Methods for treating renal cell carcinoma or cancer

Abstract

This method involves treating an individual diagnosed with renal cell carcinoma with a therapeutically effective amount of hydroxyurea methyl acyl fulvene. The treatment is applicable to various types of renal cell carcinoma, including clear cell renal cell carcinoma, papillary renal cell carcinoma, suspected renal cell carcinoma, manifold carcinoma and myeloid carcinoma.

Description

[0001] Cross-references to related applications

[0002] This international patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 451,159, filed March 9, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the treatment of renal cell carcinoma or cancer, and more specifically, this application relates to compositions comprising acyl-richene and methods of treating renal cancer using acyl-richene. Background Technology

[0004] Kidney cancer is also considered one of the ten most common cancers worldwide, affecting approximately 1 in 63 people in their lifetime. Primarily, this type of cancer affects adults between the ages of 50 and 80. A significant trend has been observed, with North America currently reporting the highest incidence of kidney cancer. However, in developing countries, cases have been steadily and alarmingly rising over the past three decades, highlighting the increasing global burden of this disease.

[0005] Renal cell carcinoma (also known as kidney cancer or renal cell adenocarcinoma) is characterized by the growth of malignant (cancer) cells within the inner lining of the renal tubules (the tiny tubules inside the kidneys). Located on each side of the spine and above the lower back, the kidneys function as the body's natural filtration system. They filter blood, removing waste products and converting them into urine. This urine then travels from each kidney through tubes called ureters to the bladder, where it is stored until it is expelled through the urethra. The most common form of kidney cancer is renal cell carcinoma (RCC), which primarily affects the tiny tubules within these organs.

[0006] Treatment of renal cell carcinoma (RCC) represents a major challenge in the medical field. Due to the limited availability of effective therapies, it is considered one of the most difficult malignancies to manage effectively. Currently, biotherapy offers some degree of benefit to patients with RCC, albeit minimally. Substantial drug resistance, often associated with RCC, further complicates treatment; although theoretical explanations suggest the role of the expression of certain membrane transport proteins and altered metabolism, the exact mechanisms underlying this resistance remain unclear. Despite ongoing research, there is a persistent shortage of anticancer drugs specifically developed for RCC, highlighting the urgent need for innovative treatments and research in this area.

[0007] Therefore, there is always a need for improved methods of treating kidney cancer. Summary of the Invention

[0008] The present application discloses the discovery of the use of acylfulvene to treat kidney cancer or renal cancer in a subject. In one aspect, the present application provides a method for treating kidney cancer by administering to a diseased subject a therapeutically effective amount of acylfulvene or a pharmaceutically acceptable salt thereof.

[0009] Another aspect includes a therapy comprising administration of a combination of active agents, including illudin or an illudin analog, such as acylfulvene.

[0010] Another aspect provides a pharmaceutical composition comprising illudin or an illudin analog (e.g., acylfulvene) or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically suitable carrier or excipient in a dosage to treat or prevent kidney cancer. The pharmaceutical composition can also be administered in combination with other therapeutic agents or modalities, either simultaneously, sequentially, or alternately.

[0011] One aspect provides a method for treating a subject, particularly a human cancer patient, in need of acylfulvene treatment. This includes patients whose kidney cancer has become refractory to standard chemotherapy regimens or whose cancer has relapsed after standard chemotherapy. This encompasses kidney cancers such as metastatic cell carcinoma, nephroblastoma (nephroblastoma), renal sarcoma, and various benign (non-cancerous) kidney tumors such as renal adenoma, oncocytoma, and angiomyolipoma, with particular emphasis on clear cell renal cell carcinoma.

[0012] Another aspect includes a therapy or method of treatment for kidney cancer that is resistant to standard therapy or is metastatic, encompassing a range of conditions from clear cell carcinoma of the kidney, metastatic cell carcinoma, nephroblastoma (nephroblastoma), renal sarcoma, to benign kidney tumors (including renal adenoma, oncocytoma, and angiomyolipoma).

[0013] Another aspect includes a therapy in which the acylfulvene is (-)-hydroxyureamyl acylfulvene.

[0014] Another aspect includes a method for treating kidney cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of hydroxyureamyl acylfulvene. The hydroxyureamyl acylfulvene can be (-)-hydroxyureamyl acylfulvene, or the hydroxyureamyl acylfulvene is (+)-hydroxyureamyl acylfulvene. The hydroxyureamyl acylfulvene can be administered at a dosage range of 0.1 mg / kg body weight to 100 mg / kg body weight per day. The kidney cancer can be clear cell renal cancer, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and collecting duct carcinoma.

[0015] Another aspect includes a pharmaceutical composition for treating kidney cancer, the pharmaceutical composition comprising hydroxyureamyl acylfulvene and a pharmaceutically acceptable carrier. The hydroxyureamyl acylfulvene can be administered in combination with at least one other anti-cancer agent.

[0016] Another aspect includes a treatment that results in a decrease in tumor size or progression.

[0017] Another aspect of the present application includes the treatment of cancer, which can include solid tumors and hematological malignancies. BRIEF DESCRIPTION OF DRAWINGS

[0018] A better understanding of the features and advantages of the present application will be obtained by reference to the following detailed description and accompanying drawings, which set forth illustrative embodiments in which the principles of the application are utilized, and in which:

[0019] Figure 1 The use of LP-184 on various renal cell lines is exemplified, including epithelial and cancer types;

[0020] Figure 2 Cells containing 6-4 photoproducts (6-4PP) are shown to be significantly eradicated after 5 and 7 hours;

[0021] Figure 3 Western blot analysis of cell lines from previous studies is presented; and

[0022] Figure 4 Sensitivity of various cell lines to LP-184 is shown, noting a significant decrease in cell viability over 72 hours. DETAILED DESCRIPTION

[0023] The present application provides therapeutic methods for treating renal cell carcinoma or cancer in a subject. One embodiment describes a method for treating a subject having renal cell carcinoma, the method comprising administering an effective amount of acylfulvene (e.g., hydroxyureamethyl acylfulvene) or a salt thereof. In other embodiments, the therapy comprises administration of a combination of various treatments. One embodiment can specifically include renal cell carcinoma (RCC). Renal cell carcinoma can include clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and other rare types of renal cell carcinoma (such as collecting duct RCC, polycystic RCC, medullary carcinoma, mucinous tubular and spindle cell carcinoma, neuroblastoma-associated RCC, and unclassified renal cell carcinoma), as well as metastatic RCC. In another embodiment, renal cancer is defined to include metastatic cell carcinoma, nephroblastoma (Wilms' tumor), renal sarcoma, and benign (non-cancerous) kidney tumors, such as renal adenoma, hamartoma, and angiomyolipoma.

[0024] Cryptochrysin or acylfulvene

[0025] In one embodiment, the use of illudins or illudin analogs such as acylfulvene is discussed herein. Acylfulvenes represent a class of cytotoxic semi-synthetic derivatives derived from illudin, a natural compound extracted from the bioluminescent Omphalotus olearius. Acylfulvenes are generated from the sesquiterpene illudin S by acid treatment (reverse Prins reaction) and exhibit significantly lower reactivity towards thiols compared to illudin S.

[0026] As an example, acylfulvene, specifically (-)-hydroxymethyl acylfulvene (referred to as LP-184, Lantern Pharma Inc.), is exemplified below, which induces a positive shift in light:

[0027]

[0028] In another example, the acylfulvene used is (+)-hydroxymethyl acylfulvene (referred to as LP-284, Lantern Pharma Inc.), which induces a negative shift in light, as exemplified below:

[0029]

[0030] (+)-hydroxymethyl acylfulvene and (-)-hydroxymethyl acylfulvene are enantiomers and are now well known.

[0031] In another example, the acylfulvene discussed is ilofulvene.

[0032] In one embodiment, the patient is treated with radiation prior to, concurrently with, and / or after treatment with acylfulvene.

[0033] In one embodiment, the method comprises administering acylfulvene to treat a kidney cancer. As used herein, the term “kidney cancer” refers to a cancer that originates in the kidney, as generally understood in the medical arts. In some embodiments, the kidney cancer is renal cell carcinoma (RCC). The terms “renal cell cancer” and “renal cell carcinoma” refer to a cancer that originates in the inner lining of the proximal convoluted tubule. Specifically, RCC includes several common histological subtypes: clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, and medullary carcinoma, with clear cell renal cell carcinoma (ccRCC) being the most common subtype.

[0034] In another embodiment, a method of treating a conventional or clear cell renal cell carcinoma is provided. The cells can be abnormal cells. They can be studied in vitro or in vivo. In certain embodiments, the cells are proliferative cells or stem cells.

[0035] In another embodiment, the second therapeutic agent can consist of one or more chemotherapeutic agents selected from the group consisting of camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and a Raf kinase inhibitor.

[0036] In another embodiment, the second therapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of paclitaxel and cisplatin.

[0037] Another embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of cryptophycin or a cryptophycin analog, derivative, or pharmaceutically acceptable salt thereof; and a therapeutically effective amount of spironolactone or an analog, derivative, or pharmaceutically acceptable salt thereof. The cryptophycin analog can be N-2'-hydroxycarbonyl-methyloxy-acyl- fulvene.

[0038] In another embodiment, a kit for treating a cancer in a subject comprises a therapeutically effective amount of cryptophycin or a cryptophycin analog, derivative, or pharmaceutically acceptable salt thereof; and a therapeutically effective amount of spironolactone or an analog, derivative, or pharmaceutically acceptable salt thereof.

[0039] In another embodiment, the second therapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and a Raf kinase inhibitor.

[0040] In another embodiment, the second therapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of paclitaxel or cisplatin.

[0041] In one embodiment, elevated expression of the ACTB gene or protein indicates more effective treatment with LP-184 or (-)-N-2'-hydroxycarbonyl-methyloxy-acyl-fulvene. The ACTB gene encodes beta-actin, which is part of the actin family. This family forms organized networks called the actin cytoskeleton, which provides structural support within cells. Of the six different types of actin, four are specific to muscle cells, helping the muscle to contract, while the remaining two, beta-actin and gamma-actin, which originate from the ACTG1 gene, are ubiquitous in various cell types throughout the body. In the treatment of renal cancer involving ACTB (beta-actin) measurements, the "predetermined level" can be a specific concentration of ACTB in a patient's tissue or blood sample.

[0042] The term "combination therapy" includes administration of the aforementioned therapeutic agents in conjunction with other biologically active ingredients and non-pharmaceutical therapies (e.g., surgery or radiation treatment). If the combination therapy includes a non-pharmaceutical treatment, the treatment can occur at any suitable time, provided that the combination of the therapeutic agent and the non-pharmaceutical treatment has a beneficial effect. For example, a beneficial effect can be realized even if the non-pharmaceutical treatment is temporally separated from the administration of the therapeutic agent, perhaps by days or even weeks.

[0043] In another aspect, the composition or combination therapy, or a pharmaceutically acceptable salt or solvate thereof, can be administered in combination with radiation therapy. Radiation therapy can be administered with the composition from the present invention and another chemotherapeutic agent as part of a multi-agent therapy.

[0044] Combination therapy can include administration of two or more agents, such as acifran, spironolactone, and one or more other therapeutic agents, each formulated and administered separately or by administration of multiple agents in a single formulation. Various combinations are possible under combination therapy. For example, two agents can be combined in one formulation and administered with a separate formulation containing a third agent. While these agents can be administered simultaneously, they can also be administered sequentially with intervals ranging from minutes to weeks.

[0045] Therapeutically effective dosages can vary according to the condition being treated, the severity of the condition, the route of administration, the age and health of the patient, excipient usage, potential concomitant therapies, and the judgment of the medical practitioner. Effective dosages can be guided by the prescribing information for hydroxymethyl acifran or relevant medical literature.

[0046] The term "effective amount" refers to the amount of an agent that is sufficient to reduce one or more symptoms of a disease or disorder. A "therapeutically effective amount" is an amount that is sufficient to provide a desired effect in a typical patient. An "effective amount" can delay the progression of symptoms, alter the disease course, or reverse disease symptoms. The precise "effective amount" can vary and should be determined by medical professionals through routine experimentation.

[0047] According to the methods described herein, a "subject in need thereof is a subject diagnosed with a kidney cancer, has an increased risk of kidney cancer compared to the general population, or has not shown a significant response to existing cancer therapies. In this context, "non-responsive" or "refractory" indicates insufficient clinical improvement following treatment. In some scenarios, a subject in need is a cancer patient whose disease is refractory to standard therapies or relapsed after standard therapies.

[0048] The dosage range of the agent to be administered depends, as described herein, on factors such as the form, potency of the agent, and the desired degree of symptom, marker or condition indicator reduction, such as a targeted percentage reduction in tumor growth. The dosage should not be so large as to cause adverse side effects. Generally, the dosage will vary with the age, condition, and sex of the patient and can be determined by a skilled professional. Moreover, the dosage can be adjusted by the individual physician, depending on the judgment of the physician and the condition of the patient.

[0049] The term "therapeutically effective amount" refers to an amount of an agent sufficient to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be assessed by any known assay. The precise amount required can depend on factors such as the subject's body mass, size, and health; the nature and extent of the condition; and the therapy or combination of therapies selected. A therapeutically effective amount can be determined by a skilled clinician, based on their skill and judgment, through routine experimentation. Preferably, the condition to be treated is cancer, but it can also be a cell proliferation disorder.

[0050] A skilled clinician can assess the efficacy of an agent in treating a condition described herein or in inducing a described response (e.g., for a solid). Treatment is considered "effective" if it beneficially alters one or more signs or symptoms of the condition, ameliorates other clinically acceptable symptoms, or induces at least 10% of the desired response as described. Efficacy can be assessed by measuring markers, indicators, symptoms, incidence of the condition being treated, or any other quantifiable parameter such as tumor size and / or growth rate. Moreover, efficacy can be assessed by lack of disease progression, as indicated by lack of hospitalization or need for additional medical intervention. Methods for measuring these indicators are well known to those skilled in the art.

[0051] Typical starting doses in a clinical trial range from 6 mg / m 2 to 12.5 mg / m 2 intravenously, typically on a schedule such as once every three or four weeks. In some cases, the effective dose can be the maximum tolerated dose.

[0052] The dose to be administered should be tailored to the needs of the individual. It is known that in humans, spironolactone is administered at a dose of 25 mg to 50 mg per day for heart failure, and 100 mg to 400 mg per day for hyperaldosteronism. Studies explore the use of spironolactone in the range of 25 mg to 400 mg, taking into account its potential adverse effects. For cancer treatment, the dose can be in the range of 25 mg to 400 mg per day. By way of example, the spironolactone dose concentration utilized can be in the range of 5 µM to 25 µM in mice (intraperitoneally), and in the range of 20 mg to 200 mg per day in a clinical setting in humans (orally).

[0053] The term "treatment" encompasses therapeutic and prophylactic treatment, aimed at reducing, inhibiting, attenuating, diminishing, arresting or stabilizing the development or progression of a disease, reducing the severity of a disease, or ameliorating symptoms associated with a disease.

[0054] The pharmaceutical composition can be included in a container, pack, or dispenser together with instructions for administration.

[0055] The compositions of the present application can form salts, more than one salt per molecule is possible, including mono, di, tri, etc. All such forms are contemplated within the scope of the present application.

[0056] "Pharmaceutically acceptable salts" refer to derivatives of the compounds of the application wherein the parent compound is modified by making acid or base salts thereof. Examples include inorganic salts or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids or bases, such as those given herein.

[0057] The term "selectively" means a preference for occurring in one population over another, often referring to different cell populations, where for example, a compound of the application acts more frequently or more effectively on cancer cells than on normal cells.

[0058] Routes of administration of the compositions, or pharmaceutically acceptable salts or solvates thereof, include oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral routes. In one embodiment, the compound is administered orally. The appropriate route of administration can be determined based on advantages recognized by those skilled in the art.

[0059] The formulation and administration of the disclosed compounds are well documented and can be found in standard reference texts, such as Remington: The Science and Practice of Pharmacy. The compounds, including pharmaceutically acceptable salts, can be used in pharmaceutical preparations with appropriate carriers or diluents, wherein the dosage is adjusted to provide the desired amount of activity in the range under discussion.

[0060] Techniques for formulating and administering the compounds disclosed herein are well- documented in standard references and are available, such as "Remington: The Science and Practice of Pharmacy, 19thedition." These compounds, including their pharmaceutically acceptable salts, are suitable for pharmaceutical preparations with appropriate carriers or diluents. The compositions will contain amounts of the compounds sufficient to provide the desired dosage in the range described herein.

[0061] All percentages and ratios used herein are by weight, unless otherwise specified. The features and advantages of the present application are apparent from the examples provided, which illustrate various components and methods. These examples should not be construed as limiting the scope of the present application. Based on the disclosure provided herein, one skilled in the art can identify additional components and methods that are suitable for use in practicing the present application.

[0062] A "subject in need thereof includes an individual having a precancerous condition or cancer. Subjects encompass mammals, such as humans, primates, dogs, cats, mice, rats, horses, and livestock. Preferably, the subject is a human diagnosed with a cancer or precancerous condition, showing symptoms of a cancer or precancerous condition, or at risk of developing a cancer or precancerous condition.

[0063] A subject can have a refractory or resistant cancer, meaning that the cancer does not respond to treatment or stops responding. This resistance can be inherent at the start of treatment, or can develop over time. In some cases, a subject can experience a relapse of cancer after a remission period, or can have exhausted all known effective cancer treatments.

[0064] In some cases, a subject can have a secondary cancer, which is caused by a previous cancer treatment, such as chemotherapy or radiation therapy.

[0065] Cancer symptoms vary widely depending on the location, size of the cancer, and its effect on surrounding organs or tissues. If the cancer has metastasized, symptoms can manifest in different parts of the body.

[0066] Treatment success is typically measured by a reduction in tumor size, referred to as "tumor regression." Ideally, after treatment, the tumor size is reduced by a significant percentage relative to the size before treatment.

[0067] Similarly, a successful treatment can result in a reduction in the number and size of tumors. This can be quantified by a significant percentage reduction relative to the condition before treatment.

[0068] An effective cancer treatment can also result in a reduction in the number of metastatic lesions in tissues or organs away from the primary tumor site, with a significant reduction in the number of lesions after treatment.

[0069] An increase in the average survival time of treated subjects compared to subjects receiving standard of care or placebo can indicate an effective treatment. This increase in survival time is preferably over a certain number of days, highlighting the efficacy of the treatment.

[0070] In addition, effective treatment of cancer can result in an increase in the average survival time compared to subjects not receiving treatment or receiving a different monotherapy.

[0071] Successful treatment of cancer can also result in a significant decrease in the population mortality rate, indicating the effectiveness of the treatment compared to no treatment or a different treatment option.

[0072] Effective treatment of cancer can result in a decrease in the rate of tumor growth. Ideally, the rate of tumor growth decreases by a significant percentage after treatment, showing the ability of the treatment to slow or stop tumor progression.

[0073] Additionally, successful treatment can result in a decrease in tumor regrowth. The likelihood or extent of tumor recurrence is significantly decreased after the initial treatment phase, further demonstrating the long-term effectiveness of the treatment.

[0074] In the context of treating or preventing a cell proliferation disorder, an impactful outcome includes a decrease in the rate of cell proliferation. This rate is significantly decreased after treatment, indicating a slowing of the proliferation of potentially cancerous or abnormal cells.

[0075] In addition, treatment or prevention of such disorders can result in a decrease in the proportion of proliferating cells. This outcome is typically measured by mitotic index or similar indicators, indicating a beneficial shift toward a lower degree of uncontrolled cell division.

[0076] A significant therapeutic effect is also seen in a decrease in the size of areas or regions of cell proliferation. These areas, indicative of aggressive or uncontrolled cell growth, are significantly decreased after treatment, reflecting the efficacy of the treatment in targeting and limiting cancer growth.

[0077] Another positive outcome is a decrease in the number or proportion of cells exhibiting abnormal appearance or morphology. This change, observable under a microscope, indicates normalization of cellular structures potentially affected by cancerous transformation.

[0078] Application of the compositions of the present invention to a cell or subject in need thereof can result in modulation of protein methyltransferase activity. This effect, whether stimulatory or inhibitory, is selectively targeted to cancer cells, leaving normal cells largely unaffected.

[0079] Treating cancer or a cell proliferation disorder can induce cell death, which is a key component of effective cancer therapy. Preferably, the treatment results in a significant reduction in the number of cells within the treated population, demonstrating the ability of the treatment to effectively eradicate cancer cells. LP-184 is a member of the acylfulvene family of compounds, which are known to induce DNA damage. These damages are typically repaired by the transcription-coupled nucleotide excision repair (TC-NER) pathway.

[0080] Contacting cells with the compositions of the present application can selectively activate cell death in cancer cells. This selective induction is critical to minimize damage to normal cells while effectively combating cancerous growth.

[0081] Methods of treating or preventing cancer include administering the compositions of the present application, resulting in one or more beneficial outcomes. These can include preventing cancer cell proliferation, inducing cell senescence, or promoting tumor cell differentiation, all while maintaining a favorable therapeutic index.

[0082] The term "kit" refers to a package that can contain one or more components of a treatment regimen, allowing for dosing flexibility. The components can be administered simultaneously or separately, with adjustments to timing and dosage made to achieve optimal therapeutic results.

[0083] "Predetermined level" is used as a threshold: if the ACTB level in a patient is above or below this threshold, it can guide a healthcare provider to decide whether to start, continue, or adjust treatment with an acylfulvene.

[0084] For detailed descriptions of techniques and methods, those skilled in the art can refer to general reference texts. These resources provide a foundation for manufacturing or using aspects of the present application, ensuring practice is based on established scientific knowledge.

[0085] Example

[0086] In order that the disclosure disclosed herein can be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present disclosure in any manner.

[0087] Example 1

[0088] Figure 1To demonstrate the effect of LP-184 on various kidney cell lines, including epithelial and cancer types. This assay evaluates the ability of cells to repair 6-4 photoproducts, showing a range of responses: non-malignant HK2 cells show typical non-malignant behavior; 786O and 769P cell lines show low sensitivity; and clear cell kidney cancer cell lines such as A498 and RXF393 show high sensitivity. After UV irradiation to induce 6-4 photoproducts (6-4PP), it was noted that almost all kidney cancer cell lines along with the non-malignant renal epithelial cell line exhibited different levels of nucleotide excision repair (NER) deficiency, as depicted. In contrast, the RPE1 cell line served as a negative control, showing different responses to treatment.

[0089] Example 2

[0090] Figure 2 The extent of nucleotide excision repair (NER) deficiency in kidney cancer and control cells was exemplified. Cells with 6-4 photoproducts (6-4PP) were significantly eliminated over a 5 and 7 hour period. 6-4PP is a specific DNA damage produced by UV radiation that links adjacent pyrimidine bases (thymine or cytosine) in DNA. If not repaired, such damage interferes with cell function and hinders DNA replication and transcription. These findings indicate that all kidney cancer cell lines and the non-malignant renal epithelial cell line have NER deficiency to some extent, which can be targeted by LP-184.

[0091] Example 3

[0092] Figure 3 Western blot analysis was presented on the aforementioned cell lines (non-malignant HK2 cells showing typical behavior; 786O and 769P cell lines exhibiting low sensitivity; and clear cell kidney cancer cell lines such as A498 and RXF393) to investigate PTGR1 and ACTB gene expression. The blots indicated that cells expressing PTGR1 were more sensitive to LP-184 treatment.

[0093] Example 4

[0094] Figure 4The sensitivity of various cell lines to LP-184 is detailed, showing cell death over 72 hours. Sensitivity, as measured by IC50 data, reflects the degree to which a substance can inhibit a particular biological or biochemical function. Here, the IC50 data reveals the rate at which cells die over a 72 hour period, a key metric for assessing the efficacy of a compound. This IC50 value, indicating the concentration required to reduce cell viability by 50%, is key to understanding the efficacy of a compound and the temporal response of cells to a substance. Such analysis is critical to new drug development and therapeutic approaches, providing important insights into how cells respond to different compounds over time.

[0095] Additional IC50 data is presented below:

[0096]

[0097] Additional IC50 data is presented below:

[0098]

[0099] Example 5

[0100] This example shows the sensitivity of various cell lines to LP-284, showing cell death over 72 hours. Sensitivity, as measured by IC50 data, reflects the degree to which a substance can inhibit a particular biological or biochemical function. Here, the IC50 data reveals the rate at which cells die over a 72 hour period, a key metric for assessing the efficacy of a compound. This IC50 value, indicating the concentration required to reduce cell viability by 50%, is key to understanding the efficacy of a compound and the temporal response of cells to a substance. Such analysis is critical to new drug development and therapeutic approaches, providing important insights into how cells respond to different compounds over time. Such data is shown below:

[0101]

[0102] While several example aspects and embodiments have been provided in the foregoing detailed description, one skilled in the art will recognize that modifications, combinations, substitutions, and changes in the present aspects can be made without departing from the true spirit and scope of the disclosure. The appended claims may, therefore, be entitled to cover all such modifications, combinations, substitutions, and changes in the present aspects.

Claims

1. A method of treating a human having renal cell carcinoma, comprising treating the human with an effective amount of hydroxymethylacylfulvene.

2. The method of claim 1, wherein the hydroxymethylacylfulvene is (-)- hydroxymethylacylfulvene.

3. The method of claim 1, wherein the hydroxymethylacylfulvene is (+)- hydroxymethylacylfulvene.

4. The method of claim 1, wherein the dose is administered intraperitoneally (IP) or intravenously (IV).

5. A method of treating renal cell carcinoma in a patient in need thereof, comprising administering to the patient an acylfulvene or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the renal cell carcinoma is localized to the kidney.

7. The method of claim 1, wherein the renal cell carcinoma has metastasized.

8. The method of claim 2, wherein the renal cell carcinoma is selected from the group consisting of clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, and medullary carcinoma.

9. The method of claim 1, wherein the subject is an animal.

10. The method of claim 1, wherein the subject is a human.

11. The method of claim 1, further comprising administering at least one additional active agent.

12. The method of claim 1, further comprising administering an additional therapeutic agent selected from the group consisting of cisplatin, paclitaxel, and other available therapies.

13. A method for treating a kidney cancer in a subject in need thereof, comprising administering to the subject an effective amount of hydroxymethylacylfulvene.

14. The method of claim 13, wherein the hydroxymethylacylfulvene is (-)- hydroxymethylacylfulvene.

15. The method of claim 13, wherein the hydroxymethylacylfulvene is (+)- hydroxymethylacylfulvene.

16. The method of claim 13, wherein the hydroxymethylacylfulvene is administered at a dose ranging from 0.1 mg / kg body weight to 100 mg / kg body weight per day.

17. The method of claim 13, wherein the kidney cancer is selected from the group consisting of clear cell renal carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and collecting duct carcinoma.

18. A pharmaceutical composition for treating a kidney cancer, comprising hydroxymethylacylfulvene and a pharmaceutically acceptable carrier.

19. The method of claim 13, wherein the hydroxymethylacylfulvene is administered in combination with at least one other anti-cancer agent.

20. The method of any preceding claim, wherein the treatment results in a reduction in tumor size or progression.

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