A, FDPS, F GF1, FGF10, FGF14, FGF2, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9 FGFR1, FGFR2, FGFR3, FGFR4, FH, FHIT, FLCN, FLT1, FLT3, FLT4, FNTB, FOXA1 FOXL2, FOXO1, FOXO3, FOX, P1, FOXQ1, FRS2, FUBP1, FUSG6PD, GABRA6, GALN T12、GATA1、GATA2、GATA3、GATA4、GATA6、GEN1、GLI1、GLI2、GNA11、GNA13、GN AQ, GNAS, GPC3, GPS2, GREM1, GRIN2A, GRM3, GSTP1, H19, H3F3A, HAS3, HAVCR 2. HDAC1, HDAC2, HDAC4, HGF, HIF1A, HIST1H1E, HIST1H3B, HIST1H4E, HLA-A 、SON-B、SON-C、SON-DMA、SON-DMB、SON-DOA、SON-DOB、SON-DPA1、SON-DPB1 HLA-DPB2、HLA-DQA1、HLA-DQA2、HLA-DQB1、HLA-DQB2、HLA-DRA、HLA-DRB1HLA-DRB5、HLA-DRB6、HLA-E、HLA-F、HLA-G、HNF1A、HNF1B、HOXA11、HOXB13、 HRAS、HSD11B2、HSD3B1、HSD3B2、HSP90AA1、HSPH1、IDH1、IDH2、IDO1、IFIT1 、IFIT2、IFIT3、IFNAR1、IFNAR2、IFNGR1、IFNGR2、IFNL3、IKBKE、IKZF1、IL1 0RA、IL15、IL2RA、IL6R、IL7R、ING1、INPP4B、IRF1、IRF2、IRF4、IRS2、ITPKB、 JAK1、JAK2、JAK3、JUN、KAT6A、KDM5A、KDM5C、KDM5D、KDM6A、KDR、KEAP1、KEL、KIF1B、KIT、KLF4、KLHL6、KLLN、KMT2A、KMT2B、KMT2C、KMT2D、KRAS、L2HGDH、 LAG3、LATS1、LCK、LDLR、LEF1、LMNA、LMO1、LRP1B、LYN、LZTR1、MAD2L2、MAF、 MAFB、MAGI2、MALT1、MAP2K1、MAP2K2、MAP2K4、MAP3K1、MAP3K7、MAPK1、MAX、M C1R、MCL1、MDM2、MDM4、MED12、MEF2B、MEN1、MET、MGMT、MIB1、MITF、MKI67、MLH1、MLH3、MLLT3、MN1、MPL、MRE11、MS4A1、MSH2、MSH3、MSH6、MTAP、MTHFD2、M THFR、MTOR、MTRR、MUTYH、MYB、MYC、MYCL、MYCN、MYD88、MYH11、NBN、NCOR1、N COR2、NF1、NF2、NFE2L2、NFKBIA、NHP2、NKX2-1、NOP10、NOTCH1、NOTCH2、NOTC H3、NOTCH4、NPM1、NQO1、NRAS、NRG1、NSD1、NSD2、NT5C2、NTH、L1、NTRK1、NTRK2、NTRK3、NUDT15、NUP98、OLIG2、P2RY8、PAK1、PALB2、PALLD、PAX3、PAX5、PA X7,PAX8,PBRM1,PCBP1,PDCD1,PDCD1LG2,PDGFRA,PDGFRB,PDK1,PHF6,PHG DH、PHLPP1、PHLPP2、PHOX2B、PIAS4、PIK3C2B、PI、K3、CA、PIK3CB、PI、K3、CD、PIK3CG, PI, K3, R1, PIK3R2, PIM1, PLCG1, PLCG2, PML, PMS1, PMS2, POLD1, POLE, POLH, POLQ, POT1, POU2F2, PPARA, PPARD, PPARG, PPM1D, PPP1R15A, PPP2R1A, PPP2R2A, PPP6C, PRCC, PRDM1, PREX2, PRKAR1A, PRKDC, PRKN, PRSS1, PTC, H, 1, PTCH2, PTEN, PTPN11, PTPN13, PTPN22, PTPRD, PTPRT, QKI, RAC1, RAD21, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, RAF1, RANBP2, RARA, RASA1, RB1, RBM10, RECQL4, RET, RHEB, RHOA, RICTOR, RINT1, RIT1, RNF139, RNF43, ROS1, RPL5, RPS15, RPS6KB1, RPTOR, RRM1, RSF1, RUNX1, RUNX1T1, RXRA, SCG5, SDHA, SDHAF2, SDHB, SDHC, SDHD, SEC23B, SEMA3C, SETBP1, SETD2, SF3B1, SGK1, SH2B3, SHH, SLC26A3, SLC47A2, SLC9A3R1, SLIT2, SLX4, SM, AD2, SMAD3, SMAD4, SMARCA1, SMARCA4, SMARCB1, SMARCE1, SMC1A, SMC3, SMO, SOCS1, SOD2, SOX10, SOX2, SOX9, SPEN, SPINK1, SPOP, SPRED1, SRC, SRSF2, STAG2, STAT3, STAT4, STAT5A, STAT5B, STAT6, STK11, SUFU, SUZ12, SYK, SYNE1, TAF1, TANC1, TAP1, TAP2, TARBP2, TBC1D12, TBL1XR1, TBX3, TCF3, TCF7L2, TCL1A, TERT (promoter), TET2, TFE3, TFEB, TFEC, TGFBR1, TGFBR2, TIGIT, TMEM127, TMEM173, TMPRSS2, TNF, TNFAIP3, TNFRSF14, TNFRSF17, TNFRSF9, TOP1, TOP2A, TP53, TP63, TPM1, TPMT, TRAF3, TRAF7, TSC1, TSC2, TSHR, TUSC3, TYMS, U2AF1UBE2T, UGT1A1, UGT1A9, UMPS, VEGFA, VEGFB, VHL, VSIR, WEE1, WNK1, WNK2, WRN, WT1, XPA, XPC, XPO1, XRCC1, XRCC2, XRCC3, YEATS4, ZFHX3, ZMYM3, ZNF217, ZNF471, ZNF620, ZNF750, ZNRF3, ZRSR2, or any combination thereof.

[0186] For the Tempus platform, the following apply: APC (APC-related conditions), ATM (ataxia-telangiectasia, breast cancer susceptibility, pancreatic cancer susceptibility), AXIN2 (oligodontia-colorectal cancer syndrome), BAP1 (BAP1 tumor predisposition syndrome), BARD1 (breast cancer susceptibility), BLM (Bloom syndrome), BMPR1A (juvenile polyposis), BRCA1 (hereditary breast and ovarian cancer), BRCA2 (hereditary breast and ovarian cancer, Fanconi anemia), BRIP1 (ovarian cancer susceptibility, Fanconi anemia), CDH1 (hereditary diffuse gastric cancer, breast cancer susceptibility), CDK4 (melanoma susceptibility), CDKN2A (melanoma-pancreatic cancer syndrome), CEBPA (acute myeloid leukemia), leukemia susceptibility), CHEK2 (breast cancer susceptibility, colon cancer susceptibility), DICER1 (DICER1 tumor predisposition syndrome), EGFR (lung cancer susceptibility, TKI resistance), EPCAM (Lynch syndrome), ETV6 (leukemia susceptibility, thrombocytopenia susceptibility), FH (hereditary leiomyomatosis and renal cell carcinoma), FLCN (Butter-Hoag-Dubé syndrome), GATA2 (GATA2 deficiency and susceptibility to myeloid malignancies), KIT (familial gastrointestinal stromal tumor), MAX (hereditary paraganglioma-pheochromocytoma syndrome), MEN1 (multiple endocrine neoplasia type 1), MET (hereditary papillary renal cell carcinoma), MLH1 (Lynch syndrome, constitutive mismatch repair deficiency), MSH2 (Lynch syndrome,Constitutive mismatch repair deficiency), MSH3 (MSH3-associated polyposis), MSH6 (Lynch syndrome, constitutive mismatch repair deficiency), MUTYH (MUTYH-associated polyposis), NBN (Nijmegen breakage syndrome, breast cancer susceptibility), NF1 (neurofibromatosis type 1), NF2 (neurofibromatosis type 2), NTHL1 (NTHL1 tumor syndrome, NTHL1-associated polyposis), PALB2 (breast cancer susceptibility, pancreatic cancer susceptibility, ovarian cancer susceptibility, Fanconi anemia), PDGFRA (familial gastrointestinal stromal tumor, GIST-plus syndrome syndrome), PHOX2B (neuroblastoma susceptibility), PMS2 (Lynch syndrome, constitutive mismatch repair deficiency), POLD1 (polymerase proofreading-associated polyposis), POLE (polymerase proofreading-associated polyposis), PRKAR1A (Carney complex), PTCH1 (Gorlin syndrome, basal cell nevus syndrome), PTEN (PTEN hamartoma syndrome), RAD51C (ovarian cancer susceptibility, breast cancer susceptibility, Fahr's syndrome), RAD51C (ovarian cancer susceptibility, breast cancer susceptibility, Fanconi anemia), RAD5 1D (ovarian cancer susceptibility, breast cancer susceptibility), RB1 (retinoblastoma), RET (multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma), RUNX1 (acute myeloid leukemia susceptibility), SDHA (hereditary paraganglioma-pheochromocytoma syndrome), SDHAF2 (hereditary paraganglioma-pheochromocytoma syndrome), SDHB (hereditary paraganglioma-pheochromocytoma syndrome), SDHC (hereditary paraganglioma-pheochromocytoma syndrome), SDHD (hereditary paraganglioma-pheochromocytoma syndrome), SMAD4 (juvenile dysplasia susceptibility), Sarcoidosis, hereditary hemorrhagic telangiectasia, SMARCA4 (rhabdoid tumor predisposition syndrome), SMARCB1 (rhabdoid tumor predisposition syndrome, schwannomatosis), STK11 (Poitz-Jegger syndrome), SUFU (Gorlin syndrome, basal cell nevus syndrome), TMEM127 (hereditary paraganglioma-pheochromocytoma syndrome), TP53 (Li-Fraumeni syndrome), TSC1 (tuberous sclerosis complex), TSC2 (tuberous sclerosis complex), VHL (von Hippel-Lindau syndrome), and WT1 (WT1-related Wilms tumor).

[0187] In one aspect of the disclosed method for extending the survival of a subject, next generation sequencing may include sequencing one or more cancer-related genes. In one aspect of the disclosed method for extending the survival of a subject, sequencing one or more cancer-related genes may include confirming one or more genomic aberrations. In one aspect, the one or more genomic aberrations may include somatic genomic aberrations. In one aspect, the disclosed one or more somatic genomic aberrations may include mutations, insertions, deletions, chromosome rearrangements, copy number aberrations, or any combination thereof.

[0188] In one aspect of the disclosed method for extending the survival of a subject, the disclosed cfDNA analysis may include quantification of one or more cancer-related genes. In one aspect, if the expression and / or quantity and / or presence of one or more genomic aberrations disclosed in the biological sample before treatment is higher than the expression and / or quantity and / or presence of the same one or more genomic aberrations in the control sample, the disclosed method for extending the survival of a subject may include diagnosing that the subject needs precision cancer treatment. In one aspect, the disclosed control sample can be a sample obtained from a subject who does not have cancer. In one aspect, the disclosed control sample can be a pooled sample obtained from multiple subjects who do not have cancer.

[0189] In one aspect, if the expression and / or amount and / or presence of one or more disclosed genomic aberrations in a biological sample after treatment is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in a sample before treatment, then the disclosed methods of extending the survival of a subject may comprise continuing to administer a disclosed precision cancer therapy to the subject. In one aspect, if the expression and / or amount and / or presence of one or more disclosed genomic aberrations in a biological sample after treatment is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in a sample after a previous treatment, then the disclosed methods of extending the survival of a subject may comprise continuing to administer a disclosed precision cancer therapy to the subject.

[0190] In one aspect, the disclosed methods of extending the survival of a subject may further comprise measuring the subject's tumor response to the precision cancer therapy. In one aspect, the subject's tumor response may comprise a partial response or a complete response. In one aspect, the disclosed partial responses may comprise a decrease in tumor size or a decrease in one or more tumors by 25% or more compared to the size of the same tumor or the same tumor(s) before treatment. In one aspect, the disclosed partial responses may comprise a decrease in tumor size or a decrease in one or more tumors by 50% or more compared to the size of the same tumor or the same tumor(s) before treatment. In one aspect, the disclosed partial responses may comprise a decrease in tumor size or a decrease in one or more tumors by about 100% or more compared to the size of the same tumor or the same tumor(s) before treatment.

[0191] In one aspect, the disclosed method of extending the survival of a subject may further comprise measuring the subject's molecular response to the disclosed precision cancer therapy. In one aspect, the disclosed molecular response may comprise a reduction in the number of somatic genomic aberrations in a biological sample obtained from the subject. In one aspect, the disclosed somatic genomic aberrations may comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, fusions, or any combination thereof. In one aspect, the disclosed method of extending the survival of a subject may further comprise administering one or more additional therapeutic agents to the subject.

[0192] In one aspect, the disclosed additional therapeutic agents can include chemotherapeutic agents, monoclonal antibodies, cell cycle inhibitors, small molecules, or any combination thereof.

[0193] Monoclonal antibodies are known to those skilled in the art. Monoclonal antibodies may include, but are not limited to, ado-trastuzumab, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, cemiplimab, cetuximab, daratumumab, denosumab, denutoximab, durvalumab, elotuzumab, gemtuzumab, ibritumomab tiuxetan, inotuzumab, ipilimumab, necituzumab, nivolumab, obinutuzumab, ofatumumab, olaratumumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab, trastuzumab, or any combination thereof.

[0194] Small molecules are known to those skilled in the art. Small molecules may include, but are not limited to, abemaciclib, afatinib, alectinib, abolib, axitinib, bimetinib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, gilteritinib, cometinib, copalixoxib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelithib, encorfenib, entrectinib, erdafitinib, erlotinib, gefit ... , ibrutinib, imatinib, ivosidenib, lapatinib, larotrectinib, lenvatinib, lorlatinib, marizomib, neratinib, nilotinib, niraparib, olaparib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sorafenib, sunitinib, tazopanib, trametinib, vandetanib, vemurafenib, or any combination thereof. In one aspect, the additional therapeutic agent may include bevacizumab, pazopanib, sorafenib, dasatinib, everolimus, or any combination thereof.

[0195] For example, in one aspect, pazopanib and / or sorafenib can be orally administered to a subject at a dosage of about 1 mg / kg / day to about 12 mg / kg / day or 2 mg / kg / day to about 6 mg / kg / day. In one aspect, the disclosed optimal dose of pazopanib and / or sorafenib can be about 3 mg / kg / day. In one aspect, dasatinib can be orally administered to a subject at a dosage of about 0.3 mg / kg / day to about 2.0 mg / kg / day or about 0.7 mg / kg / day to about 1.4 mg / kg / day. In one aspect, the disclosed optimal dose of dasatinib can be about 0.7 mg / kg / day. In one aspect, everolimus can be orally administered to a subject at a dosage of about 0.03 mg / kg / day to about 0.15 mg / kg / day or about 0.03 mg / kg / day to about 0.10 mg / kg / day. In one aspect, the disclosed optimal dose of everolimus can be about 0.07 mg / kg / day. In one aspect, bevacizumab can be administered intravenously to a subject at a dose of about 2 mg / kg / day to about 15 mg / kg / day every 1 to 3 weeks or administered to a patient at a dose of about 5 mg / kg / day to about 12 mg / kg / day every 1 to 3 weeks. In one aspect, the disclosed optimal dose of bevacizumab can be administered intravenously to a subject once every 2 weeks, with an optimal dose of about 10 mg / kg / day.

[0196] In one aspect, the disclosed molecular markers can be measured from a sample by high-density expression arrays, DNA microarrays, polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), real-time quantitative reverse transcription PCR (qRT-PCR), serial analysis of gene expression (SAGE), spotted cDNA arrays, gene chips, spotted oligonucleotide arrays, microbead arrays, RNA sequencing, tiling arrays, Northern blots, hybridization microarrays, in situ hybridization, whole exome sequencing, whole genome sequencing, liquid biopsy, next generation sequencing, or any combination thereof, which can determine one or more appropriate precision cancer treatments in one or more of the disclosed methods.

[0197] In one aspect, the disclosed molecular markers for one or more suitable precision cancer treatments for the disclosed methods of extending subject survival can be determined based on the nucleic acid sequence of at least one of circulating DNA and / or RNA. In one aspect, the disclosed molecular markers can be assessed from circulating tumor DNA and / or RNA (ctDNA and / or ctRNA); circulating cell-free DNA and / or RNA (cfDNA, cfRNA); or any combination thereof. ctDNA / ctRNA refers to DNA fragments in the blood that are not associated with cells and are derived from tumors. cfDNA / cfRNA refers to DNA that circulates freely in the bloodstream, but is not necessarily derived from tumors. In one aspect, cfDNA / ctDNA may include any complete or fragmented genomic DNA or mitochondrial DNA, and / or cfRNA / ctRNA may include mRNA, tRNA, microRNA, small interfering RNA, long non-coding RNA (lncRNA). In one aspect, cfRNA and / or ctRNA may be fragmented DNA having a length of at least about 50 base pairs (bp), about 100bp, about 200bp, about 500bp, or about 1kbp. In one aspect, cfDNA / ctDNA can be the full length or fragment of mRNA (e.g., at least 70% of the full length, at least 50% of the full length, at least 30% of the full length, etc.). In one aspect, the disclosed molecular markers can be directed against any cancer-related gene disclosed herein.

[0198] In one aspect, the disclosed method of extending the survival of a subject may further comprise surgically removing one or more tumors of the subject. In one aspect, the disclosed method of extending the survival of a subject may further comprise repeating one or more disclosed steps of the disclosed method.

[0199] For example, in one aspect, repeating one or more disclosed steps of the disclosed method of extending survival in a subject can comprise repeatedly administering a precision cancer therapy to the subject, repeatedly measuring a tumor response in the subject, repeatedly obtaining a biological sample from the subject, repeatedly performing cfDNA analysis on the biological sample, repeatedly administering one or more additional therapeutic agents, or any combination thereof.

[0200] In one aspect, the disclosed molecular markers can be detected, quantified and / or analyzed over time (at different time points) to determine the effectiveness of the disclosed precision cancer treatment (such as AS therapy) on the subject and / or determine the response of the subject or the subject's tumor to the precision cancer treatment (such as the development of drug resistance, susceptibility, etc.). In one aspect, the disclosed method of extending the survival of a subject may include obtaining multiple measurements from the same subject over time, and the same sample can be quantified at a single time point or over time. In one aspect, the treatment of the disclosed treatment regimen (e.g., the disclosed precision cancer treatment comprising one or more antineoplastons) can be designed and / or determined based on the cancer status and / or the change / type of one or more molecular markers. In one aspect, the likelihood of success of the disclosed precision cancer treatment can be determined based on the cancer status and the type / quantity of one or more molecular markers.

[0201] In one aspect, the disclosed molecular markers can be derived from genes expressed in one or more cells of a tumor or in immune cells and can indicate an immunosuppressive tumor microenvironment, the development of cancer severity, the occurrence of metastasis, the cancer state, or any combination thereof. In one aspect, the disclosed molecular markers can be proteins or peptides encoded by the genes from which the molecular markers are derived and can be targeted by antagonists or any other type of binding molecules to inhibit the function of the polypeptide.

[0202] Thus, in one aspect, increased expression of the disclosed molecular markers derived from the disclosed genes associated with an immunosuppressive tumor microenvironment (e.g., above a predetermined threshold) may indicate the presence of an immunosuppressive tumor microenvironment, and may also indicate that antagonists of peptides encoded by genes associated with an immunosuppressive tumor microenvironment are likely to inhibit the progression of cancer by suppressing the immunosuppressive tumor microenvironment and further promoting the activity of immune cells against tumor cells in such a microenvironment. In one aspect, once a molecular marker has been identified, any suitable antagonist targeting a gene or protein may be used. For example, in one aspect, a kinase inhibitor may target a specific kinase, a synthetic ligand may target a specific signaling receptor, or a synthetic antagonist or antibody may target a specific checkpoint receptor, etc. In one aspect, the target molecule antagonists disclosed herein may be administered before, after, or in combination with AS treatment.

[0203] In one aspect, the subject can be a human patient. In one aspect, the subject can be of any age (e.g., elderly, adult, youth, adolescent, child, puberty, child, toddler, infant, or newborn), male or female, of any nationality, of any ethnicity, and / or of any race. In one aspect, the subject can have terminal cancer.

[0204] In one aspect, the subject has not received treatment prior to administering the disclosed precision cancer treatment to the disclosed subject. In one aspect, the subject has received treatment prior to administering the disclosed precision cancer treatment to the disclosed subject. In one aspect of the disclosed method of extending the survival of a subject, the subject has received surgery, antibody therapy, chemotherapy, radiation therapy, immunotherapy, or any combination thereof prior to administering the disclosed precision cancer treatment. In one aspect of the disclosed method of extending the survival of a subject, the subject in need thereof has been diagnosed with cancer, or the subject in need thereof is suspected of having cancer.

[0205] In one aspect, the disclosed cancers may be refractory cancers or refractory diseases. In one aspect, "refractory" refers to a cancer and / or tumor that is unresponsive to treatment and / or develops resistance. In one aspect, the subject may have a recurrent disease. In one aspect, "relapse" or "recurrent" refers to the return or development of a tumor after improvement (e.g., a partial or complete response) with treatment. In one aspect, the disclosed cancers may include solid tumors. In one aspect, the disclosed cancers may include metastatic cancers. In one aspect, the disclosed cancers may include terminal cancers.

[0206] In one aspect, the disclosed cancers may include adenocarcinoma (including appendix and cervix), adenoid cystic epithelial carcinoma, adult T-cell leukemia, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, astrocytoma, basal cell carcinoma, B-cell carcinoma, benign and malignant lymphoma, biliary tract-cholangiocarcinoma, intestinal cancer, brain cancer (including anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, brainstem anaplastic astrocytoma, brainstem glioma, diffuse astrocytoma, DIPG H3K27 mutation, ganglioglioma, glioblastoma multiforme, medulloblastoma, pilocytic astrocytoma, brainstem glioma), breast cancer, breast cancer, breast cancer, and ovarian cancer. carcinoma), Burkitt lymphoma, bladder cancer and urothelial carcinoma, epithelial carcinoma of unknown primary site, carcinosarcoma, cervical cancer, cholangiocarcinoma, chronic atypical myeloid leukemia, chronic atypical myeloid leukemia, colon cancer, colorectal cancer, diffuse astrocytoma, diffuse intrinsic pontine glioma (DIPG), endometrial cancer, endometrial epithelial carcinoma, ependymoma, esophageal cancer and esophageal epithelial carcinoma, Ewing sarcoma, ganglioglioma, ganglioneuroma Glioblastoma, Gastrointestinal Stromal Tumor (GIST), Glioblastoma, Glioma, Head and Neck Cancer and Head and Neck Epithelial Cancer, Angiosarcoma, Hepatocellular Carcinoma, Renal Cell Carcinoma, Hodgkin's Disease, Kaposi's Sarcoma, Kidney Cancer and Renal Epithelial Cancer, Large B-Cell Lymphoma, Leptomeningeal Carcinomatosis, Leukemia, Liposarcoma, Hepatocellular Carcinoma, Lung Cancer (Non-Small Cell and Small Cell), Medulloblastoma, Melanoma, Meningeal Sarcoma, Meningioma, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative Disorders Diseases, myositis, neuroblastoma, neuroendocrine epithelial cancer, neurofibroma, non-Hodgkin's lymphoma, oligodendroglioma, osteosarcoma, ovarian cancer and ovarian epithelial cancer, pancreatic cancer and pancreatic epithelial cancer, peripheral neuroepithelial tumor, peripheral T-cell lymphoma, Philadelphia chromosome positive and positive CML, pilocytic astrocytoma, pineal cell tumor, pleomorphic sarcoma, pre-B lymphoma, primitive neuroectodermal tumor (PNET), prostate cancer and prostatic epithelial cancer, Refractory anemia, salivary gland epithelial cancer, sarcoma, Schwannoma, skin cancer and skin epithelial cancer, squamous cell epithelial cancer, gastric cancer and gastric epithelial cancer, synovial sarcoma, testicular cancer, thyroid cancer and thyroid epithelial cancer, T-line acute lymphoblastic leukemia (T-ALL), T-line lymphocytic lymphoma (T-LL), urinary tract cancer and urinary tract high-grade epithelial cancer, uterine, cervical, vulvar and / or endometrial epithelial cancer, Wilms' tumor or teratoma, or any combination thereof.

[0207] In one aspect, the disclosed cancers can include breast cancer, colorectal cancer, head and neck cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, brain cancer, adenoid cystic carcinoma, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, brain stem glioma, diffuse astrocytoma, diffuse intrinsic pontine glioma (DIPG), ganglioglioma, medulloblastoma, pilocytic astrocytoma, cholangiocarcinoma, chronic atypical myeloid leukemia, endometrial carcinoma, esophageal cancer, Ewing sarcoma, gastrointestinal stromal tumor (GIST), leptomeningeal carcinomatosis, multiple myeloma, myelodysplastic syndrome, neuroendocrine epithelial cancer, non-Hodgkin's lymphoma, pleomorphic sarcoma, primitive neuroectodermal tumor (PNET), refractory anemia, salivary gland epithelial cancer, skin cancer, gastric cancer, thyroid cancer, urinary tract cancer, or any combination thereof.

[0208] In one aspect, the disclosed method for extending the survival of a subject may further include monitoring the subject for adverse reactions (e.g., liver damage, blood toxicity, nervous system toxicity, skin toxicity, gastrointestinal toxicity, or any combination thereof). In one aspect, in the absence of adverse reactions, the disclosed method for extending the survival of a subject may further include continuing to administer the disclosed precision cancer treatment to the subject. In one aspect, in the presence of adverse reactions, the disclosed method for extending the survival of a subject may further include modifying one or more disclosed steps of the disclosed method. In one aspect, the disclosed method for extending the survival of a subject may further include treating one or more adverse reactions.

[0209] In one aspect, the disclosed method of extending the survival of a subject can include modifying the disclosed administering step. In one aspect, modifying the disclosed administering step can include changing the amount of one or more antineoplastons or compositions comprising one or more antineoplastons administered to the subject, changing the frequency of administering one or more antineoplastons or compositions comprising one or more antineoplastons to the subject, changing the duration of administering one or more antineoplastons or compositions comprising one or more antineoplastons to the subject, changing the route of administration of one or more antineoplastons or compositions comprising one or more antineoplastons to the subject, or any combination thereof.

[0210] In one aspect, the disclosed method for extending the survival of a subject may further include obtaining a tissue biopsy from the subject. In one aspect, the disclosed tissue biopsy may be subjected to next generation sequencing. In one aspect, the disclosed method for extending the survival of a subject may include subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known in the art. In one aspect, the disclosed non-invasive diagnostic assessments may include X-rays, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasound, positron emission tomography (PET), or any combination thereof. In one aspect, the disclosed invasive diagnostic assessments may include tissue biopsy or exploratory surgery.

[0211] In one aspect, the disclosed methods can improve the life expectancy of a subject. In one aspect, the life expectancy of a subject is compared to the life expectancy of a control. In one aspect, the control is a subject that has not received precision cancer therapy. In one aspect, the control is a pooled number of subjects that have not received precision cancer therapy. In one aspect, the control is one or more subjects with the same cancer type and the same cancer stage as the subject. In one aspect of the disclosed methods of extending the survival of a subject, the subject's cancer is treated.

[0212] In one aspect, the method can increase life expectancy compared to the cancer life expectancy of an untreated subject with the same or nearly the same disease condition and the same or nearly the same predicted outcome. As used herein, "life expectancy" is defined as the time at which 50% of subjects survive and 50% of subjects die. In one aspect, following treatment using the disclosed methods, a patient's life expectancy may be indeterminate. In one aspect, a patient's life expectancy can be increased by at least about 5% or more to at least about 100%, at least about 10% or more to at least about 95% or more, at least about 20% or more to at least about 80% or more, at least about 40% or more to at least about 60% or more, compared to an untreated subject with the same or nearly the same disease condition and the same or nearly the same predicted outcome.

[0213] In one aspect, life expectancy can be increased by at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 25% or more, at least about 30% or more, at least about 35% or more, at least about 40% or more, at least about 45% or more, at least about 50% or more, at least about 55% or more, at least about 60% or more, at least about 65% or more, at least about 70% or more, at least about 75% or more, at least about 80% or more, at least about 85% or more, at least about 90% or more, at least about 95% or more, at least about 100% compared to an untreated subject with the same or approximately the same disease condition and the same or approximately the same predicted outcome. In one aspect, life expectancy can be increased by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 50% or more to at least about 57% or more, at least about 58% or more to at least about 59% or more, at least about 60% or more to at least about 61% or more, at least about 62% or more to at least about 63% or more, at least about 64% or more to at least about 66% or more, at least about 67% or more to at least about 68% or more, at least about 69% or more to at least about 70% or more, at least about 71% or more to at least about 72% or more, at least about 73% or more to at least about 74% or more, at least about 75% or more to at least about 76% or more, at least about 77% or more to at least about 78% or more, at least about 79% or more to at least about 80% or more, at least about 81% or more to at least about 82% or more, at least about 83% or more to at least about 84% or more, at least about 85% or more to at least about 86% or more, at least about From at least about 45% or more to at least about 50% or more, at least about 50% or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100%.

[0214] In one aspect, the disclosed methods of extending the survival of a subject may include protecting the subject from metastasis. In one aspect, the disclosed methods of extending the survival of a subject may include reducing the risk of metastasis. In one aspect of the disclosed methods of extending the survival of a subject, treating cancer may include improving the survival rate of the subject, increasing the length of time before metastasis, reducing the likelihood of surgical intervention, reducing the need to administer one or more additional therapeutic agents or treatment regimens, reducing the size of one or more tumors in the subject, eliminating one or more tumors in the subject, reducing or eliminating the prevalence of one or more genomic aberrations, restoring normal metabolism in one or more organ systems in the subject, restoring one or more aspects of cellular homeostasis and / or cellular function, and / or metabolic disorders; or any combination thereof.

[0215] In one aspect of the disclosed method of extending the survival of a subject, one or more aspects of restoring cellular homeostasis and / or cellular function may include one or more of the following: (i) correcting cellular starvation of one or more cell types (such as, for example, liver cells and muscle cells, etc.); (ii) normalizing the autophagy pathway (such as, for example, correcting, preventing, reducing and / or improving autophagy, etc.); (iii) improving, enhancing, restoring and / or protecting mitochondrial function and / or structural integrity; (iv) improving, enhancing, restoring and / or protecting organelle function and / or structural integrity; (v) preventing, slowing and / or eliminating hypoglycemia, ketosis and / or other liver abnormalities; vi) correcting liver enzyme dysregulation; (vii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor metastasis; (viii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor growth and / or cancer spread, or (ix) any combination of the above. In one aspect, one or more aspects of restoring cellular homeostasis may include one or more aspects of improving, enhancing, restoring and / or maintaining cellular structural and / or functional integrity in, for example, an organ or system that has been affected by cancer.

[0216] For example, in one aspect, tumor growth can be attenuated by at least about 5% or more to at least about 100%, at least about 10% or more to at least about 95% or more, at least about 20% or more to at least about 80% or more, at least about 40% or more to at least about 60% or more, compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome. In one aspect, the growth of one or more tumors in a subject treated using the disclosed methods of extending the survival of a subject can be reduced by at least 5% (or more as described above) compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome.

[0217] In one aspect, tumor growth can be impaired by at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 25% or more, at least about 30% or more, at least about 35% or more, at least about 40% or more, at least about 45% or more, at least about 50% or more, at least about 55% or more, at least about 60% or more, at least about 65% or more, at least about 70% or more, at least about 75% or more, at least about 80% or more, at least about 85% or more, at least about 90% or more, at least about 95% or more, at least about 100% as compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome.

[0218] In one aspect, tumor growth can be attenuated by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 50% or more to at least about 56% or more, at least about 57% or more to at least about 58% or more, at least about 59% or more to at least about 60% or more, at least about 61% or more to at least about 62% or more, at least about 63% or more to at least about 64% or more, at least about 65% or more to at least about 66% or more, at least about 67% or more to at least about 68% or more, at least about 69% or more to at least about 70% or more, at least about 71% or more to at least about 72% or more, at least about 73% or more to at least about 74% or more, at least about 75% or more to at least about 76% or more, at least about 77% or more to at least about 78% or more, at least about 79% or more to at least about 80% or more, at least about 81% or more to at least about 82% or more, at least about 83% or more to at least about 84% or more, at least about 85% or more to at least about 86% or more, at least about From at least about 45% or more to at least about 50% or more, at least about 50% or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100%.

[0219] In one aspect, treating a tumor according to the methods disclosed herein (e.g., AS therapy) can reduce the tumor relative to its starting size. In one aspect, the tumor is reduced by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 45% or more to at least about 50% or more, at least about 50% or more, or at least about 50% or more, as compared to its starting size. % or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100% (referring to complete disappearance of the tumor after treatment).

[0220] In one aspect, the disclosed subject may present with one or more cancerous solid tumors, metastatic nodules, or any combination thereof. In any aspect, the subject herein may have a cancerous tumor cell of origin, which may be less than about 0.2 cm 3 to at least about 20cm 3 or larger, at least about 2 cm 3 to at least about 18cm 3 or larger, at least about 3cm 3 to at least about 15cm 3 or larger, at least about 4cm 3 to at least about 12 cm 3 or larger, at least about 5cm 3 to at least about 10 cm 3 or larger, or at least about 6cm 3 to at least about 8cm 3 or larger.

[0221] In one aspect, the disclosed methods of extending survival in a subject can comprise a pan-tumor approach, such as, for example, administering the disclosed ANP therapy.

[0222] E. Methods of preventing and / or reducing metastasis

[0223] Disclosed herein is a method of preventing and / or reducing metastasis, the method comprising administering a precision cancer therapy to a subject in need thereof, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein metastasis is prevented and / or reduced.

[0224] Disclosed herein is a method for preventing and / or reducing metastasis, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as in need of precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein metastasis is prevented and / or reduced.

[0225] Disclosed herein is a method for preventing and / or reducing metastasis, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; diagnosing the subject as being in need of precision cancer therapy when the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample; administering the precision cancer therapy to the subject; and, wherein the subject exhibits a tumor response and / or a molecular response of the subject to the precision cancer therapy, and, wherein metastasis is prevented and / or reduced.

[0226] Disclosed herein is a method for preventing and / or reducing metastasis, the method comprising obtaining a biological sample from a subject in need thereof; performing cell-free DNA (cfDNA) analysis on the biological sample; wherein, if the expression and / or amount of one or more genomic aberrations in the biological sample is higher than the expression and / or amount of the same one or more genomic aberrations in a control sample, diagnosing the subject as needing precision cancer therapy; and administering the precision cancer therapy to the subject, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy, and wherein metastasis is prevented and / or reduced.

[0227] In one aspect, the life expectancy of the subject is compared to the life expectancy of a control. In one aspect, the control is a subject who has not received the precision cancer treatment. In one aspect, the control is a pool of subjects who have not received the precision cancer treatment. In one aspect, the control is one or more subjects with the same cancer type and the same cancer stage as the subject. In one aspect of the disclosed method of preventing and / or reducing metastasis, the subject's cancer is treated.

[0228] In one aspect, the life expectancy of the subject is compared to the life expectancy of a control. In one aspect, the control is a subject who has not received the precision cancer treatment. In one aspect, the control is a pool of subjects who have not received the precision cancer treatment. In one aspect, the control is one or more subjects with the same cancer type and the same cancer stage as the subject. In one aspect of the disclosed method of preventing and / or reducing metastasis, the subject's cancer is treated.

[0229] In one aspect, the disclosed precision cancer treatments may include one or more antineoplastons, or may include compositions comprising one or more antineoplastons. In one aspect, the disclosed antineoplastons may include phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or any combination thereof. In one aspect, the disclosed compositions comprising one or more antineoplastons may include phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or any combination thereof.

[0230] In one aspect, the disclosed compositions comprising one or more antineoplastons may comprise a pharmaceutically acceptable carrier. In one aspect, the disclosed one or more antineoplastons may comprise sodium phenylacetylglutamine (PG) and sodium phenylacetylisoglutamine (iso-PG). In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may range from about 10:1 to about 1:10. In one aspect, the disclosed ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) may be about 4:1. In one aspect, the disclosed dosage of the one or more antineoplastons may comprise about 0.1 g / kg / day to about 20 g / kg / day. In one aspect, the disclosed therapeutically effective dose of one or more antineoplastons may comprise about 0.1 g / kg / day to about 20 g / kg / day. In one aspect, the disclosed dose of sodium phenylacetylglutamine (PG) may comprise about 0.4 g / kg / day to about 16 g / kg / day, and the disclosed dose of sodium phenylacetylisoglutamine (iso-PG) may comprise about 0.1 g / kg / day to about 4 g / kg / day. In one aspect, the disclosed therapeutically effective amount of sodium phenylacetylglutamine (PG) may comprise about 0.4 g / kg / day to about 16 g / kg / day, and the disclosed therapeutically effective amount of sodium phenylacetylisoglutamine (iso-PG) may comprise about 0.1 g / kg / day to about 4 g / kg / day.

[0231] In one aspect, the disclosed one or more antineoplastons can include phenylacetate (PN) and phenylacetylglutamine (PG). In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can be about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can range from about 10:1 to about 1:10. In one aspect, the disclosed ratio of phenylacetate (PN) to phenylacetylglutamine (PG) can be about 4:1. In one aspect, the disclosed dosage of the one or more antineoplastons can include about 0.08 g / kg / day to about 0.6 g / kg / day. In one aspect, the disclosed therapeutically effective dosage of the one or more antineoplastons can include about 0.08 g / kg / day to about 0.6 g / kg / day. In one aspect, disclosed dosages of phenylacetate (PN) may include about 0.064 g / kg / day to about 0.48 g / kg / day, and disclosed dosages of phenylacetamine (PG) may include about 0.016 g / kg / day to about 0.12 g / kg / day. In one aspect, disclosed therapeutically effective dosages of phenylacetate (PN) may include about 0.064 g / kg / day to about 0.48 g / kg / day, and disclosed therapeutically effective dosages of phenylacetamine (PG) may include about 0.016 g / kg / day to about 0.12 g / kg / day.

[0232] In one aspect of the disclosed method for preventing and / or reducing metastasis, administering the disclosed precision cancer treatment may comprise intravenous administration. In one aspect, the disclosed precision cancer treatment may be administered intravenously to a subject using, for example, a dual-channel infusion pump or two single-channel pumps and a central venous catheter. In one aspect, the disclosed precision cancer treatment may be administered once every four hours at an IV infusion rate of about 50 ml / hour to about 250 ml / hour (e.g., about 50, 75, 100, 125, 150, 175, 200, 225, 250 ml / hour), depending on the age and condition / tolerance of the subject.

[0233] In one aspect, the disclosed methods for preventing and / or reducing metastasis may comprise titrating the dose of the disclosed precision cancer therapy. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of A10, AS2-1, or a combination thereof. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed compositions, disclosed pharmaceutical compositions, disclosed therapeutic agents, disclosed immunomodulators, disclosed proteasome inhibitors, disclosed small molecules, disclosed endonucleases, disclosed oligonucleotides, disclosed RNA therapeutics, or any combination thereof to confirm an effective dose and / or to confirm an effective dose that causes only minor adverse reactions and / or side effects.

[0234] In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed precision cancer therapy in a specific or disclosed subject. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of A10, AS2-1, or a combination thereof in a specific or disclosed subject. In one aspect, the disclosed methods for treating and / or preventing cancer may comprise titrating the dose of the disclosed composition, the disclosed pharmaceutical composition, the disclosed therapeutic agent, the disclosed immunomodulator, the disclosed proteasome inhibitor, the disclosed small molecule, the disclosed endonuclease, the disclosed oligonucleotide, the disclosed RNA therapeutic agent, or any combination thereof to confirm an effective dose for a specific or disclosed subject and / or to confirm an effective dose that causes only mild adverse reactions and / or side effects to the subject.

[0235] In one aspect, administering comprises administering to the subject a maximum tolerated dose of A10, AS2-1, or both. In one aspect, administering comprises administering to the subject less than the maximum tolerated dose of A10, AS2-1, or both.

[0236] In one aspect, IV administration of the disclosed precision cancer treatments can include an outpatient setting. In one aspect, A10 can be administered before, concurrently, or after AS2-1. In one aspect, AS2-1 can be administered before, concurrently, or after A10. In one aspect, the order in which one or more antineoplastons are administered can be altered during a treatment regimen.

[0237] In one aspect, the disclosed method for preventing and / or reducing metastasis may further include obtaining a biological sample from the subject before administering the disclosed precision cancer treatment. In one aspect, the disclosed method for preventing and / or reducing metastasis may further include obtaining a biological sample from the subject after administering the disclosed precision cancer treatment. In one aspect, the disclosed method for preventing and / or reducing metastasis may further include performing cell-free DNA (cfDNA) analysis on the biological sample. cfDNA analysis is known to those skilled in the art. In one aspect, the disclosed cfDNA analysis can be repeated one or more times. In one aspect, the disclosed acquisition step can be repeated one or more times.

[0238] In one aspect of the disclosed method for preventing and / or reducing metastasis, the disclosed cfDNA analysis can include next generation sequencing. In one aspect, next generation sequencing (NGS) can include the use of one or more commercially available platforms. Commercially available NGS sequencing platforms can include, for example, Guardant 360CDx (Guardant Health), FoundationOneCDx (F1CDx) (Foundation Medicine), or TempusxT (Tempus).

[0239] In one aspect of the disclosed method for preventing and / or reducing metastasis, the disclosed cancer-related genes may include ABL1, ABL2, ACO2, ACTB, ACVR1B, AKT, AKT1 AKT2, AKT3, ALK, AMER11, APC, AR, ARAF, ARFRP1, ARID1A, ARID1B, ARID2, ASK, ASPM, ASXL1, ATF1, ATF3, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXL, BAD, BAGE, BAGE2, BAP1, BARD1, BAX, BCL2, BCL2L1, BCL2L2, BCL6, BCMA, BCOR, BCORL1, BDNF, BLM, BMPR1A, BRAF, B RCA1, BRCA2, BRD4, BRIP1, BTG1, BTK, BUB1, C10ORF54, CAGE1, CARD11, CASP5, CBFB, CBL, CCL1, CCL11, CCL13, CCL14, CCL15, CCL16 , CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL7, CCL8, CCNA 2. CCNB 1. CCNB 2. CCND, CCND1, CCND2, CCND3, CCNE1, CCNE2, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD123, CD19, CD20, CD25, CD274, CD276 , CD30, CD33, CD4, CD79A, CD79B, CD8, CD80, CD86, CDC, CDC2, CDC20, CDC25A, CDC25B, CDC25C, CDC42, CDC6, CDC6; CDC7, CDC73, CDCA8, CDH1, CDK12 , CDK2, CDK3, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CEA, CEBPA, CFS1, CHD2, CHD4, CHEK1, CHEK2, CHK-1, CIC, CLDND1, CNE2, CREBBP, CRKL, CRLF2, CSF1, CSF1R, CSF3, CTAG1, CTAG1B, CTAG2, CTAG4, CTAG5, CTAG6, CTAG9, CTCF, CTLA4, CTNNA1, CTNNB1, CUL3, CXCL1, CXCL10,CXCL11、CXCL12、CXCL13、CXCL14、CXCL16、CXCL17、CXCL2、CXCL3、CXCL5、CX CL6、CXCL9、CXCR1、CXCR2、CXCR3、CXCR5、CXCR6、CYLD、DAXX、DCC、DDR2、DEP TOR、DICER1、DLD、DLST、DNMT3A、DOT1L、DUSP1、DUSP6、E2F1、EBNA1、EBNA2、 EGFR、EMSY、ENOX2、EP300、EPCAM、EPHA3、EPHA5、EPHA7、EPHB1、ERBB2、ERBB3 、ERBB4、ERCC1、EREG、ERG、ERK、ERRFI1、ESR1、EWSR1、EZH2、FAM46C、FANCA、 FANCC、FANCD2、FANCE、FANCF、FANCG、FANCL、FAS、FAT1、FBXW7、FGF10、FGF14 、FGF19、FGF23、FGF3、FGF4、FGF6、FGFR、FGFR1、FGFR2、FGFR3、FGFR4、FH、FL CN、FLI1、FLT1、FLT3、FLT4、FOLH1、FOLR1、FOXL2、FOXP1、FRS2、FUBP1、GABRA 6、GADD45A、GAGE1、GAGE10、GAGE12D、GAGE12F、GAGE12J、GAGE13、GAGE2A、G AGE2B、GAGE2C、GAGE2D、GAGE2E、GAGE4、GART、GATA1、GATA2、GATA3、GATA4、G ATA6、GID4、GLI1、GNA、GNA11、GNA13、GNAQ、GNAS、GPNMB、GPR124、GRIN2A、G RM3、GSK3B、H3F3A、HAVCR2、HDAC、HDAC1、HDAC5、HGF、HHLA2、HIF1、HIF1A、HI ST1H1D、HNF1A、HRAS、HSD3B1、HSP90AA1、ICOSLG、IDH1、IDH2、IDH3A、IDH3B、IDO、IGF1R、IGF2、IKBKE、IKZF1、IL1、IL15、IL1A、IL1B、IL6、IL7R、IL8、INH BA、INPP4B、IRF2、IRF4、IRS2、JAK1、JAK2、JAK3、JUN、KDM5A、KDM5C、KDM6A、 KDR、KEAP、KEL、KIT、KLHL6、KLK3、KRAS、LAG1、LAG3、LMO1、LMP1、LRP1B、LYN、LZTR1、MAD2L1、MAGEA1、MAGEA10、MAGEA12、MAGEA2、MAGEA3、MAGEA4、MAGEA5、MAGEA6、MAGEA7、MAGEA8、MAGEA9、MAGEB1、MAGEB10、MAGEB16、MAGEB18、MAGEB2、MAGEB3、MAGEB4、MAGEB6、MAGEC1、MAGEC2、MAGEC3、MAGED1、MAGED2、MAGED4、MAGED4B、MAGEE1、MAGEE2、MAGEF1、MAGEH1、MAGEL2、MAGI2、MAP2K1、MAP2K2、MAP2K4、MAP3K1、MAP3K6、MAPK、MCL1、MCM、MCM2、MCM3、MCM4、MCM5、MCM6、MCM7、MDH1、MDM2、MDM4、MED12、MEF26、MEF2B、MEN1、MET、MITF、MLH1、MLL、MLL2、MLL3、MPL、MRE11A、MSH2、MSH6、MTOR、MUC1、MUTYH、MYC、MYCL、MYCN、MYD88、MYH、MYST3、NCR3LG1、Netrin、NF1、NF2、NFE2L2、NFKB、NFKB1A、NGF、NKX2-1、NOTCH1、NOTCH2、NOTCH3、NPM1、NRAS、NSD1、NTRK1、NTRK2、NTRK3、NUP93、OGDH、ORC、ORC1、ORC1L、ORC1L;、ORC6L、ORCL、ORCLPCNA、PAK3、PALB2、PAPPA、PARK2、PAX、PAX3、PBRM1、PCNA、PDCD1、PDCD1LG2、PDGFRA、PDGFRB、PDHA1、PDK1、PGR、PIK3C2B、PIK3CA、PIK3CB、PIK3CG、PIK3R1、PIK3R2、PIK3RI、PKMYT、PKMYT1、PLCG2、PLK1、PMS2、POLD1、POLE、PPM1A、PPP2R1A、PREX2、PRKAR1A、PRKC1、PRKDC、PRSS8、PTCH1、PTEN、PTPN1、PTPN11、PTPRR、PTTG、PTTG1、PTTG2、PTTG3、QK1、RAC1、RAD50、RAD51、RAF1、RANBP1、RARA、RAS、RB1、RBL1、RBM10、RET、RICTOR、RIT1、RNF43、ROS1、RPTOR、RUNX1、RUNX1T1、SDHA、SDHB, SDHC, SDHD, SETD2, SF3B1, SKP2, SLAMF7, SLIT2, SMAD2, SMAD3, SMAD4, SMARCA4, SMARCB1, SMC1A, SMC1L1, SMO, SNCAIP, SOCS1, SOX10, SOX2, SOX9, SPAG1, SPAG11A, SPAG11B, SPAG16, SPAG17, SP AG4, SPAG5, SPAG6, SPAG7, SPAG8, SPAG9, SPEN, SPOP, SPTA1, SRC, SRSF2, STAG2, STAT3, STAT4, STAT5, STAT5B, STK11, SUCLG1, SUCLG2, SUFU, SYK, T(BRACHYURY), TAF1, TBC1D8, TBX3, TERC, TERT, TERT promoter, TET2, TFDP1, TGFRB2, TNFAIP3, TNFRSF14, TOP1, TOP2A, TOP2B, TP53, TRIB3, TSC1, TSC2, TSHR, TUBB3, TYMP, TYMS, U2AF1, UNC5A, UNC5B, VEGFA, VHL, VTCN1, WEE1, WISP3, WT1, XAGE1D, XAGE2, XAGE3, XAGE5, XCL1, XCL2, XCR1, XPO1, ZBTB2, ZNF217, ZNF703, or any combination thereof.

[0240] In one aspect, the disclosed cancer-associated genes may include one or more genomic aberrations. In one aspect, the subject may have one or more genomic aberrations in the disclosed cancer-associated genes.

[0241] In one aspect, the disclosed ALK gene can encode an ALK protein having an I1461L or N1544K mutation. In one aspect, the disclosed ARID2 gene can encode an ARID2 protein having an N127fs18 mutation. In one aspect, the disclosed AKT1 gene can encode an AKT1 protein having an E17K or R346H mutation. In one aspect, the disclosed APC gene can encode an APC protein having G29G, K445K, V2716L, E918E, Q1378*, S457*, I1304fs, E888fs, R230C, Q1090Q, S1360P mutations. In one aspect, the disclosed gene can encode an AR protein having an A356EM887V or S510R mutation. In one aspect, the disclosed ARAF gene can encode an ARAF protein having a Y495Y mutation. In one aspect, the disclosed ARID1A gene may encode an ARID1A protein having an S1798L, S1167F, G246V, R1889W, or Q802fs mutation. In one aspect, the disclosed ARID2 gene may encode an ARID2 protein having an N127fs18 mutation. In one aspect, the disclosed ARTX gene may have an S850fs*2 or N179fs*26 mutation. In one aspect, the disclosed ASXL1 gene may have an R1273f*s mutation. In one aspect, the disclosed BRAF gene may encode a BRAF protein having an E264 or V600E mutation. In one aspect, the disclosed BRCA1 gene may encode a BRAC1 protein having an H662Q or R1443* mutation. In one aspect, the disclosed BRCA2 gene may encode a BRCA2 protein having a D237N or I2040V mutation. In one aspect, the disclosed CCND1 gene may encode a CCND1 protein having an R291W mutation. In one aspect, the disclosed CCNE1 gene may encode a CCNE1 protein having a P268P or R95Q mutation. In one aspect, the disclosed CDKN1B gene may encode a CDKN1B protein having a K59fs* mutation. In one aspect, the disclosed CDKN2A gene may encode a CDKN2A protein having a D74N mutation. In one aspect, the disclosed CTNNB1 gene may encode a CTNNB1 protein having a T41A mutation. In one aspect, the disclosed DDR2 gene may encode a DDR2 protein having an L749L mutation. In one aspect, the disclosed EGFR gene may encode an EGFR protein having a P753L, V524I, D321D, or V7421 mutation. In one aspect, the disclosed ERBB2 gene may encode an ERBB2 protein having a C584G or V797del (exon 20 deletion) mutation. In one aspect, the disclosed EWSR1 gene can encode an EWSR1 protein with a FLI1 fusion.In one aspect, the disclosed FBXW7 gene can encode an FBXW7 protein having a Y545C or R658* mutation. In one aspect, the disclosed FGFR gene can encode an FGFR protein having a T320T, S726F, H791H, P47P, S430fs, or R179H mutation. In one aspect, the disclosed FGFR1 gene can encode an FGFR1 protein having an S726F mutation. In one aspect, the disclosed FGFR2 gene can encode an FGFR2 protein having a KCNH7 fusion. In one aspect, the disclosed FGFR3 gene can encode an FGFR3 protein having an H290Y mutation. In one aspect, the disclosed GATA3 gene can encode a GATA3 protein having a P433fs43, P409fs, PS405fs, D336fs, S430fs, or c.1213_1214del mutation. In one aspect, the disclosed GNA11 gene can encode a GNA11 protein having an N244S mutation. In one aspect, the disclosed GNAS gene can encode a GNAS protein having an R201H* mutation. In one aspect, the disclosed HIST1H1D gene can encode a HIST1H1D protein having a K185-A186>T mutation. In one aspect, the disclosed H3F3A gene can encode an H3F3A protein having a K28N or K27 mutation. In one aspect, the disclosed IDH1 gene can encode an IDH1 protein having an R132H mutation. In one aspect, the disclosed JAK2 gene can encode a JAK2 protein having a V617 mutation. In one aspect, the disclosed KIT gene has Q 775fs (exon 16 deletion). In one aspect, the disclosed ARID1A gene can encode an ARID1A protein having an S1798L, S1167F, G246V, R1889W, or Q802fs mutation. In one aspect, the disclosed KRAS gene can encode a KRAS protein having a G12V, G12D, G12S, G13D, or p.AG11GD mutation. In one aspect, the disclosed MAP2K1 gene can encode a MAP2K1 protein having a K57E mutation. In one aspect, the disclosed MAP2K4 gene has a deletion of exon 2. In one aspect, the disclosed MAP3K1 gene can encode a MAP3K1 protein having an S398 mutation. In one aspect, the disclosed MAP3K6 gene can encode a MAP3K6 protein having a P646L mutation. The disclosed MET gene can encode a MET protein having a C385Y, T895M, T7591, or M391 mutation. In one aspect, the disclosed MPL gene can encode an MPL protein having a Y591D mutation. In one aspect, the disclosed MYC gene can encode a MYC protein having an S244S mutation.In one aspect, the disclosed NF1 gene has splice site 480-11_4801del11, splice site SNV, c.6655>T, p.D2219Y, V2378fs*8, or can encode A2617A, F710C, I1719T, or K583R mutations. In one aspect, the disclosed NOTCH1 gene can encode a NOTCH1 protein having an A465V, V220M, D1681H, or S223N mutation. In one aspect, the disclosed NOTCH2 gene can encode a NOTCH2 protein having an S2379F mutation. In one aspect, the disclosed NTRK1 gene can encode an NTRK1 protein having a P387L or R766Q mutation. In one aspect, the disclosed PDGFRA gene can encode a PDGFRA protein having an E86A or V299G mutation. In one aspect, the disclosed PIK3CA gene can encode a PIK3CA protein having a Q546H, Q546K, Q546R, Q597H, E542K, E545K, E726K, E39K, E453K, R4-P18del, H1047L, H104R, K567E, I1543I, p.E545K, or G1049R mutation. In one aspect, the disclosed PIK3R1 gene can encode a PIK3R1 protein having a S399Y408del splice site 917-1G>A mutation. In one aspect, the disclosed PTCH1 has a p.M17 start loss-LOF. In one aspect, the disclosed PTEN gene can encode a PTEN protein having H196_1203DEL, R55fs, N323fs*23, Y27C, R130*, C136Y, D252Y, or exon 4-7 deletion mutations. In one aspect, the disclosed RAF1 gene can encode a RAF1 protein having a P63P mutation. In one aspect, the disclosed RB1 gene can encode an RB1 protein having a Q217*, Y173fs*, or H673fs mutation. In one aspect, the disclosed RUNX1 gene can encode a RUNX1 protein having an R107C mutation. In one aspect, the disclosed SMAD4 gene can encode a SMAD4 protein having a P511L, D537V, Q450H, L495R, A451P, or A406T mutation. In one aspect, the disclosed SPEN gene can encode a SPEN protein having an A2510V mutation. In one aspect, the disclosed SRSF2 gene can encode an SRSF2 protein having a P95H mutation. In one aspect, the disclosed STAT5B gene can encode a STAT5B protein having an R110H mutation. In one aspect, the disclosed TET2 gene can encode a TET2 protein having a C1875G mutation.In one aspect, the disclosed TP53 gene can encode a TP53 gene having V73fs, R175G, R196, R249T, C176F, G187D, R282W, E287*, E285K, S241del, c.97-2899del, Y126D, R273H, C176W, K320*, T253A, splice site 37G-1G>AA, Q104, P151 H, H179Y, R273C, R248W, R176H, R209fscer, N235-Y236del, R248Qer, R306*, C176Y, S241F, L252-1254del, L145P, R158H, R213*, Y220C, R110P, V274G, or c.376-4_384del mutated TP53 protein.

[0242] For the Guardant 360 platform, genomic aberrations in disclosed cancer-associated genes can include single nucleotide variations. For example, in one aspect, the disclosed single nucleotide variations can be identified in AKT1, ALK, APC, AR, ARAF, ATM, BRAF, BRCA1, BRCA2, CCND1, CDH1, CDK4, CDK6, CDK12, CDKN2A, CTNNB1, EGFR, ERBB2, ESR1, FGFR1, FGFR2, FGFR3, GATA3, GNA11, GNAQ, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MAP2K2, MET, MLH1, MTOR, MYC, NF1, NFE2L2, NRAS, NTRK1, NTRK3, PDGFRA, PIK3CA, PTEN, RAF1, RET, RHEB, ROS1, SMAD4, SMO, STK11, TERT, TSC1, VHL, or any combination thereof. For the Guardant 360 platform, the genomic aberrations in the disclosed cancer-related genes may include insertions and / or deletions. For example, in one aspect, the disclosed insertions and deletions (Indels) can be confirmed in the following genes: AKT1, ALK, APC, ATM, BRAF, BRCA1, BRCA2, CDH1, CDK12, CDKN2A, EGFR, ERBB2, ESR1, FGFR2, GATA3, HNF1A, HRAS, KIT, KRAS, MET, MLH1, NF1, PDGFRA, PIK3CA, PTEN, RET, ROS1, STK11, TSC1, VHL, or any combination thereof. For the Guardant 360 platform, in one aspect, the genomic aberrations in the disclosed cancer-related genes may include copy number amplification (CNA). For example, in one aspect, the disclosed CNA can be confirmed in the following genes: ERBB2 and / or MET. For the Guardant 360 platform, in one aspect, the disclosed fusions can include ALK, NTRK1, RET, ROS1, or any combination thereof.

[0243] For the Foundation platform, in one aspect, the genomic aberrations in the disclosed cancer-related genes can include substitutions, indels, or copy number amplifications. For example, in one aspect, the disclosed substitutions, disclosed indels, or disclosed CNAs can be confirmed in the following genes: ABL1, ACVR1B, AKT1, AKT2, AKT3, ALK, ALOX12B, AMER1 (FAM723B), APC, AR, ARAF, ARFRP1, ARID1A, ASXL1, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXL, BAP1, BARD1, BCL2, BCL2L1, BCL2L2, BCL6, BCOR, BCORL1, BRAF, BRCA1, BRCA2, BRD4, BR IP1, BTG1, BTG2, BTK, C11ORF30(EMSY), CALR, CARD11, CASP8, CBFB, CBL, CCND1, CCND2, CCND3, CCNE1, CD22, CD274(PD-L7), CD70, CD79A, CD79B , CDC73, CDH1, CDK12, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CEBPA, CHEK7, CHEK2, CIC, CREBBP, CRKL, CSFIR, CSF3R, CTCF , CTNNA1, CTNNB1, CUL3, CUL4A, CXCR4, CYP17A1, DAXX, DDR1, DDR2, DIS3, DNMT3A, DOT1L, EED, EGFR, EP300, EPHA3, EPHB1, EPHB4, ERBB2, ERBB3 , ERBB4, ERCC4, ERG, ERRFI1, ESR1, EZH2, FAM46C, FANCA, FANCC, FANCG, FANCL, FAS, FBXW7, FGF10, FGF12, FGF14, FGF19, FGF23, FGF3, FGF4, FGF 6. FGFR1, FGFR2, FGFR3, FGFR4, FH, FLCN, FLT1, FLT3, FOXL2, FUBP1, GABRA6, GATA3, GATA4, GATA6, GID4(C17ORF39), GNA11, GNA13, GNAQ, GNAS, GRM3, GSK3B, H3F3A, HDAC1, HGF, HNF1A, HRAS, HSD3B1, ID3, IDH1, IDH2, IGF1R, IKBKE, IKZF1, INPP4B, IRF2, IRF4, IRS2, JAK1, JAK2, JAK3, JUN,KDM5A、KDM5C、KDM6A、KDR、KEAP1、KEL、KIT、KLHL6、KMT2A(MLL)、KMT2D( MLL2)、KRAS、LTK、LYN、MAF、MAP2K1(MEK1)、MAP2K2(MEK2)、MAP2K4、MAP 3K1、MAP3K13、MAPK1、MCL1、MDM2、MDM4、MED12、MEF2B、MEN1、MERTK、MET 、MITF、MKNK1、MLH1、MPL、MRE11A、MSH2、MSH3、MSH6、MST1R、MTAP、MTOR、 MUTYH、MYC、MYCL(MYCL1)、MYCN、MYD88、NBN、NF1、NF2、NFE2L2、NFKBIA、 NKX2-1、NOTCH1、NOTCH2、NOTCH3、NPM1、NRAS、NT5C2、NTRK1、NTRK2、NTR K3、P2RY8、PALB2、PARK2、PARP1、PARP2、PARP3、PAX5、PBRM1、PDCD1(PD- 1)、PDCD1LG2(PD-L2)、PDGFRA、PDGFRB、PDK1、PIK3C2B、PIK3C2G、PIK3CA 、PIK3CB、PIK3R1、PIM1、PMS2、POLD1、POLE、PPARG、PP2R1A、PPP2R2A、PR DM1、PRKAR1A、PRKCI、PTCH1、PTEN、PTPN11、PTPRO、OKI、RAC1、RAD21、RA D51、RAD51B、RAD51C、RAD51D、RAD52、RAD54L、RAF1、RARA、RB1、RBM10、R EL、RET、RICTOR、RNF43、ROS1、RPTOR、SDHA、SDHB、SDHC、SDHD、SETD2、SF 3B1、SGK1、SMAD2、SMAD4、SMARCA4、SMARCB1、SMO、SNCAIP、SOCS1、SOX2、 SOX9、SPEN、SPOP、SRC、STAG2、STAT3、STK11、SUFU、SYK、TBX3、TEK、TET2 、TGFBR2、TIPARP、TNFAIP3、TNFRSF14、TP53、TSC1、TSC2、TYRO3、U2AF1、 VEGFA、VHL、WHSC1(MMSET)、WHSC1L1、WT1、XPO1、XRCC2、ZNF217、ZNF703、Or any combination thereof. For the Foundation platform, the disclosed genomic aberrations of cancer-related genes may include rearrangements. For example, in one aspect, the disclosed rearrangements may be confirmed in the following genes: ALK, BCL2, BCR, BRAF, BRCA1, BRCA2, CD74, EGFR, ETV4, ETVs, ETV6, EWSRI, EZR, FGFR1, FGFR2, FGFR3, KIT, KMT2A (MLL), MSH2, MYB, MYC, NOTCH2, NTRKI NTRK2 NUTMI, PDGFRA, RAFT, RARA, RET, ROS1, RSPO2 SDC4, SLC34A2TERC (ncRNA), TERT (promoter only), TMPRSS2, or any combination thereof. ,

[0244] For the Tempus platform, in one aspect, the disclosed genomic aberrations of cancer-related genes can include rearrangements. For example, in one aspect, the disclosed rearrangements can be confirmed in the following genes: ABL1, ALK, BCR, BRAF, EGFR, ETV6, EWSR1, FGFR2, FGFR3, MYB, NRG1, NTRK1, NTRK2, NTRK3, PAX8, PDGFRA, PML, RARA, RET, ROS1, TFE3, TMPRSS2, or any combination thereof. For the Tempus platform, in one aspect, the disclosed genomic aberrations of cancer-related genes can include single nucleotide variations, indels, or copy number amplifications. For example, in one aspect, a disclosed single nucleotide variation, a disclosed indel, or a disclosed CNA can be identified in the following genes: ABCB1, ABCC3, ABL1, ABL2, ABRAXAS1, ACTA2, ACVR1, (ALK2), ACVR1B, AGO1, AJUBA, AKT1, AKT2, AKT3, ALK, AMER1, APC, APLNR, APOB, AR, ARAF, ARHGAP26, ARHGAP35, ARID1A, ARID1B, ARID2, ARID5B, ASNS, ASPSCR1, ASXL1, ATIC, ATM, ATP7B, ATR, ATRX, AURKA, AURKB, AXIN1, AXIN2, AXL, B2M , BAP1, BARD1, BCL10, BCL11B, BCL2, BCL2L1, BCL2L11, BCL6, BCL7A, BCLAF1, BCOR, BCORL1, BCR, BIRC3, BLM, BMPR1A , BRAF, BRCA1, BRCA2, BRD4, BRIP1, BTG1, BTK, BUB1B, C11orf65, C3orf70, C8orf34, CALR, CARD11, CARM1, CASP8, C ASR, CBFB, CBL, CBLB, CBLC, CBR3, CCDC6, CCND1, CCND2, CCND3, CCNE1, CD19, CD22, CD274, (PD-L1), CD40, CD70, CD7 9A, CD79B, CDC73, CDH1, CDK12, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2B, CDKN2C, CEBPA, CEP57 , CFTR, CHD2, CHD4, CHD7, CHEK1, CHEK2, CIC, CIITA, CKS1B, CREBBP, CRKL, CRLF2, CSF1R, CSF3R, CTC1, CTCF, CTLA4,CTNNA1, CTNNB1, CTRC, CUL1, CUL3, CUL4A, CUL4B, CUX1, CXCR4, CYLD, CYP1B 1. CYP2D6, CYP3A5, CYSLTR2, DAXX, DDB2, DDR2, DDX3X, DICER1, DIRC2, DIS3 DIS3L2, DKC1, DNM2, DNMT3A, DOT1L, DPYD, DYN, C2H1, EBF1, ECT2L, EGF, EG FR EGLN1 EIF1AX ELF3 ELOC (TCEB1) EMSY ENG EP300 EPCAM EPHA2 EP HA7, EPHB1, EPHB2, EPOR, ERBB2, (HER2), ERBB3, ERBB4, ERCC1, ERCC2, ERCC 3. ERCC4, ERCC5, ERCC6, ERG, ERRFI1, ESR1, ETS1, ETS2, ETV1, ETV4, ETV5, E TV6, EWSR1, EZH2, FAM46C, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FAN CG, FANCI, FANCL, FANCM, FAS, FAT1, FBXO11, FBXW7, FCGR2A, FCGR3A, FDPS, F GF1, FGF10, FGF14, FGF2, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9 FGFR1, FGFR2, FGFR3, FGFR4, FH, FHIT, FLCN, FLT1, FLT3, FLT4, FNTB, FOXA1 FOXL2, FOXO1, FOXO3, FOX, P1, FOXQ1, FRS2, FUBP1, FUSG6PD, GABRA6, GALN T12、GATA1、GATA2、GATA3、GATA4、GATA6、GEN1、GLI1、GLI2、GNA11、GNA13、GN AQ, GNAS, GPC3, GPS2, GREM1, GRIN2A, GRM3, GSTP1, H19, H3F3A, HAS3, HAVCR 2. HDAC1, HDAC2, HDAC4, HGF, HIF1A, HIST1H1E, HIST1H3B, HIST1H4E, HLA-A 、SON-B、SON-C、SON-DMA、SON-DMB、SON-DOA、SON-DOB、SON-DPA1、SON-DPB1 HLA-DPB2、HLA-DQA1、HLA-DQA2、HLA-DQB1、HLA-DQB2、HLA-DRA、HLA-DRB1HLA-DRB5、HLA-DRB6、HLA-E、HLA-F、HLA-G、HNF1A、HNF1B、HOXA11、HOXB13、 HRAS、HSD11B2、HSD3B1、HSD3B2、HSP90AA1、HSPH1、IDH1、IDH2、IDO1、IFIT1 、IFIT2、IFIT3、IFNAR1、IFNAR2、IFNGR1、IFNGR2、IFNL3、IKBKE、IKZF1、IL1 0RA、IL15、IL2RA、IL6R、IL7R、ING1、INPP4B、IRF1、IRF2、IRF4、IRS2、ITPKB、 JAK1、JAK2、JAK3、JUN、KAT6A、KDM5A、KDM5C、KDM5D、KDM6A、KDR、KEAP1、KEL、KIF1B、KIT、KLF4、KLHL6、KLLN、KMT2A、KMT2B、KMT2C、KMT2D、KRAS、L2HGDH、 LAG3、LATS1、LCK、LDLR、LEF1、LMNA、LMO1、LRP1B、LYN、LZTR1、MAD2L2、MAF、 MAFB、MAGI2、MALT1、MAP2K1、MAP2K2、MAP2K4、MAP3K1、MAP3K7、MAPK1、MAX、M C1R、MCL1、MDM2、MDM4、MED12、MEF2B、MEN1、MET、MGMT、MIB1、MITF、MKI67、MLH1、MLH3、MLLT3、MN1、MPL、MRE11、MS4A1、MSH2、MSH3、MSH6、MTAP、MTHFD2、M THFR、MTOR、MTRR、MUTYH、MYB、MYC、MYCL、MYCN、MYD88、MYH11、NBN、NCOR1、N COR2、NF1、NF2、NFE2L2、NFKBIA、NHP2、NKX2-1、NOP10、NOTCH1、NOTCH2、NOTC H3、NOTCH4、NPM1、NQO1、NRAS、NRG1、NSD1、NSD2、NT5C2、NTH、L1、NTRK1、NTRK2、NTRK3、NUDT15、NUP98、OLIG2、P2RY8、PAK1、PALB2、PALLD、PAX3、PAX5、PA X7,PAX8,PBRM1,PCBP1,PDCD1,PDCD1LG2,PDGFRA,PDGFRB,PDK1,PHF6,PHG DH、PHLPP1、PHLPP2、PHOX2B、PIAS4、PIK3C2B、PI、K3、CA、PIK3CB、PI、K3、CD、PIK3CG, PI, K3, R1, PIK3R2, PIM1, PLCG1, PLCG2, PML, PMS1, PMS2, POLD1, POLE, POLH, POLQ, POT1, POU2F2, PPARA, PPARD, PPARG, PPM1D, PPP1R15A, PPP2R1A, PPP2R2A, PPP6C, PRCC, PRDM1, PREX2, PRKAR1A, PRKDC, PRKN, PRSS1, PTC, H, 1, PTCH2, PTEN, PTPN11, PTPN13, PTPN22, PTPRD, PTPRT, QKI, RAC1, RAD21, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, RAF1, RANBP2, RARA, RASA1, RB1, RBM10, RECQL4, RET, RHEB, RHOA, RICTOR, RINT1, RIT1, RNF139, RNF43, ROS1, RPL5, RPS15, RPS6KB1, RPTOR, RRM1, RSF1, RUNX1, RUNX1T1, RXRA, SCG5, SDHA, SDHAF2, SDHB, SDHC, SDHD, SEC23B, SEMA3C, SETBP1, SETD2, SF3B1, SGK1, SH2B(此处疑似有误,原文为SH2B3), SHH, SLC26A3, SLC47A2, SLC9A3R1, SLIT2, SLX4, SM, AD2(此处疑似有误,原文为SMAD2), SMAD3, SMAD4, SMARCA1, SMARCA4, SMARCB1, SMARCE1, SMC1A, SMC3, SMO, SOCS1, SOD2, SOX10, SOX2, SOX9, SPEN, SPINK1, SPOP, SPRED1, SRC, SRSF2, STAG2, STAT3, STAT4, STAT5A, STAT5B, STAT6, STK11, SUFU, SUZ12, SYK, SYNE1, TAF1, TANC1, TAP(此处疑似有误,原文为TAP1), TAP2(此处疑似有误,原文为TAP2), TARBP2, TBC1D12, TBL1XR1, TBX3, TCF3, TCF7L2, TCL1A, TERT (promoter), TET2, TFE3, TFEB, TFEC, TGFBR1, TGFBR2, TIGIT, TMEM127, TMEM173, TMPRSS2, TNF, TNFAIP3, TNFRSF14, TNFRSF17, TNFRSF9, TOP1, TOP2A, TP53, TP63, TPM1, TPMT, TRAF3, TRAF7, TSC1, TSC2, TSHR, TUSC3, TYMS, U2AF1 说明:原文中存在一些可能的错误或不规范表述(如SH2B写成SH2B、AD2写成SMAD2、TAP写成TAP1、TAP2写成TAP2等),翻译时尽量按照正确的内容进行翻译并标注了疑似错误的地方。TERT(启动子)直接翻译为TERT (promoter) 。UBE2T, UGT1A1, UGT1A9, UMPS, VEGFA, VEGFB, VHL, VSIR, WEE1, WNK1, WNK2, WRN, WT1, XPA, XPC, XPO1, XRCC1, XRCC2, XRCC3, YEATS4, ZFHX3, ZMYM3, ZNF217, ZNF471, ZNF620, ZNF750, ZNRF3, ZRSR2, or any combination thereof.

[0245] For the Tempus platform, the following apply: APC (APC-related conditions), ATM (ataxia-telangiectasia, breast cancer susceptibility, pancreatic cancer susceptibility), AXIN2 (oligodontia-colorectal cancer syndrome), BAP1 (BAP1 tumor predisposition syndrome), BARD1 (breast cancer susceptibility), BLM (Bloom syndrome), BMPR1A (juvenile polyposis), BRCA1 (hereditary breast and ovarian cancer), BRCA2 (hereditary breast and ovarian cancer, Fanconi anemia), BRIP1 (ovarian cancer susceptibility, Fanconi anemia), CDH1 (hereditary diffuse gastric cancer, breast cancer susceptibility), CDK4 (melanoma susceptibility), CDKN2A (melanoma-pancreatic cancer syndrome), CEBPA (acute myeloid leukemia), leukemia susceptibility), CHEK2 (breast cancer susceptibility, colon cancer susceptibility), DICER1 (DICER1 tumor predisposition syndrome), EGFR (lung cancer susceptibility, TKI resistance), EPCAM (Lynch syndrome), ETV6 (leukemia susceptibility, thrombocytopenia susceptibility), FH (hereditary leiomyomatosis and renal cell carcinoma), FLCN (Butter-Hoag-Dubé syndrome), GATA2 (GATA2 deficiency and susceptibility to myeloid malignancies), KIT (familial gastrointestinal stromal tumor), MAX (hereditary paraganglioma-pheochromocytoma syndrome), MEN1 (multiple endocrine neoplasia type 1), MET (hereditary papillary renal cell carcinoma), MLH1 (Lynch syndrome, constitutive mismatch repair deficiency), MSH2 (Lynch syndrome,Constitutive mismatch repair deficiency), MSH3 (MSH3-associated polyposis), MSH6 (Lynch syndrome, constitutive mismatch repair deficiency), MUTYH (MUTYH-associated polyposis), NBN (Nijmegen breakage syndrome, breast cancer susceptibility), NF1 (neurofibromatosis type 1), NF2 (neurofibromatosis type 2), NTHL1 (NTHL1 tumor syndrome, NTHL1-associated polyposis), PALB2 (breast cancer susceptibility, pancreatic cancer susceptibility, ovarian cancer susceptibility, Fanconi anemia), PDGFRA (familial gastrointestinal stromal tumor, GIST-plus syndrome syndrome), PHOX2B (neuroblastoma susceptibility), PMS2 (Lynch syndrome, constitutive mismatch repair deficiency), POLD1 (polymerase proofreading-associated polyposis), POLE (polymerase proofreading-associated polyposis), PRKAR1A (Carney complex), PTCH1 (Gorlin syndrome, basal cell nevus syndrome), PTEN (PTEN hamartoma syndrome), RAD51C (ovarian cancer susceptibility, breast cancer susceptibility, Fahr's syndrome), RAD51C (ovarian cancer susceptibility, breast cancer susceptibility, Fanconi anemia), RAD5 1D (ovarian cancer susceptibility, breast cancer susceptibility), RB1 (retinoblastoma), RET (multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma), RUNX1 (acute myeloid leukemia susceptibility), SDHA (hereditary paraganglioma-pheochromocytoma syndrome), SDHAF2 (hereditary paraganglioma-pheochromocytoma syndrome), SDHB (hereditary paraganglioma-pheochromocytoma syndrome), SDHC (hereditary paraganglioma-pheochromocytoma syndrome), SDHD (hereditary paraganglioma-pheochromocytoma syndrome), SMAD4 (juvenile dysplasia susceptibility), Sarcoidosis, hereditary hemorrhagic telangiectasia, SMARCA4 (rhabdoid tumor predisposition syndrome), SMARCB1 (rhabdoid tumor predisposition syndrome, schwannomatosis), STK11 (Poitz-Jegger syndrome), SUFU (Gorlin syndrome, basal cell nevus syndrome), TMEM127 (hereditary paraganglioma-pheochromocytoma syndrome), TP53 (Li-Fraumeni syndrome), TSC1 (tuberous sclerosis complex), TSC2 (tuberous sclerosis complex), VHL (von Hippel-Lindau syndrome), and WT1 (WT1-related Wilms tumor).

[0246] In one aspect of the disclosed method for preventing and / or reducing metastasis, next generation sequencing may include sequencing one or more cancer-related genes. In one aspect of the disclosed method for preventing and / or reducing metastasis, sequencing one or more cancer-related genes may include confirming one or more genomic aberrations. In one aspect, the one or more genomic aberrations may include somatic genomic aberrations. In one aspect, the disclosed one or more somatic genomic aberrations may include mutations, insertions, deletions, chromosome rearrangements, copy number aberrations, or any combination thereof.

[0247] In one aspect of the disclosed method for preventing and / or reducing metastasis, the disclosed cfDNA analysis may include quantification of one or more cancer-related genes. In one aspect, if the expression and / or quantity and / or presence of one or more genomic aberrations disclosed in the biological sample before treatment is higher than the expression and / or quantity and / or presence of the same one or more genomic aberrations in the control sample, the disclosed method for preventing and / or reducing metastasis may include diagnosing that the subject needs precision cancer treatment. In one aspect, the disclosed control sample can be a sample obtained from a subject who does not have cancer. In one aspect, the disclosed control sample can be a pooled sample obtained from multiple subjects who do not have cancer.

[0248] In one aspect, if the expression and / or amount and / or presence of one or more genomic aberrations disclosed in a biological sample after treatment is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in the sample before treatment, then the disclosed methods of preventing and / or reducing metastasis may comprise continuing to administer a disclosed precision cancer therapy to the subject. In one aspect, if the expression and / or amount and / or presence of one or more genomic aberrations disclosed in a biological sample after treatment is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in the sample after the previous treatment, then the disclosed methods of preventing and / or reducing metastasis may comprise continuing to administer a disclosed precision cancer therapy to the subject.

[0249] In one aspect, the disclosed methods of preventing and / or reducing metastasis may further comprise measuring a subject's tumor response to the precision cancer therapy. In one aspect, the subject's tumor response may comprise a partial response or a complete response. In one aspect, the disclosed partial responses may comprise a decrease in tumor size or a decrease in one or more tumors by 25% or more compared to the size of the same tumor or the same tumor(s) before treatment. In one aspect, the disclosed partial responses may comprise a decrease in tumor size or a decrease in one or more tumors by 50% or more compared to the size of the same tumor or the same tumor(s) before treatment. In one aspect, the disclosed partial responses may comprise a decrease in tumor size or a decrease in one or more tumors by about 100% or more compared to the size of the same tumor or the same tumor(s) before treatment.

[0250] In one aspect, the disclosed methods for preventing and / or reducing metastasis may further comprise measuring a subject's molecular response to the disclosed precision cancer treatment. In one aspect, the disclosed molecular response may comprise a reduction in the number of somatic genomic aberrations in a biological sample obtained from a subject. In one aspect, the disclosed somatic genomic aberrations may comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, fusions, or any combination thereof. In one aspect, the disclosed methods for preventing and / or reducing metastasis may further comprise administering one or more additional therapeutic agents to the subject.

[0251] In one aspect, the disclosed additional therapeutic agents can include chemotherapeutic agents, monoclonal antibodies, cell cycle inhibitors, small molecules, or any combination thereof.

[0252] Monoclonal antibodies are known to those skilled in the art. Monoclonal antibodies may include, but are not limited to, ado-trastuzumab, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, cemiplimab, cetuximab, daratumumab, denosumab, denutoximab, durvalumab, elotuzumab, gemtuzumab, ibritumomab tiuxetan, inotuzumab, ipilimumab, necituzumab, nivolumab, obinutuzumab, ofatumumab, olaratumumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab, trastuzumab, or any combination thereof.

[0253] Small molecules are known to those skilled in the art. Small molecules may include, but are not limited to, abemaciclib, afatinib, alectinib, abolib, axitinib, bimetinib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, gilteritinib, cometinib, copalixoxib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelithib, encorfenib, entrectinib, erdafitinib, erlotinib, gefit ... , ibrutinib, imatinib, ivosidenib, lapatinib, larotrectinib, lenvatinib, lorlatinib, marizomib, neratinib, nilotinib, niraparib, olaparib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sorafenib, sunitinib, tazopanib, trametinib, vandetanib, vemurafenib, or any combination thereof. In one aspect, the additional therapeutic agent may include bevacizumab, pazopanib, sorafenib, dasatinib, everolimus, or any combination thereof.

[0254] For example, in one aspect, pazopanib and / or sorafenib can be orally administered to a subject at a dosage of about 1 mg / kg / day to about 12 mg / kg / day or 2 mg / kg / day to about 6 mg / kg / day. In one aspect, the disclosed optimal dose of pazopanib and / or sorafenib can be about 3 mg / kg / day. In one aspect, dasatinib can be orally administered to a subject at a dosage of about 0.3 mg / kg / day to about 2.0 mg / kg / day or about 0.7 mg / kg / day to about 1.4 mg / kg / day. In one aspect, the disclosed optimal dose of dasatinib can be about 0.7 mg / kg / day. In one aspect, everolimus can be orally administered to a subject at a dosage of about 0.03 mg / kg / day to about 0.15 mg / kg / day or about 0.03 mg / kg / day to about 0.10 mg / kg / day. In one aspect, the disclosed optimal dose of everolimus can be about 0.07 mg / kg / day. In one aspect, bevacizumab can be administered intravenously to a subject at a dose of about 2 mg / kg / day to about 15 mg / kg / day every 1 to 3 weeks or administered to a patient at a dose of about 5 mg / kg / day to about 12 mg / kg / day every 1 to 3 weeks. In one aspect, the disclosed optimal dose of bevacizumab can be administered intravenously to a subject once every 2 weeks, with an optimal dose of about 10 mg / kg / day.

[0255] In one aspect, the disclosed molecular markers can be measured from a sample by high-density expression arrays, DNA microarrays, polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), real-time quantitative reverse transcription PCR (qRT-PCR), serial analysis of gene expression (SAGE), spotted cDNA arrays, gene chips, spotted oligonucleotide arrays, microbead arrays, RNA sequencing, tiling arrays, Northern blots, hybridization microarrays, in situ hybridization, whole exome sequencing, whole genome sequencing, liquid biopsy, next generation sequencing, or any combination thereof, which can determine one or more appropriate precision cancer treatments in one or more of the disclosed methods.

[0256] In one aspect, the disclosed molecular markers for one or more suitable precision cancer treatments for the disclosed methods of preventing and / or reducing metastasis can be determined based on the nucleic acid sequence of at least one of circulating DNA and / or RNA. In one aspect, the disclosed molecular markers can be assessed from circulating tumor DNA and / or RNA (ctDNA and / or ctRNA); circulating cell-free DNA and / or RNA (cfDNA, cfRNA); or any combination thereof. ctDNA / ctRNA refers to DNA fragments in the blood that are not associated with cells and are derived from tumors. cfDNA / cfRNA refers to DNA that circulates freely in the bloodstream, but is not necessarily derived from tumors. In one aspect, cfDNA / ctDNA may include any complete or fragmented genomic DNA or mitochondrial DNA, and / or cfRNA / ctRNA may include mRNA, tRNA, microRNA, small interfering RNA, long non-coding RNA (lncRNA). In one aspect, cfRNA and / or ctRNA may be fragmented DNA having a length of at least about 50 base pairs (bp), about 100bp, about 200bp, about 500bp, or about 1kbp. In one aspect, cfDNA / ctDNA can be the full length or fragment of mRNA (e.g., at least 70% of the full length, at least 50% of the full length, at least 30% of the full length, etc.). In one aspect, the disclosed molecular markers can be directed against any cancer-related gene disclosed herein.

[0257] In one aspect, the disclosed method for preventing and / or reducing metastasis can further comprise surgically removing one or more tumors of the subject. In one aspect, the disclosed method for preventing and / or reducing metastasis can further comprise repeating one or more disclosed steps of the disclosed method.

[0258] For example, in one aspect, repeating one or more disclosed steps of the disclosed methods of preventing and / or reducing metastasis can comprise repeatedly administering a precision cancer therapy to a subject, repeatedly measuring a tumor response in a subject, repeatedly obtaining a biological sample from a subject, repeatedly performing cfDNA analysis on a biological sample, repeatedly administering one or more additional therapeutic agents, or any combination thereof.

[0259] In one aspect, the disclosed molecular markers can be detected, quantified and / or analyzed over time (at different time points) to determine the effectiveness of the disclosed precision cancer treatment (such as AS therapy) on the subject and / or determine the response of the subject or the subject's tumor to the precision cancer treatment (such as the development of drug resistance, susceptibility, etc.). In one aspect, the disclosed method for preventing and / or reducing metastasis may include obtaining multiple measurements from the same subject over time, and the same sample can be quantified at a single time point or over time. In one aspect, the treatment of the disclosed treatment regimen (e.g., the disclosed precision cancer treatment comprising one or more antineoplastons) can be designed and / or determined based on the cancer status and / or the change / type of one or more molecular markers. In one aspect, the likelihood of success of the disclosed precision cancer treatment can be determined based on the cancer status and the type / quantity of one or more molecular markers.

[0260] In one aspect, the disclosed molecular markers can be derived from genes expressed in one or more cells of a tumor or in immune cells and can indicate an immunosuppressive tumor microenvironment, the development of cancer severity, the occurrence of metastasis, the cancer state, or any combination thereof. In one aspect, the disclosed molecular markers can be proteins or peptides encoded by the genes from which the molecular markers are derived and can be targeted by antagonists or any other type of binding molecules to inhibit the function of the polypeptide.

[0261] Thus, in one aspect, increased expression of the disclosed molecular markers derived from the disclosed genes associated with an immunosuppressive tumor microenvironment (e.g., above a predetermined threshold) may indicate the presence of an immunosuppressive tumor microenvironment, and may also indicate that antagonists of peptides encoded by genes associated with an immunosuppressive tumor microenvironment are likely to inhibit the progression of cancer by suppressing the immunosuppressive tumor microenvironment and further promoting the activity of immune cells against tumor cells in such a microenvironment. In one aspect, once a molecular marker has been identified, any suitable antagonist targeting a gene or protein may be used. For example, in one aspect, a kinase inhibitor may target a specific kinase, a synthetic ligand may target a specific signaling receptor, or a synthetic antagonist or antibody may target a specific checkpoint receptor, etc. In one aspect, the target molecule antagonists disclosed herein may be administered before, after, or in combination with AS treatment.

[0262] In one aspect, the subject can be a human patient. In one aspect, the subject can be of any age (e.g., elderly, adult, youth, adolescent, child, puberty, child, toddler, infant, or newborn), male or female, of any nationality, of any ethnicity, and / or of any race. In one aspect, the subject can have terminal cancer.

[0263] In one aspect, the subject has not received treatment prior to the administration of the disclosed precision cancer treatment to the disclosed subject. In one aspect, the subject has received treatment prior to the administration of the disclosed precision cancer treatment to the disclosed subject. In one aspect of the disclosed method for preventing and / or reducing metastasis, the subject has received surgery, antibody therapy, chemotherapy, radiation therapy, immunotherapy, or any combination thereof prior to the administration of the disclosed precision cancer treatment. In one aspect of the disclosed method for preventing and / or reducing metastasis, the subject in need has been diagnosed with cancer, or the subject in need thereof is suspected of having cancer.

[0264] In one aspect, the disclosed cancers may be refractory cancers or refractory diseases. In one aspect, "refractory" refers to a cancer and / or tumor that is unresponsive to treatment and / or develops resistance. In one aspect, the subject may have a recurrent disease. In one aspect, "relapse" or "recurrent" refers to the return or development of a tumor after improvement (e.g., a partial or complete response) with treatment. In one aspect, the disclosed cancers may include solid tumors. In one aspect, the disclosed cancers may include metastatic cancers. In one aspect, the disclosed cancers may include terminal cancers.

[0265] In one aspect, the disclosed cancers may include adenocarcinoma (including appendix and cervix), adenoid cystic epithelial carcinoma, adult T-cell leukemia, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, astrocytoma, basal cell carcinoma, B-cell carcinoma, benign and malignant lymphoma, biliary tract-cholangiocarcinoma, intestinal cancer, brain cancer (including anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, brainstem anaplastic astrocytoma, brainstem glioma, diffuse astrocytoma, DIPG H3K27 mutation, ganglioglioma, glioblastoma multiforme, medulloblastoma, pilocytic astrocytoma, brainstem glioma), breast cancer, breast cancer, breast cancer, and ovarian cancer. carcinoma), Burkitt lymphoma, bladder cancer and urothelial carcinoma, epithelial carcinoma of unknown primary site, carcinosarcoma, cervical cancer, cholangiocarcinoma, chronic atypical myeloid leukemia, chronic atypical myeloid leukemia, colon cancer, colorectal cancer, diffuse astrocytoma, diffuse intrinsic pontine glioma (DIPG), endometrial cancer, endometrial epithelial carcinoma, ependymoma, esophageal cancer and esophageal epithelial carcinoma, Ewing sarcoma, ganglioglioma, ganglioneuroma Glioblastoma, Gastrointestinal Stromal Tumor (GIST), Glioblastoma, Glioma, Head and Neck Cancer and Head and Neck Epithelial Cancer, Angiosarcoma, Hepatocellular Carcinoma, Renal Cell Carcinoma, Hodgkin's Disease, Kaposi's Sarcoma, Kidney Cancer and Renal Epithelial Cancer, Large B-Cell Lymphoma, Leptomeningeal Carcinomatosis, Leukemia, Liposarcoma, Hepatocellular Carcinoma, Lung Cancer (Non-Small Cell and Small Cell), Medulloblastoma, Melanoma, Meningeal Sarcoma, Meningioma, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative Disorders Diseases, myositis, neuroblastoma, neuroendocrine epithelial cancer, neurofibroma, non-Hodgkin's lymphoma, oligodendroglioma, osteosarcoma, ovarian cancer and ovarian epithelial cancer, pancreatic cancer and pancreatic epithelial cancer, peripheral neuroepithelial tumor, peripheral T-cell lymphoma, Philadelphia chromosome positive and positive CML, pilocytic astrocytoma, pineal cell tumor, pleomorphic sarcoma, pre-B lymphoma, primitive neuroectodermal tumor (PNET), prostate cancer and prostatic epithelial cancer, Refractory anemia, salivary gland epithelial cancer, sarcoma, Schwannoma, skin cancer and skin epithelial cancer, squamous cell epithelial cancer, gastric cancer and gastric epithelial cancer, synovial sarcoma, testicular cancer, thyroid cancer and thyroid epithelial cancer, T-line acute lymphoblastic leukemia (T-ALL), T-line lymphocytic lymphoma (T-LL), urinary tract cancer and urinary tract high-grade epithelial cancer, uterine, cervical, vulvar and / or endometrial epithelial cancer, Wilms' tumor or teratoma, or any combination thereof.

[0266] In one aspect, the disclosed cancers can include breast cancer, colorectal cancer, head and neck cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, brain cancer, adenoid cystic carcinoma, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, brain stem glioma, diffuse astrocytoma, diffuse intrinsic pontine glioma (DIPG), ganglioglioma, medulloblastoma, pilocytic astrocytoma, cholangiocarcinoma, chronic atypical myeloid leukemia, endometrial carcinoma, esophageal cancer, Ewing sarcoma, gastrointestinal stromal tumor (GIST), leptomeningeal carcinomatosis, multiple myeloma, myelodysplastic syndrome, neuroendocrine epithelial cancer, non-Hodgkin's lymphoma, pleomorphic sarcoma, primitive neuroectodermal tumor (PNET), refractory anemia, salivary gland epithelial cancer, skin cancer, gastric cancer, thyroid cancer, urinary tract cancer, or any combination thereof.

[0267] In one aspect, the disclosed method for preventing and / or reducing metastasis may further include monitoring the adverse reactions (e.g., liver damage, blood toxicity, nervous system toxicity, skin toxicity, gastrointestinal toxicity, or any combination thereof) of the subject. In one aspect, in the absence of adverse reactions, the disclosed method for preventing and / or reducing metastasis may further include continuing to administer the disclosed precision cancer treatment to the subject. In one aspect, in the presence of adverse reactions, the disclosed method for preventing and / or reducing metastasis may further include modifying one or more disclosed steps of the disclosed method. In one aspect, the disclosed method for preventing and / or reducing metastasis may further include treating one or more adverse reactions.

[0268] In one aspect, the disclosed methods for preventing and / or reducing metastasis can include modifying the disclosed administering steps. In one aspect, modifying the disclosed administering steps can include changing the amount of one or more antineoplastons or compositions comprising one or more antineoplastons administered to a subject, changing the frequency of administering one or more antineoplastons or compositions comprising one or more antineoplastons to a subject, changing the duration of administering one or more antineoplastons or compositions comprising one or more antineoplastons to a subject, changing the route of administration of one or more antineoplastons or compositions comprising one or more antineoplastons to a subject, or any combination thereof.

[0269] In one aspect, the disclosed method for preventing and / or reducing metastasis may further include obtaining a tissue biopsy from the subject. In one aspect, the disclosed tissue biopsy may be subjected to next generation sequencing. In one aspect, the disclosed method for preventing and / or reducing metastasis may include subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known in the art. In one aspect, the disclosed non-invasive diagnostic assessments may include X-rays, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasound, positron emission tomography (PET), or any combination thereof. In one aspect, the disclosed invasive diagnostic assessments may include tissue biopsy or exploratory surgery.

[0270] In one aspect, the disclosed methods improve the life expectancy of a subject. In one aspect, the life expectancy of a subject is compared to the life expectancy of a control. In one aspect, the control is a subject that has not received precision cancer therapy. In one aspect, the control is a pool of subjects that have not received precision cancer therapy. In one aspect, the control is one or more subjects with the same cancer type and the same cancer stage as the subject. In one aspect of the disclosed methods for preventing and / or reducing metastasis, the subject's cancer is treated.

[0271] In one aspect, the disclosed methods of preventing and / or reducing metastasis can increase life expectancy compared to the life expectancy of an untreated subject with the same or nearly the same disease state and the same or nearly the same predicted outcome. As used herein, "life expectancy" is defined as the time at which 50% of subjects survive and 50% of subjects die. In one aspect, following treatment with the disclosed methods, a patient's life expectancy may be indefinite. In one aspect, a patient's life expectancy can be increased by at least about 5% or more to at least about 100%, at least about 10% or more to at least about 95% or more, at least about 20% or more to at least about 80% or more, at least about 40% or more to at least about 60% or more, compared to an untreated subject with the same or nearly the same disease state and the same or nearly the same predicted outcome.

[0272] In one aspect, life expectancy can be increased by at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 25% or more, at least about 30% or more, at least about 35% or more, at least about 40% or more, at least about 45% or more, at least about 50% or more, at least about 55% or more, at least about 60% or more, at least about 65% or more, at least about 70% or more, at least about 75% or more, at least about 80% or more, at least about 85% or more, at least about 90% or more, at least about 95% or more, at least about 100% compared to an untreated subject with the same or approximately the same disease condition and the same or approximately the same predicted outcome. In one aspect, life expectancy can be increased by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 50% or more to at least about 57% or more, at least about 58% or more to at least about 59% or more, at least about 60% or more to at least about 61% or more, at least about 62% or more to at least about 63% or more, at least about 64% or more to at least about 66% or more, at least about 67% or more to at least about 68% or more, at least about 69% or more to at least about 70% or more, at least about 71% or more to at least about 72% or more, at least about 73% or more to at least about 74% or more, at least about 75% or more to at least about 76% or more, at least about 77% or more to at least about 78% or more, at least about 79% or more to at least about 80% or more, at least about 81% or more to at least about 82% or more, at least about 83% or more to at least about 84% or more, at least about 85% or more to at least about 86% or more, at least about From at least about 45% or more to at least about 50% or more, at least about 50% or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100%.

[0273] In one aspect, the disclosed methods for preventing and / or reducing metastasis may include protecting a subject from metastasis. In one aspect, the disclosed methods for preventing and / or reducing metastasis may include reducing the risk of developing metastasis. In one aspect of the disclosed methods for preventing and / or reducing metastasis, treating cancer may include improving the survival rate of a subject, increasing the length of time before metastasis, reducing the likelihood of surgical intervention, reducing the need to administer one or more additional therapeutic agents or treatment regimens, reducing the size of one or more tumors in a subject, eliminating one or more tumors in a subject, reducing or eliminating the prevalence of one or more genomic aberrations, restoring normal metabolism in one or more organ systems in a subject, restoring one or more aspects of cellular homeostasis and / or cellular function, and / or metabolic disorders; or any combination thereof.

[0274] In one aspect of the disclosed method for preventing and / or reducing metastasis, one or more aspects of restoring cellular homeostasis and / or cellular function may include one or more of the following: (i) correcting cellular starvation of one or more cell types (such as, for example, liver cells and muscle cells, etc.); (ii) normalizing the autophagy pathway (such as, for example, correcting, preventing, reducing and / or improving autophagy, etc.); (iii) improving, enhancing, restoring and / or protecting mitochondrial function and / or structural integrity; (iv) improving, enhancing, restoring and / or protecting organelle function and / or structural integrity; (v) preventing, slowing and / or eliminating hypoglycemia, ketosis and / or other liver abnormalities; vi) correcting liver enzyme dysregulation; (vii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor metastasis; (viii) reversing, inhibiting, preventing, stabilizing and / or slowing the rate of progression of tumor growth and / or cancer spread, or (ix) any combination of the above. In one aspect, one or more aspects of restoring cellular homeostasis may include one or more aspects of improving, enhancing, restoring and / or maintaining cellular structural and / or functional integrity in, for example, an organ or system that has been affected by cancer.

[0275] For example, in one aspect, tumor growth can be attenuated by at least about 5% or more to at least about 100%, at least about 10% or more to at least about 95% or more, at least about 20% or more to at least about 80% or more, at least about 40% or more to at least about 60% or more, compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome. In one aspect, the growth of one or more tumors in a subject treated using the disclosed methods of preventing and / or reducing metastasis can be reduced by at least 5% (or more as described above) compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome.

[0276] In one aspect, tumor growth can be impaired by at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 25% or more, at least about 30% or more, at least about 35% or more, at least about 40% or more, at least about 45% or more, at least about 50% or more, at least about 55% or more, at least about 60% or more, at least about 65% or more, at least about 70% or more, at least about 75% or more, at least about 80% or more, at least about 85% or more, at least about 90% or more, at least about 95% or more, at least about 100% as compared to an untreated subject with the same or approximately the same disease state and the same or approximately the same predicted outcome.

[0277] In one aspect, tumor growth can be attenuated by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 50% or more to at least about 56% or more, at least about 57% or more to at least about 58% or more, at least about 59% or more to at least about 60% or more, at least about 61% or more to at least about 62% or more, at least about 63% or more to at least about 64% or more, at least about 65% or more to at least about 66% or more, at least about 67% or more to at least about 68% or more, at least about 69% or more to at least about 70% or more, at least about 71% or more to at least about 72% or more, at least about 73% or more to at least about 74% or more, at least about 75% or more to at least about 76% or more, at least about 77% or more to at least about 78% or more, at least about 79% or more to at least about 80% or more, at least about 81% or more to at least about 82% or more, at least about 83% or more to at least about 84% or more, at least about 85% or more to at least about 86% or more, at least about From at least about 45% or more to at least about 50% or more, at least about 50% or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100%.

[0278] In one aspect, treating a tumor according to the methods disclosed herein (e.g., AS therapy) can reduce the tumor relative to its starting size. In one aspect, the tumor is reduced by at least about 5% or more to at least about 10% or more, at least about 10% or more to at least about 15% or more, at least about 15% or more to at least about 20% or more, at least about 20% or more to at least about 25% or more, at least about 25% or more to at least about 30% or more, at least about 30% or more to at least about 35% or more, at least about 35% or more to at least about 40% or more, at least about 40% or more to at least about 45% or more, at least about 45% or more to at least about 50% or more, at least about 50% or more, or at least about 50% or more, as compared to its starting size. % or more to at least about 55% or more, at least about 55% or more to at least about 60% or more, at least about 60% or more to at least about 65% or more, at least about 65% or more to at least about 70% or more, at least about 70% or more to at least about 75% or more, at least about 75% or more to at least about 80% or more, at least about 80% or more to at least about 85% or more, at least about 85% or more to at least about 90% or more, at least about 90% or more to at least about 95% or more, at least about 95% or more to at least about 100% (referring to complete disappearance of the tumor after treatment).

[0279] In one aspect, the disclosed subject may present with one or more cancerous solid tumors, metastatic nodules, or any combination thereof. In any aspect, the subject herein may have a cancerous tumor cell of origin, which may be less than about 0.2 cm 3 to at least about 20cm 3 or larger, at least about 2 cm 3 to at least about 18cm 3 or larger, at least about 3cm 3 to at least about 15cm 3 or larger, at least about 4cm 3 to at least about 12 cm 3 or larger, at least about 5cm 3 to at least about 10 cm 3 or larger, or at least about 6cm 3 to at least about 8cm 3 or larger.

[0280] In one aspect, the disclosed methods of preventing and / or reducing metastasis can include a pan-tumor approach, such as, for example, administering the disclosed ANP therapy.

[0281] F. Kit

[0282] Disclosed herein are kits comprising one or more disclosed antineoplastons, disclosed pharmaceutical formulations, or any combination thereof. In one aspect, the kits can include disclosed pharmaceutical formulations comprising one or more antineoplastons, one or more additional agents and / or therapeutic agents, or any combination thereof. "Agents" and "therapeutic agents" are known in the art and are described above.

[0283] In one aspect, one or more agents can treat, prevent, inhibit, and / or improve one or more complications of a subject. In one aspect, one or more active agents can treat, inhibit, prevent, and / or improve cellular and / or metabolic complications associated with cancer or cancerous cells or cancerous cells.

[0284] In one aspect, the disclosed kit may include at least two components that constitute the kit. These components together constitute a functional unit for a specific purpose (such as, for example, treating a subject diagnosed with or suspected of having a disease or condition such as cancer). The individual component parts may be physically packaged together or separately. For example, a kit containing instructions for use of the kit may or may not physically include the instructions and other individual component parts. Alternatively, the instructions may be provided as separate component parts, either in paper form or in electronic form, the electronic form of which may be provided on a computer-readable storage device or downloaded from an internet website, or in the form of a recorded presentation. In one aspect, the kit for the disclosed method may include one or more containers for holding one or more disclosed antineoplastons, disclosed pharmaceutical formulations, one or more therapeutic agents and / or additives, or any combination thereof, and a label or package insert with instructions for use. In one aspect, suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be made of a variety of materials, such as glass or plastic. The container can hold one or more disclosed antineoplastons, disclosed pharmaceutical formulations, or any combination thereof and can have a sterile access port (e.g., the container can be an intravenous fluid bag or a vial with a stopper pierceable by a hypodermic needle). The label or package insert can indicate that one or more disclosed antineoplastons, disclosed pharmaceutical formulations, or any combination thereof can be used to treat, prevent, inhibit, and / or ameliorate a disease or condition (such as cancer or metastatic cancer, etc.) or a complication and / or symptom associated with the disease or condition. The kit can include other components required for administration, such as, for example, other buffers, diluents, filters, needles, and syringes.

[0285] In one aspect, the disclosed kits can be used to treat and / or prevent cancer, prolong survival, prevent and / or reduce metastasis, or any combination thereof. VI. Examples

[0286] Example 1

[0287] Patients diagnosed with 34 terminal cancers received the antineoplastic AS2-1 (AS) therapy to reduce and / or eliminate tumors and other signs of cancer, as well as reduce and / or eliminate oncogene expression. Briefly, patients were diagnosed with terminal, stage IV, different types of cancer with multiple metastases, and refractory to standard therapy. A few were treatment-naive patients who were ineligible for standard therapy due to very advanced disease and a life expectancy of less than six months. Estimated survival for these patients ranged from less than one month to less than six months. Patients underwent radiographic evaluation and genomic profiling (usually performed at admission) for advanced metastatic cancers within four weeks of treatment initiation, including the Guardant 360 blood test and / or the Foundation One and / or Tempus blood or tissue test and / or the SEMA4 tissue test. Their histological diagnosis was confirmed at a medical institution unrelated to the Burzynski Clinic (BC).

[0288] AS and A10 (ANP) and targeted, immune, hormonal and / or chemotherapeutic agents are anti-cancer treatments administered to patients. In some cases, palliative radiotherapy (RT) and / or surgery are used in addition to anti-cancer drugs. ANP is delivered every 4 hours via a mobile infusion pump and a subclavian catheter. The dose of AS is gradually increased from 0.1 g / kg / day to a maximum dose of 0.4 g / kg / day after 4 days, with a flow rate increased from 50 ml / hour to 250 ml / hour. The dose of A10 is increased to a maximum of 12 g / kg / day. Most patients continue to receive treatment at a best tolerated dose of AS of 0.2 to 0.4 g / kg / day, A10 of 5 g / kg / day, and a flow rate of 200 to 250 ml / hour.

[0289] Medications deemed beneficial to the patient's health and not interfering with treatment are prescribed at the discretion of the treating physician. Patients receive comprehensive supportive care and dietary guidance. Treatment is provided on an outpatient basis in collaboration with the patient's local physician.

[0290] Baseline examinations include medical history taking, physical examination, and necessary laboratory, genomic, and radiological assessments. The two largest perpendicular diameters of radiographically significant lesions (including contrast-enhancing lesions on brain and spinal cord MRI) are measured. Follow-up scans are usually performed every 4 to 8 weeks to determine response. A complete response (CR) requires the disappearance of all enhancing lesions as shown by CT scan, stabilization or improvement of non-enhancing lesions, disappearance of lesions outside the target tissue as shown by CT, or disappearance of metabolically active lesions as shown by PET. A partial response (PR) requires a 50% or greater decrease in the sum of the product of the two largest perpendicular diameters of the lesion, and progressive disease (PD) requires an increase of more than 25%. Stable disease (SD) refers to a state between PR and PD, and a minor response (MR) is a decrease of more than 25%. A mixed response is determined when some lesions are CR or PR, while other lesions are PD.

[0291] In clinical trials, CR and PR should last at least 4 weeks, and SD should last at least 7 weeks. In private practice, some patients do not consent to follow-up radiological assessments due to radiation exposure or the additional cost. These responses are labeled CR* or PR*. Some patients with metastases in multiple organs achieve a CR or PR in one organ (such as the liver) but not in other sites. These responses are labeled accordingly, for example, CR(HEP) and SD(OSS), meaning CR in the liver and SD in the bones.

[0292] Molecular response is determined by repeated Guardant 360 testing. Briefly, the Guardant 360 test typically involves a panel test of circulating tumor DNA (ctDNA) from free cells in a blood (e.g., plasma) sample, and serves as an alternative to a tissue biopsy in the diagnosis of cancer and clinical response to targeted agents for cancer treatment. Here, a patient's blood sample is collected and provided to Guardant for panel testing, where a "panel" is defined as the testing of five or more ctDNA genes or gene mutation variants by the same provider (i.e., Guardant) on the same day for the same patient.

[0293] Treatment was tailored to the patient's medical history and assessment, including genomic data. All patients received AS therapy to cover the 158 abnormal genes, with additional targeted drugs targeting genes not affected by AS. Table 1 lists the genes affected by AS and A10. In some cases, mild chemotherapy was used initially to accelerate the response, and in some patients, A10 was added.

[0294] Table 1 - Genes affected by AS and A10 in Example 1

[0295] ACO2 CCNE2 CHK-1 IL1A ORC1 RAS TBC1D8 AKT CDC2 CLDND1 IL1B ORC1L RBL1 TFDP1 ASK CDC42 CSF1 IL6 ORC6L SDHC TP53 ASPM CDC6 CSF3 IL8 ORCL SKP2 TRIB3 ATF3 CDC7 CXCL2 IL15 PCNA SMC1A UNC5B BAD CDC20 DLD JUN PDHA1 SMC1L1 WEE1 BAX CDC25A DLST MAD2L1 PIK3CA STAT5 OGDH BCL2 CDC25B DUSP1 MAPK PKMYT1 SUCLG1 IL1 BDNF CDC25C DUSP6 MCM2 PLK1 SUCLG2 CFS1 BLM CDCA8 E2F1 MCM3 MCM4 ERK GADD45A BRAF CDK2 BUB1 CDK3 MCM5 FH MDH1 HIF1A PTTG3 PTPRR PPM1A CDKN2B MEF26 HDAC1 IDH2 NGF PTTG1 PTEN CDKN2C NF1 HDAC5 IDH3A CCNE1 PTTG2 PTPN11 NFKB CDKN1B MCM7 CCL2 CDK6 CASP5 CDK4 MCM6 CDKN2A IDH3B CCNA2 CDKN1A CCNB1 CCND2 CCND3 CCNB2

[0296] The goal of treatment is to achieve a complete response (CR), with complete disappearance of the abnormal gene in the patient's blood. At this point, patients are recommended to continue maintenance therapy for up to 8 months, with CR monitored by radiographic assessment (ideally every 8 weeks) and blood genomic testing (every 3 months). In this representative example, only evaluable patients who underwent the recommended follow-up radiographic and genomic assessments were included.

[0297] This article presents the results of this study in three parts: Part 1 describes the results for common cancers; Part 2 describes the results for rare cancers; and Part 3 summarizes the results for all evaluable patients.

[0298] The following abbreviations are used in this article: am (amplification); AS (antineoplastic AS2-1); BC (Buzynski Clinic, the site of the study reported in this article); BRA (brain metastasis); CH (chemotherapy); CR (complete response); CR* (complete response not confirmed by follow-up scan); DAMA (discontinuation without medical advice); Dd (patient died of malignancy during treatment); De (patient died of a condition other than malignancy during treatment); Dx (patient died during treatment, cause not recorded); DEPB (dasatinib, everolimus, pazopanib, bevacizumab); DESB (dasatinib, everolimus, sorafenib, bevacizumab); ER+ (estrogen-positive); GBM (glioblastoma, glioblastoma multiforme); H (hormonal therapy); HER-2 - (HER-2 negative); HER-2 + (HER-2 positive); IM (improved); LMN (leptomeningeal metastasis); LYM (lymph node metastasis); MR (minor response); ND (not detected); OR (objective response); OS (overall survival from the start of treatment); OSS (bone metastasis); PE (physical examination); PR (partial response); PR+ (progesterone positive); PUL (lung metastasis); RT (radiotherapy); SKI (skin metastasis); SU (surgery, the number in front indicates the number of surgeries); TN BC (triple-negative breast cancer); TT (targeted therapy, the target of TT is in brackets).

[0299] Part 1 - Common Cancers

[0300] Breast cancer. A total of 19 patients diagnosed with advanced, terminal breast cancer met the criteria for inclusion in this report. All patients were female, 11 of whom were aged 51-65 years, and 8 were aged 38-48 years. Patients were divided into three groups: 11 were HER2-negative, 2 were triple-negative, 6 were HER2-positive, and 1 had a heterogeneous population of cells with some HER2-negative and some HER2-positive cancer cells. Ten patients had a long-term disease history of 4 to 16 years, and 9 had a history of 1 to 3 years. With the exception of one patient who was ineligible for standard treatment due to near-death status and was therefore receiving first-line treatment, all patients had failed multiple lines of therapy, including surgery, radiation therapy, chemotherapy, and hormonal and / or targeted therapies. These patients had extensive metastatic disease, including involvement of the brain, meninges, bones, liver, lungs, lymph nodes, pleura, peritoneum, ovaries, skin, thyroid, and contralateral breast. The estimated survival was 1 to 3 months for 11 patients and less than 6 months for 8 patients.

[0301] Five patients had previously received surgery, radiotherapy, chemotherapy, and hormonal therapy; five patients had previously received surgery, radiotherapy, chemotherapy; three patients had previously received surgery, radiotherapy, and hormonal therapy; and one patient had previously received radiotherapy, chemotherapy, hormonal therapy, and targeted therapy. Eight patients had previously received targeted therapy, and one patient had previously received surgery and targeted therapy. Three patients had undergone multiple surgeries, and two patients had received multiple lines of radiotherapy. Five patients had received multiple chemotherapy regimens, and three patients had received multiple lines of targeted therapy. Details are provided in Table 2.

[0302] Table 2 - Demographics of breast cancer patients

[0303]

[0304]

[0305] Patients were treated as described above. Details of the treatment and the results are provided in Tables 3, 4, 5, and 6. Five patients in the HER-2 negative group achieved CR, the remaining five patients achieved PR, and one patient achieved MR. The responses in two patients were probably related to brain radiation therapy (Table 3). In four patients, blood genomic abnormalities confirmed at baseline were no longer found after treatment. Two patients in the triple negative group, including one with brain and meningeal involvement, achieved CR. One patient no longer had multiple mutated genes in the blood on repeated Guardant 360 testing (Table 4). HER-2 +Five patients in the treatment group achieved a CR, but four of them had a radiologically confirmed CR in one organ, while other organs showed variable responses. One patient achieved a PR. Three patients who had previously failed targeted therapy with a HER2 inhibitor responded to this targeted therapy in combination with AS (Table 5). All baseline genomic abnormalities detected in the blood by Guardant 360 were no longer present after treatment, except for one patient who had an 85% decrease in CCNE1 gene expression (Table 5).

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312] Table 6 - Comparison of the use of the antineoplastic AS2-1 and targeted agents in breast cancer treatment versus AS2-1 alone and prior targeted therapy

[0313]

[0314] Table 6 summarizes responses in a phase 2 trial of AS and A10 in breast cancer compared with responses to previous targeted therapies. As shown in Table 6, the objective response rate was very high, with 12 CRs, 6 PRs, and 1 MR, and no PD. There were no objective responses with AS and A10 in clinical trials, and 4 PDs were seen with previous targeted therapies. The 2-year overall survival rate was 78.9%, and the 3-year overall survival rate was 42.1%.

[0315] An additional group of 14 patients treated under the right-to-try law were not evaluated in this report. Four of these patients died from cancer and can be classified as PD, but two patients with PR and one with MR are still alive. Adding these seven patients brings the patient population to 26. In this expanded group, the following responses were observed: CR (12 patients), 46.1%; PR (8 patients), 30.7%; MR (2 patients), 7.6%; PD (4 patients), 15.3%; and objective response (OR) of 84.7%.

[0316] Table 7 provides genes and site mutations affected by antineoplastic AS2-1 according to clinical outcomes of breast cancer.

[0317] Table 7 - Genes affected by AS2-1 according to breast cancer clinical outcome

[0318]

[0319]

[0320] Colorectal cancer. A total of 8 terminally ill patients were treated. This group of patients included 4 women and 4 men, with ages ranging from 50 to 78 years. One patient was diagnosed with rectal adenocarcinoma, and the remaining patients were diagnosed with colon adenocarcinoma. Four patients had a medical history of 3 to 7 years, and the remaining three patients had a medical history of less than 1 to 2 years. These patients had extensive metastatic disease: four of them had liver, lung, and lymph node metastases, and four had peritoneal metastases. One patient had an estimated survival of less than 4 months, and five patients had an estimated survival of less than 6 months. One patient had previously received surgery, radiotherapy, chemotherapy, and targeted therapy; three patients had received surgery, chemotherapy, and targeted therapy; another three patients had only surgery, and one patient had not received previous treatment (Table 8).

[0321] Table 8 - Demographics of patients with colorectal cancer

[0322]

[0323]

[0324] Patients were treated as described above. Treatment details and outcomes are provided in Tables 9, 10, and 11. Four patients achieved a complete response (CR), two achieved a partial response (MR), and one achieved complete survival (SD). Objective responses were observed in both colon and rectal cancer patients. Table 10 summarizes these responses and compares them with responses in a Phase 2 trial of AS and A10 for colon cancer and with responses to previous targeted therapies. As shown in Table 10, the response rate in the current treatment group was very high, with four patients achieving a complete response (CR), one patient achieving a partial response (MR), and one patient achieving complete survival (SD), whereas no objective responses were observed in clinical trials or previous targeted therapies.

[0325]

[0326]

[0327] Table 10 - Comparison of the use of the antineoplastic AS2-1 and targeted agents in colorectal cancer versus AS2-1 alone and prior targeted therapy

[0328]

[0329] Patients experienced significant improvements and reductions in the concentrations of mutant genomic markers in their blood, which are summarized in Table 11. Before treatment, the estimated survival was less than 4 to 6 months. However, after treatment, the 4-year survival rate was 77.8%.

[0330] Table 11 - Genes affected by antineoplastic AS2-1 according to clinical outcome in colorectal cancer

[0331]

[0332] An additional group of 8 patients treated according to the weight-of-trial approach was not evaluated in this report. Of these, 4 died of cancer and were classified as PD, but 4 achieved MR, 3 are alive, and 1 died of other causes. In this expanded group, responses were as follows: CR (4 patients), 25%; PR (0 patients), 0%; MR (7 patients), 43.7%; SD (1 patient), 6.2%; PD (4 patients), 25%; and OR (12 patients), 74.9%.

[0333] Head and Neck Cancer. A group of four patients diagnosed with end-stage head and neck cancer were eligible for inclusion in this report. This group included three men and one woman. Their medical history ranged from 2 to 14 years, and their life expectancy ranged from less than 1 month to 6 months. These patients had extensive metastatic disease that had spread to the lymph nodes, lungs, pleura, liver, and bones. Their pathological diagnoses included squamous cell epithelial carcinoma, mucoepidermoid carcinoma of the submandibular gland, and poorly differentiated acinar cell carcinoma of the parotid gland. Their previous treatments included surgery, radiotherapy, three chemotherapy regimens, and two targeted therapies; surgery, radiotherapy, and targeted therapy; surgery, radiotherapy, and two chemotherapy regimens; and radiotherapy and targeted therapy (Table 12).

[0334] Table 12 - Demographics of patients with head and neck cancer

[0335]

[0336]

[0337] Patients were treated as described above. Details and results of the treatment are provided in Tables 13, 14, and 15. A single patient achieved PR, MR, and SD, and one patient developed PD. Genomic analysis showed activity against two mutated genes and one amplified gene (Table 15). Table 14 summarizes the responses compared to previous AS and A10 clinical trials and targeted therapies (which showed no OR).

[0338]

[0339]

[0340] Table 15 - Genes potentially affected by AS2-1 based on clinical results (tissue genomic analysis) in stage IV head and neck cancer

[0341] patient mutation 1HK ARID1A.GNAQ 2HK GATA3 amplification 3HK NA

[0342] Before treatment, estimated survival ranged from less than 1 month to 6 months. As a result of treatment, survival was extended to more than 4 to more than 12 months, with symptomatic improvement. Two patients in the additional group treated according to the right-to-try approach were not evaluated in this report. Both patients discontinued treatment before response assessment. Both patients are currently alive.

[0343] Kidney cancer. Two patients diagnosed with end-stage renal cell carcinoma were eligible for inclusion in this report. Both patients were 39-year-old men. Their medical history ranged from 1 to 3 years, and their estimated survival ranged from less than 2 months to less than 6 months. These patients had extensive metastatic disease that had spread to the lymph nodes, lungs, brain, bones, and contralateral kidney. The pathological diagnosis was renal cell carcinoma. Previous treatment for one patient included surgery, three radiotherapy regimens, and targeted therapy, while the second patient's previous treatment included two surgeries and targeted therapy (Table 16).

[0344] Table 16 - Demographics of Renal Cancer Patients

[0345] feature N＝2 Age (years) 39 2 Disease duration (years) 1-3 2 Estimated survival time (months) <2-<6 Metastatic sites LYM, PUL, BRA, contralateral kidney 1 LYM, PUL, BRA, OSS 1 Previous treatment 1KI SU, 3RT, TT 2KI 2SU、TT

[0346] Patients were treated as described above. Details of treatment and outcomes are provided in Tables 17 and 18. One patient achieved a PR and another achieved a CR. Genomic analysis demonstrated effects on CDKN2A / B, SDKN2A, PTENY27C, and AKT2 proliferation (Table 19). Table 18 summarizes responses compared to clinical trials with AS and A10 and previous targeted therapies, which did not achieve any objective responses.

[0347]

[0348] Table 18 - Comparison of the use of the antineoplastic AS2-1 and targeted agents in the treatment of renal cell carcinoma (stage IV) versus AS2-1 alone and prior targeted therapy

[0349]

[0350] Table 19 - Genes potentially affected by AS2-1 based on clinical results (tissue genomic analysis) in stage IV renal cell carcinoma

[0351] patient mutation 1KI CDKN2A / B, SDKN2A 2KI PTEN Y27C, AKT2 amplification

[0352] Estimated survival before treatment was less than 2 and 6 months, but after treatment, survival increased to more than 7 and 11 months, with associated clinical improvement. Only one other patient with this type of cancer who received right-to-try treatment discontinued treatment within less than 60 days and died of unexplained causes.

[0353] Lung cancer. A total of 7 terminal patients received treatment, including 4 males and 3 females, 1 of whom was 23 years old, and the remaining patients were between 53 and 79 years old. Five patients had a history of less than one year, and two patients had a history of 3 to 5 years. All patients were diagnosed with non-small cell epithelial carcinoma. One case was squamous cell epithelial carcinoma and six were adenocarcinoma. The patients had extensive metastases, including lymph nodes, lungs, pleura, liver, brain, bones, peritoneum, pericardium, adrenal glands, thyroid, spleen and muscle metastases. The estimated survival time of two patients was less than 3 months, one patient was less than 4 months, and four patients were less than 6 months. Two patients had previously received surgery, radiotherapy and chemotherapy, one patient had received two radiotherapy treatments and three chemotherapy treatments, one patient had only surgery, and two patients had only received targeted therapy. One patient had not received previous treatment (Table 20).

[0354] Table 20 - Demographics of Lung Cancer Patients

[0355]

[0356]

[0357] Patients were treated as described above. Treatment details and responses are provided in Tables 21 and 22. One patient achieved a complete response (CR), four achieved a partial response (PR), and two achieved a partial response (MR). Table 22 summarizes the patient responses and compares them with responses in clinical trials of AS and A10, as well as with responses to previous targeted therapies, which showed no positive responses. Table 23 lists the genes affected by AS.

[0358]

[0359] Table 22 - Comparison of the use of the antineoplastic agent AS2-1 and targeted drugs in the treatment of stage IV lung cancer with multiple metastases versus AS2-1 alone and prior targeted therapy

[0360]

[0361] Table 23 - Genes potentially affected by AS2-1 based on clinical results (tissue genomic analysis) in stage IV lung cancer with multiple metastases

[0362] 1LU EWSR1-F LI1 fusion 2LU TERT promoter SNV 3LU FBXW7 Y545C 4LU SMAD4 A406T 5LU EGFR P753L (possibly) 6LU NF1 splice site SNV 7LU TP53 Y126D and R273H

[0363] Two patients had an estimated survival of less than 3 months, one less than 4 months, and the remaining less than 6 months. Following treatment, thr...

Claims

1. A method for treating cancer, comprising: A therapeutically effective amount of a precision cancer therapy is administered to a subject in need thereof, wherein the subject exhibits a tumor response and / or a molecular response to the precision cancer therapy.

2. The method of claim 1, wherein the precision cancer therapy comprises one or more antineoplastons, or the precision cancer therapy comprises a composition comprising one or more antineoplastons.

3. The method of claim 2, wherein the one or more antineoplastons comprise phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or a combination thereof, or the composition comprising the one or more antineoplastons comprises phenylacetate, phenylacetylglutamine salt, sodium phenylacetylglutamine, sodium phenylacetylisoglutamine, or a combination thereof.

4. The method of claim 2 or claim 3, wherein the composition comprising one or more antineoplastons comprises a pharmaceutically acceptable carrier.

5. The method of claim 3, wherein the one or more antineoplastons include sodium phenylacetylglutamine (PG) and sodium phenylacetylisoglutamine (iso-PG).

6. The method of claim 5, wherein the ratio of sodium phenylacetylglutamine (PG) to sodium phenylacetylisoglutamine (iso-PG) is about 4:

1.

7. The method of claim 5, wherein the dosage of sodium phenylacetylglutamine (PG) comprises about 0.4 g / kg / day to about 16 g / kg / day, and wherein the dosage of sodium phenylacetylisoglutamine (iso-PG) comprises about 0.1 g / kg / day to about 4 g / kg / day.

8. The method of claim 3, wherein the one or more antineoplastons comprise phenylacetate (PN) and phenylacetylglutamine (PG).

9. The method of claim 8, wherein the ratio of phenylacetate (PN) to phenylacetylglutamine (PG) is about 4:

1.

10. The method of claim 8, wherein the dosage of phenylacetate (PN) comprises about 0.064 g / kg / day to about 0.48 g / kg / day, and wherein the dosage of phenylacetylglutamine (PG) comprises about 0.016 g / kg / day to about 0.12 g / kg / day.

11. The method of claim 1, wherein administering the precision cancer therapy comprises intravenous administration.

12. The method of claim 1, further comprising obtaining a biological sample from the subject prior to administering the precision cancer therapy.

13. The method of claim 1, further comprising obtaining a biological sample from the subject after administering the precision cancer therapy.

14. The method according to any one of claims 12-13, further comprising performing cell-free DNA (cfDNA) analysis on the biological sample.

15. The method of claim 14, wherein the cfDNA analysis comprises next generation sequencing.

16. The method of claim 15, wherein next generation sequencing comprises sequencing one or more cancer-related genes.

17. The method of claim 17, wherein sequencing one or more cancer-related genes comprises identifying one or more genomic aberrations.

18. The method of claim 17, wherein the one or more genomic aberrations comprise somatic genomic aberrations.

19. The method of claim 18, wherein the one or more somatic genomic aberrations comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, or any combination thereof.

20. The method of claim 17, wherein the subject is diagnosed as needing precision cancer treatment when the expression and / or amount of one or more genomic aberrations in the biological sample before treatment is higher than the expression and / or amount of the same one or more genomic aberrations in the control sample.

21. The method of claim 20, wherein the control sample is a sample obtained from a subject who does not have cancer.

22. The method according to claim 16, wherein the cancer-related genes include: ACO2; AKT; ASK; ASPM; ATF3; BAD; BAX; BCL2; BDNF; BLM; BRAF; BUB1; CASP5; CCL2; CCNA2; CCNB1; CCNB2; CCND; CCND3; CCNE1; CNE2; CDC2; CDC42; CDC6; CDC; CDC20; CDC25A; CDC25B; CDC25C; CDCA8; CDK2; CDK3; CDK4; CDK6; CDKN1A; CDKN1B; CDKN2A; CDKN2B; CDKN2C; CFS1; CHK-1; CLDND1; C SF1; CSF3; CXCL2; DLD; DLST; DUSP1; DUSP6; E2F1; ERK; FH; GADD45A; HDAC; HDAC5; HIF1; IDH2; IDH3A; IDH3B; IL1; IL1A; IL1B; IL6; IL8; IL15; JUN; MA or any combination thereof.

23. The method according to claim 16, wherein the cancer-related genes include: ALK, H3F3A, AKT1, HIST1H1D, APC, IDH1, AR, JAK2, ARAF, KIT, ARID1A, KRAS, ARID2, MAP2K1, ASXL1, MAP2K4, ATRX, MAP3K1, BRCA1, MAP3K6, BRCA2, MET, BRAF, MPL, CCND1, MYC, CCNE1, NF1, CDK4, NOTCH1, CDK6, CDKN2A, PDGFRA, CTNNB1, PIK3CA, DDR2, PIK3R1, EGFR, PTCH1, PTEN, EWSR1, FBXW7, RB1, FGFR, RUNX1, FGFR1, SMAD4, FGFR2, SPEN, FGFR3, SRSF2, GATA3, STAT5B, GNA, GNAQ, TET2, GNAS, TP53, Tert promoter, or any combination thereof.

24. The method of claim 17, wherein the precision cancer therapy continues to be administered to the subject when the expression and / or amount of one or more genomic aberrations in the biological sample after treatment is lower than the expression and / or amount of the same one or more genomic aberrations in the sample before treatment.

25. The method of claim 17, wherein the precision cancer therapy continues to be administered to the subject when the expression and / or amount of one or more genomic aberrations in a post-treatment biological sample is lower than the expression and / or amount of the same one or more genomic aberrations in a previous post-treatment sample.

26. The method of claim 1, further comprising measuring the subject's tumor response to the precision cancer therapy.

27. The method of claim 1, further comprising measuring the subject's molecular response to the precision cancer therapy.

28. The method of claim 27, wherein the subject's molecular response comprises a decrease in the number of genomic aberrations in a post-treatment biological sample obtained from the subject.

29. The method of any preceding claim, further comprising administering to the subject one or more additional therapeutic agents.

30. The method of claim 29, wherein the one or more additional therapeutic agents comprises a chemotherapeutic agent, a monoclonal antibody, a small molecule, or any combination thereof.

31. The method of claim 29, wherein the additional therapeutic agent comprises bevacizumab, pazopanib, sorafenib, dasatinib, everolimus, or any combination thereof.

32. The method of claim 30, wherein the monoclonal antibody comprises: Ado-trastuzumab, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, cemiplimab, cetuximab, daratumumab, denosumab, denutumab, durvalumab, elotuzumab, gemtuzumab, ibritumomab tiuxetan, inotuzumab, ipilimumab, necituzumab, nivolumab, obinutuzumab, ofatumumab, olaratumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab, trastuzumab, or any combination thereof.

33. The method of claim 30, wherein the small molecule comprises: Abemaciclib, afatinib, alectinib, abolib, axitinib, bimetinib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, gilteritinib, cometinib, copalixoxib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelithib, encofenib, entrectinib, erdafitinib, erlotinib, gefitinib, ibrutinib, ibrutinib, Matinib, ivosidenib, lapatinib, larotrectinib, lenvatinib, lorlatinib, marizomib, neratinib, nilotinib, niraparib, olaparib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sorafenib, sunitinib, tazopanib, trametinib, vandetanib, vemurafenib, or any combination thereof.

34. A method according to any preceding claim, further comprising repeating one or more steps of the method.

35. The method of claim 34, wherein repeating one or more steps of the method comprises: repeatedly administering the precision cancer therapy to the subject, repeatedly measuring the subject's tumor response, repeatedly obtaining biological samples from the subject, Repeating the cfDNA analysis on the biological sample, Repeated administration of one or more additional therapeutic agents, or Any combination thereof.

36. The method according to any of the preceding claims, wherein the subject has not received treatment prior to the implementation of the precision cancer therapy.

37. The method of any preceding claim, wherein the subject has received treatment prior to the precision cancer therapy being implemented.

38. The method according to any of the preceding claims, wherein the subject has received surgery, antibody therapy, chemotherapy, radiation therapy, immunotherapy, or any combination thereof prior to the implementation of the precision cancer therapy.

39. The method according to any preceding claim, wherein the subject in need thereof has been diagnosed with cancer.

40. The method of claim 39, wherein the cancer comprises a solid tumor.

41. The method of claim 39, wherein the cancer comprises metastatic cancer and / or terminal cancer.

42. The method of claim 39, wherein the cancer comprises: Adenocarcinoma (including appendix and cervix), adenoid cystic epithelial carcinoma, adult T-cell leukemia, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, astrocytoma, basal cell epithelial carcinoma, B-cell carcinoma, benign and malignant lymphoma, biliary tract-cholangiocarcinoma, intestinal cancer, brain cancer (including anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, brain stem anaplastic astrocytoma, brain stem glioma, diffuse astrocytoma, DIPG h3k27 mutation, ganglioglioma, glioblastoma multiforme, medulloblastoma, pilocytic astrocytoma, brain stem glioma), breast cancer, mammary epithelial carcinoma, Burkitt's lymphoma, bladder cancer and urothelial carcinoma, epithelial carcinoma of unknown primary, carcinosarcoma, cervical cancer, bile duct cancer, chronic atypical myeloid leukemia, chronic atypical myeloid leukemia, colon cancer, colorectal cancer, diffuse astrocytoma, diffuse intrinsic pontine glioma (DIPG), endometrial carcinoma, endometrial epithelial carcinoma, ependymoma, esophageal cancer and esophageal epithelial cancer, Eustachian sarcoma, ganglioglioma, gangliocytoma, gastrointestinal stromal tumor (GIST), glioblastoma, glioma, head and neck cancer and head and neck epithelial cancer, angiosarcoma, hepatocellular carcinoma, renal cell carcinoma, Hodgkin's disease, Kaposi's sarcoma, renal cancer and renal epithelial cancer, large B-cell lymphoma, leptomeningeal carcinomatosis, leukemia, liposarcoma, hepatocarcinoma, lung epithelial cancer (non-small cell and small cell epithelial cancer), medulloblastoma, melanoma, meningeal sarcoma, meningioma , multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, myeloid sarcoma, neuroblastoma, neuroendocrine epithelial cancer, neurofibroma, non-Hodgkin lymphoma, oligodendroglioma, osteosarcoma, ovarian cancer and ovarian epithelial cancer, pancreatic cancer and pancreatic epithelial cancer, peripheral neuroepithelial tumor, peripheral T-cell lymphoma, Philadelphia chromosome positive and positive CML, pilocytic astrocytoma, pineal cell tumor, pleomorphic sarcoma, pre-B lymphoma, primitive neuroectodermal tumor (PNET), pre- prostate cancer and prostate epithelial cancer, refractory anemia, salivary gland epithelial cancer, sarcoma, Schwannoma, skin cancer and skin epithelial cancer, squamous cell epithelial cancer, gastric cancer and gastric epithelial cancer, synovial sarcoma, testicular cancer, thyroid cancer and thyroid epithelial cancer, T-line acute lymphoblastic leukemia (T-all), T-line lymphocytic lymphoma (T-LL), urinary tract cancer and urinary tract high-grade epithelial cancer, uterine, cervical, vulvar and / or endometrial epithelial cancer, Wilms' tumor or teratoma, or any combination thereof.

43. The method of any preceding claim, further comprising monitoring the subject for adverse reactions.

44. The method of claim 43, wherein in the absence of adverse reactions, the method further comprises continuing to administer the cancer precision therapy to the subject.

45. The method of claim 43, wherein in the presence of an adverse reaction, the method further comprises modifying one or more steps of the method.

46. ​​The method of claim 45, further comprising treating one or more of the adverse events.

47. The method of claim 45, wherein modifying one or more steps of the method comprises modifying an administering step.

48. The method of claim 47, wherein modifying the administering step comprises: Including changing the amount of the one or more antineoplastons or compositions comprising one or more antineoplastons administered to the subject, changing the frequency of administering the one or more antineoplastons or compositions comprising one or more antineoplastons to the subject, changing the duration of administering the one or more antineoplastons or compositions comprising one or more antineoplastons, changing the route of administration of the one or more antineoplastons or compositions comprising one or more antineoplastons administered to the subject, or any combination thereof.

49. The method of any preceding claim, wherein treating the cancer comprises: The invention also includes improving the survival of the subject, increasing the length of time before metastasis, reducing the likelihood of surgical intervention, reducing the need for administration of one or more additional therapeutic agents or treatment regimens, reducing the size of one or more tumors in the subject, eliminating one or more tumors in the subject, reducing or eliminating the prevalence of one or more genomic aberrations, restoring normal metabolism to one or more organ systems in the subject, restoring one or more aspects of cellular homeostasis and / or cellular function, and / or metabolic dysregulation; or any combination thereof.

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