Methods for treating pancreatic cancer

Abstract

Methods for the treatment of pancreatic cancer by administration of a hydroxyurea methyl acyl fulvene Some embodiments relate to the treatment of pancreatic cancer by administration of a hydroxyurea methyl acyl fulvene.

Description

Technical Field

[0001] This application relates to the fields of chemistry and oncology. More specifically, this application relates to methods for treating pancreatic cancer using hydroxyurea methyl acylfulvene.

Background Art

[0002] Pancreatic cancer is one of the cancers with the highest mortality rates, and is expected to cause more than 60,000 deaths in the United States. For all stages of pancreatic cancer combined, the 1-year to 5-year relative survival rates are low, and this high mortality rate due to pancreatic cancer is, at least in part, due to the high incidence of metastatic disease at the time of diagnosis. As a result, the treatment options for pancreatic cancer are very limited.

[0003] Furthermore, pancreatic cancer is difficult to detect early because it does not present symptoms immediately. When symptoms are present, such symptoms are often vague or difficult to notice. Since the pancreas is hidden behind other organs, medical personnel cannot usually see or touch the tumor during a normal examination. Physicians use physical examinations, blood tests, imaging tests, and biopsies to diagnose. Pancreatic cancer is often detected late and spreads rapidly, making it difficult to treat.

[0004] Therefore, there is a need for treatments for primary and metastatic pancreatic cancer.

Brief Description of the Drawings

[0005] [Figure 1] Figure 1 is a diagram showing the cytotoxicity of hydroxyurea methyl acylfulvene or LP-184 in the first test of four pancreatic cancer cell lines by IC50 values. [Figure 2] Figure 2 is a diagram showing the cytotoxicity of hydroxyurea methyl acylfulvene or LP-184 in the second test of six pancreatic cancer cell lines by IC50 values. [Figure 3]Figure 3 shows the IC50 values ​​from tissues derived from prostate cancer tissue models treated ex vivo with hydroxyureamethylacylfluben or LP-184. [Figure 4] Figure 4 shows the increase in tumor volume over 60 days in a xenograft mouse model treated with hydroxyurea methylacylfluben or LP-184. [Overview of the project]

[0006] One aspect of this application includes a method for treating pancreatic cancer in a subject requiring treatment, the method comprising the step of administering a therapeutically effective amount of hydroxyureamethylacylfluben to the subject. The pancreatic cancer may be endocrine or exocrine. The pancreatic cancer may be pancreatic adenocarcinoma. In one embodiment, the subject or the subject cancer may express high levels of PTGR1. The pancreatic cancer may be stage I, II, III, or IV.

[0007] Another aspect of this application includes the treatment of a patient suffering from one or more of the following: pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, borderline resectable pancreatic cancer, locally advanced ductal adenocarcinoma, borderline resectable ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, ductal adenocarcinoma, squamous cell pancreatic cancer, pancreatic progenitor cells, immunogenic pancreatic cancer, abnormally differentiated endocrine and exocrine (ADEX) tumors, exocrine pancreatic cancer, intraepithelial neoplastic lesions of the pancreas, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, mucinous pancreatic cancer, adenosquamous cell carcinoma, signet ring cell carcinoma, hepatoid carcinoma, gelatinous carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumors, islet cell tumors, pancreatic endocrine tumors, or pancreatic neuroendocrine tumors.

[0008] Another embodiment also includes treatment comprising the use of one or more additional therapeutic agents selected from the group consisting of, for example, temozolomide, bevacizumab, everolimus, carmustine, lomustine, procarbazine, vincristine, irinotecan, cisplatin, carboplatin, methotrexate, etoposide, vinblastine, bleomycin, actinomycin, cyclophosphamide, and ifosfamide.

[0009] Another embodiment includes the use of one or more additional therapeutic agents selected from the group consisting of, for example, cisplatin, paclitaxel, and combinations thereof.

[0010] Another embodiment includes treatment that also involves subjecting the subject to radiotherapy. The subject or patient may be undergoing surgery, radiotherapy, and chemotherapy.

[0011] Another embodiment is a method for treating a target pancreatic cancer, comprising the steps of (a) obtaining or already obtaining expression levels in a sample from the target for a plurality of targets, wherein the plurality of targets include PTRG1, (b) determining that the target is sensitive to treatment with hydroxyureamethylacylflubene, and (c) administering a cancer treatment comprising hydroxyureamethylacylflubene. The patient may have previously received or is currently receiving radiotherapy.

[0012] [Definition] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the subject matter herein belongs. For the purposes of facilitating the understanding of the present invention, the following definitions are provided:

[0013] As used herein, the term “antibody” includes intact molecules, as well as molecules containing or composed of fragments thereof, such as Fab, F(ab')2, Fv, and scFv, and designed variants, including diabodies, triabodies, minibodies, and single-domain antibodies that can bind to epitope determinants. Thus, antibodies may exist as intact immunoglobulins or as various forms of modifications.

[0014] The term "biomarker" refers to any molecule produced by a subject, such as a gene, gene transcript (e.g., mRNA), peptide, or protein, or a fragment thereof, that is useful in identifying a subject to predict a patient's response to a treatment involving hydroxyureamethylacylflubene or an analogue thereof. A biomarker that is differentially present (i.e., increased or decreased) in a biological sample from a subject or group of subjects is considered to have a first phenotype (e.g., disease) compared to a biological sample from a subject or group of subjects having a second phenotype (e.g., disease-free). Biomarkers can be differentially present at any level, but generally at at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, and at least The biomarker is present at a level that increases by 140%, at least 150%, or more, or is generally present at a level that decreases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% (i.e., absent). The biomarker is preferably present differentially at a statistically significant level (e.g., a p-value less than 0.05 and / or a q-value less than 0.10 determined using either Welch's t-test or Wilcoxon's rank-sum test).

[0015] The term "pancreatic cancer" refers to neoplasms of pancreatic origin. Pancreatic cancers include exocrine and endocrine cancers. Most pancreatic cancers are exocrine tumors. Pancreatic endocrine tumors are also called islet cell tumors. Pancreatic cancers that can be treated by the methods described herein include, but are not limited to, exocrine and endocrine pancreatic cancers. Exocrine pancreatic cancers include, but are not limited to, adenocarcinoma, acinar cell carcinoma, adenosquamous carcinoma, gelatinous carcinoma, anaplastic carcinoma with osteoclast-like giant cells, hepatoid carcinoma, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, pancreaticblastoma, serous cystadenoma, signet ring cell carcinoma, solid pseudopapillary neoplasm, ductal carcinoma, and anaplastic carcinoma. In some embodiments, exocrine pancreatic cancer is ductal carcinoma. Endocrine pancreatic cancers include, but are not limited to, insulinoma and glucagonoma.

[0016] As used herein, the terms “patient,” “subject,” “individual,” and “host” refer to either a human or non-human animal suffering from or suspected to suffer from a disease or disorder associated with abnormal biological or cellular proliferation activity.

[0017] When used in relation to a condition or disease such as cancer, the term “prevent” refers to reducing the frequency of symptoms of the condition or delaying the onset of the disease. Therefore, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a group of patients receiving prophylactic treatment compared to an untreated control group, and / or delaying the appearance of detectable cancerous growths in the treated group versus the untreated group by, for example, a statistically and / or clinically significant amount.

[0018] The term "person in need of treatment" refers to a person diagnosed with a specific condition for which treatment is intended, such as pancreatic cancer or a specific type of pancreatic cancer.

[0019] As used herein, the terms “expression level” and “expression level” refer to the amount of gene products, such as DNA, RNA (e.g., messenger RNA (mRNA)), or the amount of protein corresponding to a particular gene in a cell, tissue, biological specimen, organism, or patient.

[0020] The term "pharmaceutically acceptable" generally means safe, non-toxic, and useful in preparing desirable pharmaceutical compositions by biological or other means, including those acceptable for veterinary and human pharmaceutical use.

[0021] The term “healthy individual” is interpreted to mean an individual known not to have cancer (e.g., cancer), and such knowledge is derived from the individual’s clinical data, including but not limited to diagnostic assays different from those described herein.

[0022] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal (e.g., a salt that has mammalian safety acceptable for a given administration regimen). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, depending on the specific substituents found in the compounds described herein. If the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compound in its original form or in a suitable inert solvent with a sufficient amount of the desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary, tertiary, and quaternary amines, including substituted amines such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, meglumine (N-methylglucamine), cyclic amines, and natural amines. If the compounds of the present disclosure have relatively basic functionalities, the acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either in its original form or in a suitable inert solvent.Salts derived from pharmaceutically acceptable acids include acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, and phosphorus. Examples include acids, succinic acid, sulfuric acid, hydroiodic acid, carbonic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, embonic acid (pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, stearic acid, cyclohexylaminosulfonic acid, alginic acid, hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0023] The term "effective dose" refers to the amount of a compound or composition sufficient to treat a particular disorder, condition, or disease, such as by improving, alleviating, reducing, and / or delaying one or more of its symptoms. In relation to pancreatic cancer, an effective dose includes an amount sufficient to shrink the tumor and / or reduce the rate of tumor growth (such as inhibiting tumor growth), or to prevent or delay other undesirable cell growth in pancreatic cancer. In some embodiments, an effective dose is sufficient to delay the onset of pancreatic cancer. In some embodiments, an effective dose is sufficient to prevent or delay recurrence. An effective dose may be administered in one or more doses. In the case of pancreatic cancer, an effective amount of the drug or composition is to (i) reduce the number of pancreatic cancer cells, (ii) reduce the size of the tumor, (iii) inhibit, delay, delay to some extent, and preferably stop the invasion of pancreatic cancer cells into peripheral organs, (iv) inhibit tumor metastasis (i.e., delay to some extent, and preferably stop it), (v) inhibit tumor growth, (vi) prevent or delay the onset and / or recurrence of the tumor, (vii) alleviate to some extent one or more of the symptoms associated with pancreatic cancer, and / or (viii) disrupt (destroy, etc.) the pancreatic cancer stroma.

[0024] The term "therapeutic dose" means the amount of an active agent that (i) treats or prevents pancreatic cancer, (ii) reduces, improves or eliminates one or more symptoms of pancreatic cancer, or (iii) prevents or delays the onset of one or more symptoms of pancreatic cancer. A therapeutic dose of a drug may reduce the number of cancer cells, shrink the size of a tumor, inhibit (i.e., delay, preferably stop) the invasion of cancer cells into peripheral organs, inhibit (i.e., delay, preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more of the symptoms associated with cancer. A drug may be inhibitory and / or cytotoxic to the extent that it can inhibit growth and / or kill existing cancer cells. In the case of cancer treatment, efficacy can be measured, for example, by evaluating the time to disease progression (TTP) and / or determining the response rate (RR).

[0025] The term "therapeutic effect" refers to beneficial local or systemic effects in animals, particularly mammals, more specifically humans, caused by administration of the compounds or compositions of the present invention. The phrase "therapeutically effective amount" means an amount of the compounds or compositions of the present invention that is effective to treat a disease or condition caused by abnormal biological activity with a reasonable benefit / risk ratio. In some embodiments, a therapeutically effective amount of hydroxyurea methyl-acylfulvene or a pharmaceutically acceptable salt thereof is selected from the group consisting of 0.5 mg / day, 1 mg / day, 2.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 60 mg / day, 90 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

[0026] "Reference level" means the level of a compound or additional biomarker of the present invention that indicates a particular medical condition, phenotype, or the absence thereof, and combinations of medical conditions, phenotypes, or the absence thereof.

[0027] "Reference sample" refers to a sample that includes the reference level of a biomarker. For example, a reference sample can be obtained from a subject that does not have a particular disease, medical condition, or phenotype such as cancer or acute injury.

[0028] The therapeutically effective amount of such a substance varies depending on the subject and the medical condition being treated, the subject's weight and age, the severity of the medical condition, the mode of administration, etc., and these can be readily determined by those skilled in the art.

MODE FOR CARRYING OUT THE INVENTION

[0029] Hydroxyurea methylacylflubene (currently referred to as LP-184 by Lantern Pharma, Inc.) is a semi-synthetic or synthetic antitumor agent derived from the mushroom toxin illudin S. The structure of hydroxyurea methylacylflubene is shown below. [ka]

[0030] Certain embodiments provide a method for treating pancreatic cancer (e.g., metastatic pancreatic cancer or unresectable locally advanced pancreatic cancer) in a subject (e.g., a human) using hydroxyureamethylacylflubene or a salt thereof. The particular embodiments relate to a method for treating pancreatic cancer comprising administering an effective amount of hydroxyureamethylacylflubene or a salt thereof to a subject in need. In one example, hydroxyureamethylacylflubene may be administered as monotherapy. Pancreatic cancer may be in an early or late stage and may be metastatic. The combinations described herein can be used to treat cancer at any stage, including metastatic cancer.

[0031] One embodiment involves administering hydroxyureamethylacylfluben and an additional therapeutic agent as separate compositions or as the same composition simultaneously. Accordingly, some embodiments include a first pharmaceutical composition comprising (a) a safe and therapeutically effective amount of hydroxyureamethylacylfluben or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof; and a second pharmaceutical composition comprising (a) a safe and therapeutically effective amount of an additional therapeutic agent, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. Some embodiments include a pharmaceutical composition comprising (a) a safe and therapeutically effective amount of an additional therapeutic agent, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. In some embodiments, the methods described herein may further include subjecting the subject to radiotherapy. In some embodiments, cell proliferation is inhibited by at least about 10% (for example, including at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%).

[0032] In some embodiments, the pancreatic cancer being treated is stage 0, stage I, stage II, stage III, or stage IV. In some embodiments, the pancreatic cancer being treated is stage 0, stage IA, stage IB, stage IIA, stage IIB, stage III, or stage IV. In some embodiments, the pancreatic cancer is metastatic pancreatic cancer. In some embodiments, the pancreatic cancer is stage M0. In some embodiments, the pancreatic cancer is stage M1. In some embodiments, the individual has distant metastases. In some embodiments, the individual does not have distant metastases. In some embodiments, the individual had one of the pancreatic cancers, stage I, II, III, or IV, at the time of diagnosis of pancreatic cancer. The treatment methods disclosed herein may lead to increased progression-free survival and overall survival in subjects treated with combination therapy.

[0033] Some embodiments relate to a method for inhibiting the proliferation of pancreatic cancer cells, comprising the step of contacting pancreatic cancer cells with hydroxyureamethylacylfluben. In some embodiments, the contact step includes administering an effective amount of hydroxyureamethylacylfluben to a subject having pancreatic cancer cells.

[0034] Some embodiments relate to a method for inducing apoptosis in pancreatic cancer cells, comprising the step of contacting the pancreatic cancer cells with hydroxyureamethylacylfluben. In some embodiments, the contact step includes administering an effective amount of hydroxyureamethylacylfluben to a subject having pancreatic cancer cells. In some embodiments, the pancreatic tumor is pancreatic adenocarcinoma.

[0035] The duration of administration may be a treatment cycle of several weeks, or when the tumor is under control and the regimen is clinically acceptable. In some embodiments, a single dose of hydroxyureamethylacylfluben or other therapeutic agent may be administered once a week, preferably once on day 1 and once on day 8 of a 3-week (21-day) treatment cycle. In some embodiments, a single dose of hydroxyureamethylacylfluben or other therapeutic agent may be administered once, twice, three, four, five, six times a week, or daily during a 1-week, 2-week, 3-week, 4-week, or 5-week treatment cycle. Administration may be performed on the same day or different days each week of the treatment cycle.

[0036] Another embodiment includes a method for treating pancreatic cancer or determining the sensitivity of pancreatic cancer to hydroxyureamethylacylflubene therapy by evaluating the level of gene expression.

[0037] Another embodiment includes a method for treating pancreatic cancer in a subject, comprising the steps of (a) obtaining, or already obtaining, expression levels in a sample from the subject for a plurality of targets, wherein the plurality of targets comprises one or more genes (e.g., PTGR1), (b) determining that the subject is sensitive to treatment with hydroxyureamethylacylflubene, and (c) administering a cancer treatment comprising hydroxyureamethylacylflubene.

[0038] Another embodiment includes a method for treating pancreatic cancer in a subject requiring it, comprising administering a therapeutically effective dose of hydroxyureamethylacylfluben to the subject and further administering additional therapy. Additional therapy may be radiotherapy, surgery (e.g., tumor resection and mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination thereof. Additional therapy may be in the form of adjuvant therapy or neoadjuvant therapy. In some embodiments, additional therapy is the administration of an anti-metastatic agent. In some embodiments, additional therapy is the administration of a side effect limiter (e.g., an antiemetic, such as an antiemetic, intended to reduce the occurrence and / or severity of side effects of the treatment). In some embodiments, additional therapy is radiotherapy. In some embodiments, additional therapy is surgery. In some embodiments, additional therapy is a combination of radiotherapy and surgery. In some embodiments, additional therapy is gamma irradiation. In some embodiments, additional therapy is applied before, during, or after the administration of hydroxyureamethylacylfluben.

[0039] Hydroxyureamethylacylfluben for use in accordance with the present invention may be administered primarily by parenteral administration, specifically including subcutaneous, intramuscular, intravenous, transdermal, intrathecal, epidural, intra-articular, and topical administration, or, for example, by various dosage forms if possible.

[0040] Injectable solutions for parenteral administration include, for example, sterile, aqueous, or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may contain auxiliary agents such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (e.g., lactose), and solubilizers (e.g., meglumine). These are sterilized by filtration with a bacterial-retaining filter, formulation with a bactericide, or irradiation. Alternatively, they may be formed once into a sterile solid composition and then dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0041] In some embodiments, pancreatic cancer may be selected from pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, borderline resectable pancreatic cancer, locally advanced ductal adenocarcinoma, borderline resectable ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, ductal adenocarcinoma, squamous cell pancreatic cancer, pancreatic progenitor cells, immunogenic pancreatic cancer, abnormally differentiated exocrine and endocrine (ADEX) tumors, exocrine pancreatic cancer, intraepithelial neoplastic lesions of the pancreas, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, mucinous pancreatic cancer, adenosquamous cell carcinoma, signet ring cell carcinoma, hepatoid carcinoma, gelatinous carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumors, islet cell tumors, pancreatic endocrine tumors, or pancreatic neuroendocrine tumors.

[0042] Liquid compositions for oral administration include, for example, pharmaceutically acceptable emulsions, liquids, suspensions, syrups, and elixirs, and include inert diluents for common use such as distilled water and ethanol. In addition to inert diluents, the compositions may also include auxiliary agents such as humectants and suspending agents, sweeteners, flavoring agents, fragrances, and preservatives.

[0043] It should be understood that specific dosages and treatment plans for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combinations, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition. [Examples]

[0044] <Cell line testing> Cell line studies demonstrated LP-184 activity in various cell lines representing different molecular and clinical subtypes of pancreatic cancer, as well as in patient-derived pancreatic cancer models.

[0045] Figures 1 and 2 show that LP-184 demonstrated nanomolar potency in pancreatic cancer cell lines. Individual cell lines were treated with LP-184 for 72 hours, and cell viability was assayed. IC50 values ​​were generated from dose-response curves plotted in GraphPad Prism. Figure 1 shows the cytotoxicity of LP-184 by IC50 values ​​in the first test of four pancreatic cancer cell lines, with cytotoxicity ranging from approximately 110 to approximately 310 nM. Figure 2 shows the cytotoxicity of LP-184 by IC50 values ​​in the second test of the same four pancreatic cancer cell lines, with cytotoxicity ranging from approximately 130 to approximately 180 nM.

[0046] <Ex vivo trial> Figure 3 shows the IC50 values ​​of tissue from prostate cancer models ex vivo-treated with LP-184. Five low-passage patient-derived tumor graft models were treated with LP-184. Patient-derived xenografts (PDX) are cancer models in which tissue or cells from a patient's tumor are transplanted into immunodeficient or humanized mice. Individual tumor models were treated with LP-184 for 120 hours, and cell viability was assayed. IC50 values ​​were generated from dose-response curves plotted in GraphPad Prism.

[0047] <Animal testing> All animal studies were conducted in accordance with the National Institutes of Health animal guidelines. Dosages were selected to ensure resistance in the xenografts. Capan-1 cell line-derived xenograft tumors were transplanted into SCID mice and treated with either (a) a vehicle control of 95% saline / 5% ethanol (N=3) or (b) 3 mg / kg of LP-184 (N=5), administered by intraperitoneal injection three times a week for three weeks. In other words, one group was treated with LP-184 and the other group with the vehicle control.

[0048] Figure 4 shows the increase in tumor volume over 60 days in a xenograft mouse model. Complete tumor regression is observed in LP-184 treated animals at the end of the study period or 60 days.

[0049] The aforementioned invention has been described in detail with specific examples and embodiments for the purpose of clarifying understanding, but it will be obvious to those skilled in the art that certain minor changes and modifications will be made. Therefore, the description and embodiments should not be construed as limiting the scope of the invention.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of hydroxyureamethylacylfluben for treating metastatic pancreatic cancer or unresectable locally advanced pancreatic cancer in a subject.

2. The pharmaceutical composition according to claim 1, wherein the pancreatic cancer is endocrine in nature.

3. The pharmaceutical composition according to claim 1, wherein the pancreatic cancer is exocrine.

4. The pharmaceutical composition according to claim 1, wherein the pancreatic cancer is pancreatic adenocarcinoma.

5. The pharmaceutical composition according to claim 1, wherein the subject has a high level of PTGR1.

6. The pharmaceutical composition according to claim 1, wherein the subject is suffering from one or more of the following: pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, borderline resectable pancreatic cancer, locally advanced ductal adenocarcinoma, borderline resectable ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, ductal adenocarcinoma, squamous cell pancreatic cancer, pancreatic progenitor cells, immunogenic pancreatic cancer, abnormally differentiated endocrine and exocrine (ADEX) tumors, exocrine pancreatic cancer, pancreatic intraepithelial neoplastic lesions, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, mucinous pancreatic cancer, adenosquamous cell carcinoma, signet ring cell carcinoma, hepatoid carcinoma, gelatinous carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor.

7. The pharmaceutical composition according to claim 1, wherein the pancreatic cancer is stage I, II, III, or IV.

8. The pharmaceutical composition according to claim 1, comprising an additional therapeutic agent selected from the group consisting of temozolomide, bevacizumab, everolimus, carmustine, lomustine, procarbazine, vincristine, irinotecan, cisplatin, carboplatin, methotrexate, etoposide, vinblastine, bleomycin, actinomycin, cyclophosphamide, and ifosfamide.

9. The pharmaceutical composition according to claim 1, comprising an additional therapeutic agent selected from the group consisting of cisplatin, paclitaxel, and combinations thereof.

10. The pharmaceutical composition according to claim 1, further comprising subjecting the subject to radiotherapy.

11. The pharmaceutical composition according to claim 1, wherein the cells in the target are animal cells.

12. The pharmaceutical composition according to claim 1, wherein the subject is a human.

13. The pharmaceutical composition according to claim 1, which is for primary treatment.

14. The pharmaceutical composition according to claim 5, for use in combination with one or more additional therapies selected from surgery, chemotherapy, or a combination thereof.

15. The pharmaceutical composition according to claim 1, wherein the subject has already undergone surgery.

16. The pharmaceutical composition according to claim 1, wherein the subject has already received radiotherapy.

17. The pharmaceutical composition according to claim 1, wherein the subject has already received chemotherapy treatment.

18. A pharmaceutical composition comprising hydroxyureamethylacylfluben for treating a target pancreatic cancer, wherein the treatment is (a) A step of obtaining or obtaining expression levels in a sample from a subject for multiple targets, wherein the multiple targets include PTGR1 and the expression level of PTGR1 in the sample is at least 50% higher than the reference level of PTGR1 in a reference sample from a healthy individual. (b) A step of determining whether the subject is sensitive to treatment with hydroxyureamethylacylflubene, (c) A pharmaceutical composition comprising the step of administering cancer treatment containing hydroxyureamethylacylfluben.

19. The pharmaceutical composition according to claim 18, wherein the subject has already received radiotherapy.

20. The pharmaceutical composition according to claim 18, comprising an additional therapeutic agent selected from the group consisting of cisplatin, paclitaxel, and combinations thereof.

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