WO2023025312A1 - 使用th-302治疗parp抑制剂耐药的患者 - Google Patents

使用th-302治疗parp抑制剂耐药的患者 Download PDF

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WO2023025312A1
WO2023025312A1 PCT/CN2022/115284 CN2022115284W WO2023025312A1 WO 2023025312 A1 WO2023025312 A1 WO 2023025312A1 CN 2022115284 W CN2022115284 W CN 2022115284W WO 2023025312 A1 WO2023025312 A1 WO 2023025312A1
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cancer
tumor
mutations
brca2
brca1
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French (fr)
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齐天阳
刘星
段建新
孟繁英
李安蓉
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深圳艾欣达伟医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a method for treating cancer, especially a method for treating cancer patients resistant to PARP inhibitors (PARPi).
  • PARP inhibitors PARPi
  • PARPi drug Olaparib The first human clinical trial of PARPi drug Olaparib confirmed for the first time that PARPi can inhibit the growth of tumor cells carrying BRCA1/2 mutations, which is mainly based on the theory of synthetic lethality (Ashworth, A., & Lord, CJ (2018 ).Synthetic lethal therapies for cancer: what's next after PARP inhibitors?.Nature rev iews.Clinical oncology,15(9),564–576.https://doi.org/10.1038/s41571-018-0055-6): PARP inhibitors can inhibit the DNA single-strand damage repair function of PARP, resulting in a large number of single-strand DNA damage in cells that cannot be repaired in time.
  • Double-strand DNA damage with strong cytotoxicity can be mediated by BRCA1 and BRCA2 proteins in normal cells.
  • BRCA1/2-deficient tumor cells double-strand DNA damage cannot be repaired, resulting in the eventual death of tumor cells.
  • PARPi was originally developed for radiotherapy and chemotherapy sensitization, and preclinical studies support that PARPi can be developed as a single drug for the treatment of BRCA1/2 gene deficient cancers. Therefore, the initial target population for PA RPi-BRCA hypothesis verification was selected as carriers of BRCA1/2 germline mutation (gBRCA1/2).
  • Niraparib and Rucaparib Two other PARPi have been approved in ovarian cancer: Niraparib and Rucaparib: FDA and EMA approve Niraparib maintenance regimen (regardless of BRCA1/2 status); Rucaparib It is also registered by the FDA and EMA as an optional treatment option for patients with BRCA1/2 mutation-related ovarian cancer who have previously received two lines of chemotherapy; and talazoparib has also been approved by the FDA for the treatment of BRCA Mutant/HER-2-negative metastatic breast cancer (Mateo, J., Lord, CJ, Serr a, V., Tutt, A., J., Castroviejo-Bermejo, M., Cruz, C., Oaknin, A., Kaye, SB, & de Bono, JS (2019). A decade of clinical development of PARP inhibitors in perspective. Annals of oncology: official journal of the European Society for Medical Oncology, 30(9), 1437–1447. https://doi.org/10.1093/annonc/md
  • TH-302 (Evofosfamide, cas number 918633-87-1) is a 2-nitroimidazole-triggered hypoxia-activated prodrug (HAP) bromoifosfamide developed by Threshold Corporation of the United States. Under hypoxia, the inactive TH-302 prodrug released highly toxic Br-IPM. TH-302 has broad-spectrum biological activity in vivo and in vitro, specific hypoxia selective activation activity, induction of H2AX phosphorylation and DNA cross-linking activity, resulting in cell cycle arrest, so this compound has been developed by many pharmaceutical companies and scientific research institutes Development of anticancer drugs.
  • HAP hypoxia-activated prodrug
  • TH-302 has broad-spectrum activity against various tumors, and has excellent hypoxia-selective activity enhancement effect.
  • Cytochrome P450 oxidoreductase reduces the prodrug TH-302 to obtain intermediate free radical anion, and then the free radical anion is unstable and decomposed into cytotoxic cytotoxin Br-IPM to play a role.
  • the key step in this step is the one-electron reduction process. Studies have confirmed that the presence of oxygen will reverse the one-electron reduction process. It can be restored to produce stronger cytotoxicity.
  • DNA repair mutant cell lines based on Chinese hamster ovary cells including cell lines lacking base excision, nucleotide excision, non-homologous end-joining repair or homologous end-joining repair (the cell line is a cell line lacking homologous source-dependent repair cell line) to test the in vitro cytotoxicity of TH-302.
  • the study found that cell lines lacking homologous end-joining repair alone or combined with nucleotide excision were significantly more sensitive to TH-302 hypoxia. However, cell lines with defective base excision, nucleotide excision, or non-homologous end-joining repair alone had no effect on TH-302 sensitivity.
  • H460 cell line human large cell lung cancer cells
  • HCT116 cell line human colon cancer cell
  • A375 cell line human malignant melanoma cells
  • hypoxia targeting compositions and combinations thereof with a parp inhibitor and methods of use thereof it is pointed out that the use of hypoxia-activated drugs or their prodrugs (such as apaziquone, AQ4N, etanidazole, evofosfamide (TH-302), nimorazole, pimonidazole, porfiromycin, PR-104, tarloxotinib, tirapazamine (tirapazamine)) and PARPi have an additive effect when combined with PARPi.
  • hypoxia-activated drugs or their prodrugs such as apaziquone, AQ4N, etanidazole, evofosfamide (TH-302), nimorazole, pimonidazole, porfiromycin, PR-104, tarloxotinib, tirapazamine (tirapazamine)
  • PARPi have an additive effect when combined with PARPi.
  • TH-302 single drug can have excellent therapeutic effect on PARPi-resistant cancer models!
  • the present application provides the following cancer treatment methods.
  • Therapeutic method which uses the drug containing the hypoxia-activated compound of formula (1) as a single drug or in combination to treat PARPi-resistant cancer and tumor patients:
  • each R is independently selected from H, -CH 3 , -CH 2 CH 3
  • each X is independently selected from Cl, Br, MsO, TsO and other leaving functional groups.
  • Therapeutic method which uses the drug containing the hypoxia-activated compound of formula (1) in combination with PARP inhibitors to treat cancer and tumor patients resistant to PARP inhibitors:
  • each R is independently selected from H, -CH 3 , -CH 2 CH 3
  • each X is independently selected from Cl, Br, MsO, TsO and other leaving functional groups.
  • the medicines mentioned herein refer to medicines or preparations, the prepared medicines contain the hypoxia-activated compound of formula (1) or their salts or solvates as active ingredients in a specific dose range, and/or the prepared medicines are specific dosage ranges. Dosage form, specific mode of administration.
  • the prepared medicines, medicaments and preparations may also contain pharmaceutically acceptable auxiliary materials or excipients.
  • the medicine can be in any dosage form for clinical application, such as tablet, suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated agent, granule, dry powder, oral solution, small needle for injection , Freeze-dried powder for injection or large infusion.
  • the pharmaceutically acceptable adjuvant or excipient in the medicine may include one or more of the following: diluent, solubilizer, disintegrant, suspending agent, lubricant, viscose Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • Threshold related patents: WO2010048330A1, WO2012142520A2, and WO2008083101A1.
  • Threshold related patents: WO2010048330A1, WO2012142520A2, and WO2008083101A1.
  • the present invention will The text of the above application is incorporated in its entirety.
  • TH-302 or its similar compounds It is a DNA alkylating agent anticancer drug with a wide range of cancer treatment potentials.
  • Cancer refers to leukemias, lymphomas, carcinomas and other malignancies (including solid tumors) of potentially unrestricted growth that can spread locally by invasion and systemically by metastasis.
  • cancers that can be treated include, but are not limited to, adrenal, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nervous tissue, pancreas, prostate, Cancer of the parathyroid, skin, stomach, and thyroid.
  • cancers include acute and chronic lymphocytic and granulocytic neoplasms, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, multiple Type glioblastoma, hair cell tumor, enteric ganglioneuroma, proliferative corneal neuroma, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid tumor, malignant melanoma , malignant hypercalcemia, marfanoid tumor, medullary epithelial carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, osteogenic and other sarcomas, Ovarian tumor, pheochromocytoma, polycythemia
  • PARP is an enzyme, the full name is polyadenylate diphosphate-ribose polymerase (Poly ADP-ribose Polymerase, PARP).
  • PARP is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARP is activated when DNA is damaged and broken. As a molecular sensor of DNA damage, it has the function of recognizing and binding to the position of DNA breakage, and then activates and catalyzes the poly ADP-ribosylation of receptor proteins to participate in the DNA repair process. .
  • PARP inhibitors inhibit the work of PARP enzymes, so that these PARP enzymes, which are equivalent to "repairmen", cannot work normally. If DNA damage is not repaired, cells will die.
  • PARP inhibitors are used to specifically enter cancer cells, the PARP enzyme activity is inhibited and cannot function normally, and the DNA of cancer cells cannot be repaired. In this way, PARP inhibitors can only kill cancer cells but not normal cells.
  • Synthetic lethality means that when two different genes (BRCA) or protein (PRAP) change at the same time, it will lead to cell death. However, if only one of these two genes/proteins is abnormal, it will not cause cell death.
  • PARP inhibitors are compounds that inhibit PARP enzymes, that is, all substances that can inhibit the activity of PARP enzymes are PARP inhibitors.
  • the PARP inhibitor here essentially refers to the drug containing the active ingredient of PARP inhibitor.
  • Talazoparib indicated for adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer.
  • the commercially available dosage form is 0.25 mg/1 mg talazoparib tosylate capsules, 1 mg orally once a day, considering treatment interruption or dose reduction in case of adverse reactions:
  • the oral dose is reduced to 0.75mg (three 0.25mg capsules), once a day;
  • the oral dose is reduced to 0.5mg (two 0.25mg capsules), once a day;
  • the oral dose was reduced to 0.25 mg (one 0.25 mg capsule), once a day.
  • Niraparib for the maintenance treatment of adult patients with platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer after complete remission or partial remission of platinum-containing chemotherapy.
  • the commercially available dosage form is 100mg Niraparib Tosylate Capsules, 300mg orally once a day, until disease progression or intolerable adverse reactions occur. In the case of adverse reactions, consider treatment interruption or dose reduction:
  • a second dose reduction can be made, from 2 capsules (200 mg) per day to 1 capsule per day (100 mg);
  • Rucaparib for women with advanced ovarian cancer whose tumors carry a specific gene mutation (harmful BRCA) and who have been treated with two or more chemotherapy drugs.
  • the commercially available dosage forms are tablets: 200mg, 250mg and 300mg, three specifications.
  • the recommended dose is 600 mg orally twice daily with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider interruption of treatment or dose reduction.
  • Olaparib for treatment-na ⁇ ve adult patients with germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy Maintenance therapy after chemotherapy; maintenance therapy for adult patients with platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer after complete remission or partial remission of platinum-based chemotherapy.
  • the commercially available dosage forms are tablets: 150mg and 100mg, two specifications. The recommended dose is 300 mg (two 150 mg tablets) twice daily, equivalent to a total daily dose of 600 mg. 100mg tablet for dose reduction use:
  • treatment interruption or dose reduction may be considered;
  • the recommended dose is reduced to 250 mg (one 150 mg tablet, one 100 mg tablet), taken twice a day (equivalent to a total daily dose of 500 mg);
  • the recommended dose is reduced to 200 mg (two 100 mg tablets) taken twice daily (equivalent to a total daily dose of 400 mg).
  • Fluzoparib for the treatment of patients with platinum-sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer with germline BRCA mutation (gBRCAm) who have previously received second-line or more chemotherapy.
  • Commercially available capsules 50mg specification.
  • Weekly doses of 480 mg/m 2 to about 670 mg/m 2 or, for example, 575 mg/m 2 are administered intravenously.
  • TH-302 (Concentrate for Administration Solution) for clinical trials is a sterile liquid formulation of TH-302.
  • TH-302 was formulated with 70% absolute ethanol, 25% dimethylacetamide and 5% polysorbate 80. It is supplied by the sponsor in a 10 mL glass vial with a rubber stopper and flip-off closure.
  • TH-302 drug product is a clear, colorless to pale yellow solution substantially free of visible particles.
  • each single-use vial contains TH-302 drug product in a nominal fill volume of 6.5 mL (equivalent to 100 mg/mL) and is clearly labeled as The batch number, route of administration, required storage conditions, name of the sponsor and appropriate precautionary labels required by applicable regulations are disclosed. It needs to be diluted according to the pharmacy manual before administration.
  • TH-302 Dilute to a total volume of 500 mL (1000 mL for a total dose > 1000 mg) with commercially available 5% dextrose in water before administration to obtain the desired final concentration.
  • Each dose of TH-302 was prepared with 5% dextrose in water without bis(2-ethylhexyl) phthalate (DEHP-free) and administered intravenously using a DEHP-free IV administration set.
  • lyophilized preparations developed by Threshold can also be used:
  • a solution (20 mL) of TH-302 (100 mg) and sucrose (1 g) was added to a lyophilized vial and lyophilized to produce a lyophilized unit dosage form of TH-302 with a drug loading of less than 5 mg/cm 3 .
  • the unit dosage form is dissolved in 5% dextrose injection, and an appropriate amount of the solution is administered to the patient;
  • TH-302 lyophilized preparations for injection are prepared in 100mL glass vials with a drug loading of 100mg/100ml. Store under controlled conditions, inject 250mL of 5% glucose injection into a freeze-dried preparation bottle when used, and infuse intravenously within 30 minutes through an infusion pump.
  • Monotherapy that is, monotherapy.
  • Combined use that is, combined drug therapy.
  • Monotherapy refers to the use of only one anticancer drug in a course of treatment.
  • Combination therapy refers to the simultaneous or successive use of two or more anticancer drugs in one course of treatment.
  • combination therapy needs to explore different dosages and administration cycles according to the characteristics of the disease and the types of drugs used in combination. Only based on the above conditions can the combination drug treatment plan obtained through exploration be able to achieve better therapeutic effects than single drug therapy.
  • the drug dosage and dosage cycle of the single drug and combined treatment regimens need to be obtained through clinical trials with reference to the dosage and dosage regimen of TH-302 and its similar compounds and PARPi mentioned above.
  • damaged DNA repair enzymes are selected from:
  • Nucleotide excision repair enzyme (nucleotide excision repair) damage
  • base excision repair enzyme base excision repair
  • Mismatch repair enzyme mismatch repair
  • Impairment of one or more of the repair enzymes in the Fanconi's anemia pathway is Impairment of one or more of the repair enzymes in the Fanconi's anemia pathway.
  • any one or more of damaged homologous recombination DNA repair enzymes, damaged nucleotide excision repair enzymes, and damaged base excision repair enzymes more preferably a single damaged homologous recombination DNA repair enzyme Or both homologous recombination DNA repair enzyme damage and nucleotide excision repair enzyme damage.
  • the patient's tumor or cancer tissue is detected to have any one or two gene mutations in the genes corresponding to BRCA1 and BRCA2; or the patient is detected to have any one of the genes corresponding to BRCA1 and BRCA2 A genetic mutation or both genetic mutations.
  • BRACAnalysis CDx a companion detection kit for Olaparib, is used to detect BRCA gene mutations in blood samples of ovarian cancer patients;
  • BRCA1/2 Gene Mutation Detection Kit (Combined Probe-Anchor Polymerization Sequencing Method), which is used to detect germline mutations in exon regions and adjacent intron regions of BRCA1/2 genes in clinically diagnosed ovarian cancer and breast cancer patients carry out qualitative testing;
  • Human BRCA1 gene and BRCA2 gene mutation detection kit (reversible terminal termination sequencing method), which can be used for the relevant medication guidance of PARP inhibitor olaparib tablets.
  • BRCA1 and BRCA2 mutations include germline mutations (gBRCAm) and systemic mutations (sBRCAm) of BRCA1 and BRCA2 mutations.
  • hypoxia-activating compound of formula (1) is selected from compounds of the following structures:
  • TH-302 is preferred.
  • the cancer and tumor are selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, lung cancer, liver cancer, colon cancer, rectal cancer, bladder cancer, etc.
  • the lung cancer is preferably Non-small cell lung cancer, small cell lung cancer.
  • Therapeutic method uses the drug monotherapy that contains the hypoxia activation compound of following formula to treat Olaparib Olaparib resistant ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, non Patients with small cell lung cancer, small cell lung cancer, liver cancer, colon cancer, rectal cancer, bladder cancer:
  • the patient's tumor or cancer tissue is detected to have any one or two gene mutations in the genes corresponding to BRCA1 and BRCA2; or the patient is detected to have any one of the genes corresponding to BRCA1 and BRCA2 A genetic mutation or both genetic mutations.
  • Therapeutic method which uses the drug containing the hypoxia activation compound of the following formula in combination with Olaparib to treat Olaparib-resistant ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer , prostate cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, colon cancer, rectal cancer, bladder cancer patients:
  • the patient's tumor or cancer tissue is detected to have any one or two gene mutations in the genes corresponding to BRCA1 and BRCA2; or the patient is detected to have any one of the genes corresponding to BRCA1 and BRCA2 A genetic mutation or both genetic mutations.
  • a method of treatment comprising the following steps:
  • the drug containing the hypoxia-activating compound of formula (1) is used for treatment alone or in combination with PARP inhibitors:
  • each R is independently selected from H, -CH 3 , -CH 2 CH 3
  • each X is independently selected from Cl, Br, MsO, TsO and other leaving functional groups.
  • the TMB (Tumor Mutation Burden) level of the gene mutation is medium.
  • hypoxia-activated compound of formula (1) in the preparation of drugs for the treatment of cancer in patients as a single drug or in combination with PARP inhibitors:
  • the patient is a PARP inhibitor-resistant patient
  • Each R is independently selected from H, -CH 3 , -CH 2 CH 3 , and each X is independently selected from Cl, Br, MsO, TsO and other leaving functional groups.
  • the patient has impaired DNA repair enzymes
  • the patient's tumor or cancer tissue is detected to have any one or two gene mutations in the genes corresponding to BRCA1 and BRCA2; or
  • the patient is detected to have any one gene mutation or two gene mutations in the genes corresponding to BRCA1 and BRCA2.
  • BRCA1 and BRCA2 mutations include germline mutations (gBRCAm) and systemic mutations (sBRCAm) of BRCA1 and BRCA2 mutations.
  • hypoxia-activating compound of the formula (I) is selected from compounds of the following structures:
  • the PARP inhibitor is selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib; or
  • the cancer and tumor are selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, colon cancer, rectal cancer, and bladder cancer; or
  • the TMB (Tumor Mutation Burden) level of the gene mutation is moderate.
  • TMB Tumor mutation load (burden) is tumor gene mutation load
  • TMB Tumor mutation load
  • Mb represents every million bases
  • CheckMate-032 This is a Phase II clinical trial of 401 advanced lung cancer patients who failed first-line treatment, receiving PD-1 inhibitors alone or in combination with Yipimu.
  • TMB Tumor mutation load
  • the effective rates of the three groups are 62%, 20%, and 23%, respectively, and the effective rate of the high TMB group is 3 times; and the median overall survival of the three groups were: 22.0 months, 3.6 months, 3.4 months - 22.0 months and 3.4 months, a difference of 6 times!
  • the present invention also provides a drug for treating PARP inhibitor-resistant cancer and tumor patients, the drug contains the hypoxia-activating compound of formula (I), and the drug can be used alone or in combination to treat PARP inhibitor-resistant cancer , Tumor patients:
  • each R is independently selected from H, -CH 3 , -CH 2 CH 3
  • each X is independently selected from Cl, Br, MsO, TsO and other leaving functional groups.
  • said patient has impaired DNA repair enzymes; or
  • the patient's tumor or cancer tissue is detected to have any one or two gene mutations in the genes corresponding to BRCA1 and BRCA2; or
  • the patient is detected to have any one gene mutation or two gene mutations in the genes corresponding to BRCA1 and BRCA2.
  • the BRCA1 and BRCA2 mutations include germline mutations (gBRCAm) and systemic mutations (sBRCAm) of BRCA1 and BRCA2 mutations.
  • hypoxia-activating compound of formula (1) is selected from compounds of the following structures:
  • the PARP inhibitor is selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib; or
  • the cancer and tumor are selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, colon cancer, rectal cancer, and bladder cancer; or
  • the TMB (Tumor Mutation Burden) level of the gene mutation is moderate.
  • the above-mentioned medicine should also add pharmaceutically acceptable auxiliary materials or excipients according to the characteristics of medicines, medicines and preparations.
  • the medicine can be in any dosage form for clinical application, such as tablet, suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated agent, granule, dry powder, oral solution, small needle for injection , Freeze-dried powder for injection or large infusion.
  • the pharmaceutically acceptable adjuvant or excipient in the medicine may include one or more of the following: diluent, solubilizer, disintegrant, suspending agent, lubricant, viscose Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • the above drugs can be used alone or in combination with PARPi drugs for treatment.
  • Fig. 1 is the inhibitory rate curve of compound TH-302 and tirapazamine (tirapazamine) to Capan-1 cell line under normoxic and hypoxic conditions, wherein, con.Log (nM) represents the concentration value under the unit of nmol/L The logarithm value with base 10, inhibition represents inhibition rate;
  • Fig. 2 is the inhibitory rate curve of compound TH-302 and tirapazamine (tirapazamine) to Capan-1 cell line under normoxic and hypoxic conditions, wherein, con.Log (nM) represents the concentration value under the unit of nmol/L The logarithm value with base 10, inhibition represents inhibition rate;
  • Fig. 3 is the growth curve of the tumor volume of mice in each group in the subcutaneous model of human pancreatic cancer Capan-1;
  • Figure 4 is a graph showing the relative tumor inhibition rates of mice in each group in the subcutaneous model of human pancreatic cancer Capan-1;
  • Figure 5 is a graph of the body weight of mice in each group in the subcutaneous model of human pancreatic cancer Capan-1;
  • Figure 6 is a graph showing the percent change in body weight of mice in each group in the subcutaneous model of human pancreatic cancer Capan-1;
  • Fig. 7 is the growth curve of the tumor volume of mice in each group in the pancreatic cancer Capan-1CDX model
  • Figure 8 is a graph showing the change in body weight over time in each treatment group in the pancreatic cancer Capan-1CDX model
  • Figure 9 is a growth curve of the tumor volume of each group of mice in the lung cancer LU6429 PDX model
  • Figure 10 is a graph showing the body weight of each treatment group over time in the lung cancer LU6429 PDX model
  • Figure 11 is a growth curve of the tumor volume of each group of mice in the bladder cancer BL3325 PDX model
  • Figure 12 is a graph showing the change in body weight over time in each treatment group in the bladder cancer BL3325 PDX model.
  • a patient and “individual” are used interchangeably and refer to a mammal in need of cancer treatment.
  • the patient is a human.
  • the patient is a human being diagnosed with cancer.
  • a "patient” or “individual” may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, for screening, characterization and evaluation of drugs and therapies or rats.
  • Prodrug refers to a compound (or drug) that, upon administration or administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
  • Prodrugs are chemically modified relative to the drug in such a way that they are less or inactive relative to the drug, but the chemical modification allows the corresponding drug to be produced by metabolism or other biological processes after administration of the prodrug.
  • Prodrugs may have altered metabolic stability or delivery characteristics, fewer side effects or toxicity, or improved flavor relative to the active drug.
  • Prodrugs can be synthesized using reactants other than the corresponding drug.
  • Treating or “treating a patient” refers to administering, using or administering to a patient a therapeutically effective amount of a drug relevant to the present invention.
  • administering or “administering” "using" a drug to a patient refers to direct administration or administration (which may be administered or administered to the patient by a medical professional or may be self-administered or administered) and/or indirect administration or administration, which may prescribe the drug the behavior of.
  • direct administration or administration which may be administered or administered to the patient by a medical professional or may be self-administered or administered
  • indirect administration or administration which may prescribe the drug the behavior of.
  • a physician who instructs a patient to self-administer or administer a drug and/or provides a prescription for the drug to the patient is administering or administering the drug to the patient.
  • a "therapeutically effective amount" of a drug means that when administered or administered or used to a patient with cancer, it will have a desired therapeutic effect (such as alleviation, improvement, remission or elimination of the clinical manifestations of one or more cancers in the patient) amount of drug.
  • a therapeutic effect does not necessarily occur through the administration or administration of one dose, and may only occur after the administration or administration of a series of doses. Thus, a therapeutically effective amount may be administered or administered in one or more doses.
  • Treatment of a condition or patient refers to steps taken to obtain beneficial or desired results (including clinical results).
  • beneficial or desired clinical outcomes include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer; reduction in extent of disease; delay or slowing of disease progression; amelioration, remission or stabilization of disease state; or other beneficial outcomes.
  • treatment of cancer can result in a partial response or stable disease.
  • Tumor cell refers to a tumor cell of any appropriate species (eg, a mammal such as murine, canine, feline, equine or human).
  • TH-302 is a small molecule prodrug that can be activated under hypoxic conditions and release cytotoxins to kill tumor cells and tumor tissues.
  • DLD1 human colon cancer cell line
  • BRCA2 knockout DLD1-BRCA2-/- tumor cell line to detect Whether there is any difference in the killing ability of TH-302 to the above two tumor cell lines with or without BRCA2 protein expression.
  • This clonogenic assay uses IC 90 (90% inhibitory concentration) value as an evaluation of the ability of compound TH-302 to kill cells.
  • the specific experimental method is as follows:
  • DLD1 and DLD1-BRCA2-/- cells were cultured in RPMI medium, added with 10% FBS and 1% double antibody, and cultured at 37°C and 5% CO 2 .
  • the cells are routinely cultured until the cell saturation is 80%-90%, and the cells are collected when the number reaches the requirement.
  • the cells were cultured in a 37°C, 5% CO 2 incubator for 2 days.
  • the cells were resuspended with 3 mL of culture medium and seeded in a 6-well culture plate, wherein the density of DLD1-BRCA2-/- cells was 2000/well, and the density of DLD1 cells was 300/well.
  • the IC 90 values of the test compound TH-302 in the two cells measured by the above-mentioned experimental method are listed in Table 1 below.
  • Table 1 IC 90 data of the inhibitory effect of compound TH-302 on two tumor cell lines under hypoxic conditions
  • the applicant specifically studied the in vitro cell proliferation inhibition experiments of hypoxia-activated anticancer prodrugs TH-302 and tirapazamine in Capan-1 and BxPc-3 cell lines under normoxia and hypoxia conditions, respectively.
  • the Capan-1 cell line is a BRCA mutant cell line
  • the BxPc-3 cell line is a BRCA wild-type cell line, that is, a non-BRCA mutant cell line.
  • This experiment was used to verify the difference in the sensitivity of TH-302 and tirapazamine, which are both hypoxia-activated anticancer prodrugs, to BRCA mutations.
  • hypoxic workstation Adjusts the hypoxic workstation to an anaerobic environment (O 2 ⁇ 0.01%) and confirm hypoxia in the workstation using an oxygen indicator.
  • the 24-well plate with glass inserts was sent to the hypoxic workstation.
  • the IC 50 of TH-302 in the BRCA mutant Capan-1 cell line was 0.82 ⁇ M
  • the IC 50 in the BRCA wild-type BxPc-3 cell line was 3.07 ⁇ M.
  • the difference is 3.7 times, indicating that BRCA mutation makes TH-302 have stronger proliferation inhibitory activity on tumor cell lines, that is, BRCA mutation will enhance the sensitivity of tumor cells to TH-302 drug.
  • Tirapazamine which is also a hypoxia-activated anticancer prodrug, had an IC 50 of 29.06 ⁇ M in the BRCA-mutated Capan-1 cell line under hypoxic conditions, and an IC 50 of 29.06 ⁇ M in the BRCA wild-type BxPc-3 cell line.
  • the IC 50 was 33.23 ⁇ M, with a difference of 1.1 times, and there was no significant difference, which indicated that tirapazamine had no correlation with BRCA mutations, that is, BRCA mutations did not significantly affect the proliferation inhibitory activity of tirapazamine on tumor cell lines, that is, BRCA The mutation did not enhance the sensitivity of tumor cells to the drug tirapazamine.
  • Capan-1 CDX model is an olaparib-resistant model with a BRCA2 pathogenic variant.
  • Each BALB/c female nude mouse was inoculated subcutaneously with 5 ⁇ 10 5 Capan-1 cells on the lower back of the right side, and the cells were resuspended in 1:1 PBS and Matrigel (0.1ml/mouse), and a total of 64 female mice were inoculated .
  • the date of inoculation is June 23, 2021.
  • the average tumor volume is 140mm 3 , the patients will be randomly divided into groups according to tumor size.
  • test drug Olaparib 100mg/kg single drug group (Group 2), TH-302 75mg/kg and Olaparib 100mg/kg combined administration group (Group 5), TH-302 75mg/kg single drug group (Group 7) And 10% absolute ethanol + 10% polyoxyethylene (35) castor oil + 80% glucose injection D5W (pH7.4) vehicle control group, a total of 7 groups, 6 mice in each group.
  • vehicle control group, TH-302 single drug and combined drug groups were given tail vein administration once a week for a total of three weeks; the test drug Olaparib group was administered orally by gavage once a day for a total of three weeks. Medicine for 30 days.
  • the curative effect is evaluated according to the relative tumor inhibition rate TGI (%), and the safety evaluation is carried out according to the animal body weight change and death.
  • the test drug Olaparib 100mg/kg (Group 2) treatment group had no tumor inhibitory effect on the 35th day after tumor cell inoculation, and the relative tumor inhibition rate TGI (%) was -7.1%, which was not statistically significantly different from the control group (p>0.05).
  • the combined treatment group (Group 5) of Olaparib 100mg/kg and TH-302 75mg/kg had a significant tumor inhibitory effect on the 35th day after tumor cell inoculation, and there was a statistically significant difference compared with the control group (p ⁇ 0.001 ), the relative tumor inhibition rate TGI (%) was 84.47%.
  • TH-302 75mg/kg monotherapy group (Group 7) showed a significant tumor inhibitory effect on the 35th day after tumor cell inoculation (Day 35), which was statistically significantly different from the control group (p ⁇ 0.001 ), the relative tumor inhibition rate TGI (%) was 87.66%.
  • TGI tumor inhibition rate
  • mice The tumor volumes of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 7 below.
  • Table 7 Changes in tumor volume of mice in each group with treatment time in the Capan-1 model of human pancreatic cancer (unit: mm 3 )
  • Table 8 Drug efficacy analysis table of each group in the subcutaneous model of human pancreatic cancer Capan-1
  • T/C% Relative tumor proliferation rate
  • T and C are the average relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
  • Table 9 Relative tumor inhibition rates of tumors in each group in the human pancreatic cancer Capan-1 subcutaneous model
  • mice The body weights of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 10 below.
  • Table 10 Body weight of mice on different days of inoculation in the subcutaneous animal model experiment of human pancreatic cancer Capan-1 treated with drugs
  • Figure 5 is, the body weight curves of mice in each group in the subcutaneous model of human pancreatic cancer Capan-1.
  • Capan-1 CDX model is indeed an Olaparib-resistant model, and Olaparib has no inhibitory effect on the tumor growth of this model, that is, it is resistant to Olaparib;
  • TH-302 monotherapy has a good therapeutic effect on Olaparib-resistant pancreatic cancer (TGI is 82.67%);
  • TH-302 combined with Olaparib has a good therapeutic effect on Olaparib-resistant pancreatic cancer (TGI is 87.43%);
  • the TH-302 monotherapy group had a slightly better antitumor effect, but there was no significant difference (p>0.05);
  • the inventors also studied the efficacy and safety of TH-302 in the olaparib-resistant lung cancer LU6429 PDX model and bladder cancer BL3325 PDX model.
  • mice were subcutaneously inoculated with human pancreatic cancer Capan-1 cells to establish a subcutaneous transplantation model of human pancreatic cancer.
  • the test is divided into test drug Olaparib 100mg/kg single drug group (Group 2), TH-302 50mg/kg single drug group (Group 3, QD), TH-302 100mg/kg single drug group (Group 4), TH-302 50mg/kg single drug group (Group 5, QW), TH-302 25mg/kg single drug group (Group 6), TH-302 25mg/kg and Olaparib 100mg/kg combined administration group (Group 7) and 10% no Water ethanol + 10% polyoxyethylene (35) castor oil + 80% glucose injection D5W (pH7.4) vehicle control group (Group 1), a total of 7 groups, 6 mice in each group.
  • Olaparib 100mg/kg single drug group Group 2
  • TH-302 50mg/kg single drug group Group 3, QD
  • TH-302 100mg/kg single drug group Group 4
  • the vehicle control group and each test drug of TH-302 were administered by tail vein injection.
  • the TH-302 50mg/kg single-drug group (Group 3, QD) was administered once a day for 3 consecutive days, rested for 4 days, and then rested for two weeks; then administered daily for 3 consecutive days.
  • TH-302 100mg/kg (Group 4, QW), 50mg/kg (Group 5, QW), 25mg/kg (Group 6, QW) single drug group and combined administration of TH-302 25mg/kg and Olaparib 100mg/kg TH-302 in Group 7 was administered once a week for a total of three weeks.
  • the test drug Olaparib in each group was administered orally by gavage, once a day, for a total of 30 days.
  • the specific administration route, dose and scheme in the human pancreatic cancer Capan-1 animal model are shown in Table 12.
  • Table 12 Administration routes, doses and regimens in human-derived pancreatic cancer Capan-1 animal model
  • the dosing volume is 10 ⁇ L/g.
  • the tumor growth of each treatment group and control group was recorded on different days of the experiment, as shown in Table 13, and the growth curves of the tumor volumes of mice in each group are shown in FIG. 7 .
  • the curative effect was evaluated according to the relative tumor proliferation rate and the relative tumor inhibition rate, and the efficacy analysis of each group is shown in Table 14.
  • the results of the mouse body weight change rate on the 43rd day are shown in Table 15.
  • the body weight of each treatment group changed with time The change curve is shown in Figure 8.
  • Relative tumor proliferation rate, T/C% that is, at a certain time point, the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group.
  • T/C% T TW /C TW ⁇ 100% (T TW : the average tumor weight at the end of the experiment in the treatment group; C TW : the average tumor weight at the end of the experiment in the vehicle control group).
  • T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively).
  • Table 13 Changes in tumor volume of mice in each group with treatment time in the Capan-1 model of human pancreatic cancer (mm 3 )
  • Table 14 Drug efficacy analysis table of each group in the subcutaneous model of human pancreatic cancer Capan-1
  • Table 15 Body weight changes in each group in the human pancreatic cancer Capan-1 subcutaneous model
  • mice in the vehicle control group were 1301.38 mm 3 on day 43 after tumor cell inoculation (Day 43).
  • the average tumor volume of the test drug Olaparib 100mg/kg (Group 2) treatment group was 846.86mm 3 on the 43rd day after tumor cell inoculation (Day 43), and the relative tumor inhibition rate TGI (%) was 37.43%. There was no statistically significant difference (p>0.05).
  • the test drug TH-302 50mg/kg treatment group (Group 3, QD) had an average tumor volume of 146.99mm 3 on the 43rd day after tumor cell inoculation (Day 43), which was statistically significantly different from the control group ( p ⁇ 0.001), the relative tumor inhibition rate TGI (%) was 89.17%.
  • the test drug TH-302 100mg/kg treatment group (Group 4) had an average tumor volume of 124.68mm 3 on the 43rd day after tumor cell inoculation (Day 43), which was statistically significantly different from the control group (p ⁇ 0.001), and the relative tumor inhibition rate TGI (%) was 90.89%.
  • the test drug TH-302 50mg/kg treatment group (Group 5, QW) had an average tumor volume of 263.45mm 3 on the 43rd day after tumor cell inoculation (Day 43), which was statistically significantly different from the control group ( p ⁇ 0.001), the relative tumor inhibition rate TGI (%) was 80.18%, and the complete tumor inhibition rate was 33.3%.
  • TH-302 100mg/kg (Group 4), 50mg/kg (Group 5, QW) and 25mg/kg (Group 6) monotherapy groups showed a dose-dependent antitumor effect.
  • TH-302 100mg/kg (Group 4, QW), 50mg/kg (Group 5, QW) monotherapy group compared with TH-302 25mg/kg monotherapy group (Group 6, QW) had statistically significant Sex difference (all p ⁇ 0.001).
  • the combination therapy group of Olaparib 100mg/kg and TH-302 25mg/kg (Group 7) has better anti-tumor effect than Olaparib 100mg/kg (Group 2) and TH-302 25mg/kg single drug group (Group 6), statistics There are significant differences (p ⁇ 0.05 and p ⁇ 0.001), and the specific dose combination of Olaparib and TH-302 can show a synergistic effect on tumor inhibition.
  • the LU6429 PDX model is an olaparib-resistant model with a BRCA2 pathogenic mutation.
  • mice Balb/c nude female mice were inoculated subcutaneously
  • the tumor mass of lung cancer LU6429 was used to establish the subcutaneous transplantation tumor model of human lung cancer.
  • the test is divided into test drug Olaparib 50mg/kg single drug group (Group 02), TH-302 80mg/kg single drug group (Group 03), TH-302 40mg/kg single drug group (Group 04), TH-302 20mg/kg single drug group (Group 04), TH-302 20mg/kg kg single drug group (Group 05), TH-302 40mg/kg and Olaparib 50mg/kg combined administration group (Group 06), and glucose injection vehicle control group (Group 01).
  • mice in each group There were 6 groups in this study, 6 mice in each group, in which the vehicle control group and TH-302 were given tail vein administration once a week for a total of 3 weeks; Olaparib was administered by intragastric administration and administered daily Medicine 1 time, a total of 28 days of administration.
  • Table 16 shows the administration route, dosage and regimen in the lung cancer LU6429 animal model.
  • Table 16 Administration route, dosage and regimen in animal model of lung cancer LU6429
  • the administration volume is 10 ⁇ L/g; 2. QD ⁇ 28: once a day for 28 consecutive days; 3. QW ⁇ 3: once a week for 3 consecutive weeks.
  • the tumor growth of each treatment group and control group was recorded on different days of the experiment, as shown in Table 17, and the growth curves of the tumor volumes of mice in each group are shown in FIG. 9 .
  • the curative effect was evaluated according to the relative tumor proliferation rate and the relative tumor inhibition rate, and the efficacy analysis of each group is shown in Table 18. Record the changes in body weight after administration of the treatment group and the control group.
  • the safety of each group in the subcutaneous model of lung cancer LU6429 is shown in Table 19, and the body weight change results of the mice on day 25 are shown in Table 10.
  • Table 17 In Changes of tumor volume in each group of mice in lung cancer LU6429 model with treatment time (mm 3 )
  • Table 18 In Drug efficacy analysis table of each group in the subcutaneous model of lung cancer LU6429
  • Olaparib alone did not produce tumor inhibitory effect, showing the resistance of lung cancer LU6429 PDX model to Olaparib.
  • the TH-302 80mg/kg (Group 03) dose treatment group the tumor of 1 mouse was completely cleared, and the clearance rate was 16.7%.
  • the test drug TH-302 80mg/kg, 40mg/kg and 20mg/kg treatment groups had statistically significant differences (p ⁇ 0.05), showing dose dependence.
  • mice in each test drug treatment group did not lose weight and were well tolerated.
  • the BL3325 PDX model is an olaparib-resistant model with a BRCA2 pathogenic mutation.
  • mice Balb/c nude female mice were inoculated subcutaneously
  • the tumor mass of bladder cancer BL3325 was used to establish a subcutaneous transplanted tumor model of human bladder cancer.
  • the test is divided into test drug Olaparib 50mg/kg single drug group (Group 02), TH-302 80mg/kg single drug group (Group 03), TH-302 40mg/kg single drug group (Group 04), TH-302 20mg/kg single drug group (Group 04), TH-302 20mg/kg kg single drug group (Group 05), TH-302 40mg/kg and Olaparib 50mg/kg combined administration group (Group 06), and glucose injection vehicle control group (Group 01).
  • mice in each group There were 6 groups in this study, 6 mice in each group, in which the vehicle control group and TH-302 were given tail vein administration once a week for a total of 3 weeks; Olaparib was administered by intragastric administration and administered daily 1 dose, for a total of 30 days.
  • Table 20 shows the administration route, dosage and regimen in the bladder cancer BL3325 animal model.
  • Table 20 Administration route, dosage and regimen in bladder cancer BL3325 animal model
  • the administration volume is 10 ⁇ L/g; 2. QD ⁇ 30: once a day for 30 consecutive days; 3. QW ⁇ 3: once a week for 3 weeks; 4. i.v. is tail vein administration, p.o. is intragastric administration.
  • Table 21 In Changes of tumor volume in each group of mice in bladder cancer BL3325 model with treatment time (mm 3 )
  • Table 22 In Drug efficacy analysis table of each group in bladder cancer BL3325 subcutaneous model
  • Table 23 In Body weight changes of each group in bladder cancer BL3325 subcutaneous model
  • Test drug TH-302 in 80mg/kg, 40mg/kg, 20mg/kg dose alone treatment group, and TH-302 40mg/kg combined with Olaparib 50mg/kg treatment group Bladder cancer BL3325 subcutaneous models all have significant anti-tumor proliferation effects, and Olaparib 50mg/kg alone has no significant anti-tumor effect.
  • the TH-302 80mg/kg treatment group Group 03
  • the combined treatment effect of TH-302 40mg/kg and Olaparib 50mg/kg was significantly better than that of Olaparib 50mg/kg alone, better than that of TH-302 40mg/kg alone, and the difference was significant.
  • mice in each test drug treatment group did not lose weight and were well tolerated.
  • the PARP inhibitor selected in the examples of the present application is Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib, etc. It is also a PARP inhibitor, and its mechanism of action is similar to that of Olaparib, both of which block the function of enzymes involved in the repair of damaged DNA. Therefore, it can be inferred that Rucaparib, Niraparib, and Talazopa PARPi such as Talazoparib, Fluzoparib, and Pamiparib have similar tumor inhibitory efficacy to Olaparib in the above experiment.
  • TH-302 is the DNA alkylating agent activated by hypoxia, the general formula compound of claim 1:

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Abstract

本发明提供TH-302单药或联用治疗PARP抑制剂耐药的患者的治疗方法、药物及其制药用途。

Description

使用TH-302治疗PARP抑制剂耐药的患者 技术领域
本发明涉及癌症的治疗方法，特别是对PARP抑制剂(PARPi)耐药的癌症患者的治疗方法。
背景技术
PARPi药物奥拉帕利Olaparib的第一个人体临床试验，首次证实了PARPi可抑制携带BRCA1/2突变的肿瘤细胞的生长，这主要基于合成致死性理论(Ashworth,A.,&Lord,C.J.(2018).Synthetic lethal therapies for cancer:what's next after PARP inhibitors？.Nature rev iews.Clinical oncology,15(9),564–576.https://doi.org/10.1038/s41571-018-0055-6)：PARP抑制剂可以抑制PARP的DNA单链损伤修复功能，导致细胞内大量单链DNA损伤不能及时修复。未被修复的单链DNA损伤会引发复制叉崩解并由此产生双链DNA损伤，具有较强细胞毒性的双链DNA损伤在正常细胞内可通过BRCA1及BRCA2等蛋白共同参与介导的同源重组修复(HR)途径进行修复，而在BRCA1/2缺陷的肿瘤细胞内，双链DNA损伤无法修复，导致肿瘤细胞的最终死亡。PARPi最初开发用于放射治疗和化疗增敏，也有临床前研究支持PARPi可以作为治疗BRCA1/2基因缺陷癌症的单一药物进行开发。由此，PA RPi-BRCA假说验证的初始目标人群选定为BRCA1/2胚系突变(gBRCA1/2)携带者。PA RPi在卵巢癌中的最初研究入组人群均是既往已接受过铂类化疗，且研究发现铂类敏感与P ARPi响应有直接关联(铂类化疗药是DNA损伤剂，会导致DNA交联，部分可由HR通路修复；因此DNA修复缺陷型肿瘤预期会对铂类化疗敏感)。另外两个PARPi已在卵巢癌中获批：尼拉帕利Niraparib和芦卡帕利Rucaparib：FDA和EMA批准了尼拉帕利的维持治疗方案(不管BRCA1/2状态如何)；芦卡帕利也被FDA和EMA登记为BRCA1/2突变相关卵巢癌患者，既往接受过两线化疗方案之后的可选治疗方案；而他拉唑帕利现也得到了F DA的获批，用于治疗BRCA突变/HER-2阴性转移性乳腺癌(Mateo,J.,Lord,C.J.,Serr a,V.,Tutt,A.,
Figure PCTCN2022115284-appb-000001
J.,Castroviejo-Bermejo,M.,Cruz,C.,Oaknin,A.,Kaye,S.B.,&de Bono,J.S.(2019).A decade of clinical development of PARP inhibitors in pers pective.Annals of oncology:official journal of the European Society for Medical Oncol ogy,30(9),1437–1447.https://doi.org/10.1093/annonc/mdz192)。
随着PARPi在临床的应用，PARPi耐药即将成为其在临床应用的不可避免的问题，有超过40％的BRCAm(BRCA突变)卵巢癌患者未能从PARPi获益。现有的研究表明同源重组恢复(Homologous recombination repair restoration，HRR)、DNA复制叉保护、PAR Pi药代动力学改变等是导致PARPi耐药的主要原因。为了克服PARPi耐药，增加PARPi药物敏感性，多种的联合治疗手段正在被开发，其中许多联合治疗手段已经进入临床阶段。主要包括：PARPi-DNA烷化剂联合；PARPi-单孢酵解性疱疹病毒(oHSVs)联合；PARPi-离子辐射联合；PARPi-免疫治疗联合；PARPi-HSP90抑制剂联合；PARPi-WEE1/ATR抑制剂联合；PARPi-DNMTi抑制剂联合；PARPi-CDK抑制剂联合等(He Li,Zhao-Yi Liu,Na yiyuan Wu,Yong-Chang Chen,Quan Cheng and Jing Wang.PARP inhibitor resistance:the underlying mechanisms and clinical implications.Mol Cancer,2020 Jun 20；19(1):107.2020.https://doi.org/10.1186/s12943-020-01227-0；Rose,M.,Burgess,J.T.,O'Byrne,K.,Richar d,D.J.,&Bolderson,E.(2020).PARP Inhibitors:Clinical Relevance,Mechanisms of A ction and Tumor Resistance.Frontiers in cell and developmental biology,8,564601.https://doi.org/10.3389/fcell.2020.564601)。
TH-302(Evofosfamide，埃夫索胺，cas号918633-87-1)是一种2-硝基咪唑引发的乏氧激活前药(HAP)溴代异磷酰胺，由美国Threshold公司开发。在乏氧情况下，无活性T H-302前药可释放高毒性的Br-IPM。TH-302具有广谱的体内外生物活性以及特异的乏氧选 择性激活活性以及诱导H2AX磷酸化、DNA交联活性，从而导致细胞周期停滞，因而该化合物被多家制药公司以及科研院所进行抗癌药物的开发。
Meng F Y(孟繁英)等人发表的研究文章指出：TH-302对于各种肿瘤具有广谱活性，并且具有优异的缺氧选择性的活性增强效应。研究表明，缺氧条件下32个人癌细胞系中TH-302的体外细胞毒性均明显强于常氧条件下的，显示该化合物对于缺氧环境下的癌细胞具有选择性的细胞毒性。使用单电子还原酶(POR)过表达的人源细胞证实了TH-302在乏氧条件下单电子还原酶依赖性的活性增强原理，，如下反应式1：
Figure PCTCN2022115284-appb-000002
反应式1
细胞色素P450氧化还原酶将TH-302这个前药进行还原，得到中间体自由基负离子，然后自由基负离子不稳定而被分解为具有细胞毒性的细胞毒素Br-IPM发挥作用。该步骤的关键步骤是单电子还原过程，研究证实氧气的存在会使得单电子还原过程逆转，也就是说，氧气的存在会阻碍单电子还原过程，所以只有乏氧的环境能下，TH-302才可还原产生具有更强的细胞毒性。进一步使用基于中国仓鼠卵巢细胞的DNA修复突变细胞系，包括缺乏碱基切除、核苷酸切除，非同源末端连接修复的细胞系或同源末端连接修复的细胞系(该细胞系为缺乏同源依赖性修复的细胞系)检测TH-302的体外细胞毒性。研究发现缺乏同源末端连接修复单独缺损或与核苷酸切除共同修复缺损的细胞系，对TH-302缺氧敏感性明显增强。但是单独缺损碱基切除、核苷酸切除或非同源末端连接修复的细胞系对TH-302敏感性无影响。与该发现一致的是，在缺乏BRCA1、BRCA2和FANCA的细胞体外实验中也观察到对TH-302的敏感性增强；并且在临床试验中也观察到TH-302对于BRCA基因突变的患者具有更好的治疗效果(Meng F,Evans J W,Bhupathi D,et al.Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302.[J].Molecular Cancer Therapeutics,2012,11(3):740；Conroy,M.,Borad,M.J.,&Bryce,A.H.(2017).Hypoxia-Activated Alkylating Agents in BRCA1-Mutant Ovarian Serous Carcinoma.Cureus,9(7),e1517.https://doi.org/10.7759/cureus.1517；WO2015013448A1，Treatment of pancreatic cancer with a combination of a hypoxia-acti vated prodrug and a taxane；WO2020007106A1，埃夫索胺的抗癌医药用途)。
这些关于TH-302的作用机理研究，特别是揭示的TH-302对于BRCA突变的特别敏感性事实启发TH-302药物可能通过联用来克服PARPi的耐药性缺陷。
然而在PCT/US2012/031677申请(公开号WO2012135757A2，Methods for treating cancer，申请人美国Threshold公司)中，Threshold的研究人员使用TH-302与PARPi候选药物ABT-888(即Veliparib，CAS：912444-00-9)在体外进行了联用研究；
不同癌细胞在常氧下用ABT-888预处理1h，然后在常氧或缺氧条件下与TH-302共同孵育另外的2h。在ABT-888存在下孵育3天之后，使用阿尔玛蓝确定细胞生活力。结果如下表：
H460细胞系(人大细胞肺癌细胞)结果：
Figure PCTCN2022115284-appb-000003
HCT116细胞系(人结肠癌细胞)结果：
Figure PCTCN2022115284-appb-000004
A375细胞系(人恶性黑色素瘤细胞)结果：
Figure PCTCN2022115284-appb-000005
上述结果显示在体外细胞实验中，TH-302与ABT-888联用没有加合效应，即TH-302活性实质上不受ABT-888存在的影响。
然而在PCT/US2019/065065申请(公开号WO2020118251A2，发明名称Hypoxia targeting compositions and combinations thereof with a parp inhibitor and methods of use thereof)中则指出使用缺氧活化的药物或其前药(如apaziquone,AQ4N,etanidazole,evofosfamide(TH-302),nimorazole,pimonidazole,porfiromycin,PR-104,tarloxotinib，tirapazamine(替拉扎明))与PARPi联用有加合效应，特别的其还公开了替拉扎明与奧拉帕尼的动物体内联合用药试验，结果显示对比使用替拉扎明或PARPi的单一用药方案，包含有缺氧活化抗癌前药替拉扎明与一种PARPi奧拉帕尼的联合给药方案能显著地延迟PDX动物模型中肿瘤的生长速率，即缺氧活化抗癌药物与PARPi联用具有加合效应。
即在不同研究的试验中，对于缺氧活化抗癌前药与PARPi联用是否有加合效应仍然存在争议，这显示了加合效应的复杂性。
发明内容
申请人的研究人员在药效试验中发现TH-302与PARPi联用在部分动物体内肿瘤增殖抑制试验中显示加合效应，这与Threshold公司在2012年进行的体外细胞实验结果完全不同，为此申请人进一步进行了研究，得到了进一步的出乎意料的结果：TH-302单药既能对PARPi耐药的癌症模型具有优异的治疗效果！
基于实验结果，本申请提供以下的治疗癌症方法。
治疗方法，其使用含有式(1)的乏氧激活化合物的药物单药或联用治疗PARPi耐药的癌症、肿瘤患者：
Figure PCTCN2022115284-appb-000006
其中，R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
治疗方法，其使用含有式(1)的乏氧激活化合物的药物联用PARP抑制剂治疗PARP抑制剂耐药的癌症、肿瘤患者：
Figure PCTCN2022115284-appb-000007
其中，R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
关于本文所述药物是指药品或制剂，所制得的药品包含特定剂量范围的有效成分式(1)的乏氧激活化合物或其盐或溶剂合物，和/或所制得的药物为特定剂型、特定给药方式施用。
所制得的药品、药物、制剂还可包含药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
与TH-302或其类似化合物
Figure PCTCN2022115284-appb-000008
相关的制剂包括口服制剂、冻干制剂和浓缩注射液，并且相关处方、制备方法和临床配伍、施用方法被Threshold公司的相关专利：WO2010048330A1、WO2012142520A2、WO2008083101A1所详细说明并公开，在此本发明将上述申请文本的全文引入。
TH-302或其类似化合物
Figure PCTCN2022115284-appb-000009
是一个DNA烷化剂类抗癌药，具有广泛的癌症治疗潜力，这些相关的癌症适应症实验、临床试验被公开在相关的Threshold公司及其他制药公司的专利申请文本中(比如WO2016011195A2、WO2004087075A1、WO2007002931A1、WO2008151253A2、WO2009018163A1、WO2009033165A2、WO2010048330A2、WO2012142520A1、WO2008083101A2、WO2020007106A1、WO2020118251A1、WO2014169035A1、WO2013116385A1、WO2019173799A2、WO2016081547A1、WO2014062856A1、WO2015069489A1、WO2012006032A2、WO2018026606A2、WO2010048330A2、WO2015171647A1、WO2013096687A1、WO2013126539A2、WO2013096684A2、WO201200 9288A2、WO2012145684A2、WO2016014390A2、WO2019055786A2、WO2012135757A2、WO2015013448A2、WO2016011328A2、WO2013177633A2、WO2016011195A2、WO2015051921A2)以及FDA登记的临床试验中(NCT02402062、NCT02020226、NCT02076230、NCT01381822、NCT02093962、NCT01440088、NCT02255110、NCT02342379、NCT01864538、NCT01149915、NCT02433639、NCT00743379、NCT01485042、NCT01721941、NCT02047500、NCT00742963、NCT01497444、NCT00495144、NCT01746979、NCT01144455、NCT01403610、NCT01522872、NCT01833546、NCT02598687、NCT03098160、NCT02496832、NCT02712567)，在此本发明将上述相关申请文本以及临床试验信息全部引入。
“癌症”是指可通过侵袭而局部扩展且通过转移而全身扩展的潜在无限制生长的白血病、淋巴瘤、癌及其他恶性肿瘤(包括实体肿瘤)。
在此列举TH-302或其类似化合物
Figure PCTCN2022115284-appb-000010
能治疗的癌症的实例包括(但不限于)肾上腺、骨、脑、乳房、支气管、结肠及/或直肠、胆囊、头及颈、肾、喉、肝、肺、神经组织、胰脏、前列腺、副甲状腺、皮肤、胃及甲状腺的癌症。癌症的某些其他实例包括急性及慢性淋巴细胞及粒细胞肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈上皮分化不良及原位癌、尤文氏肉瘤、表皮样癌、巨细胞瘤、多型性神经胶母细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性黑色素瘤、恶性高钙血症、马方样体型肿瘤、髓样上皮癌、转移性皮肤癌、黏膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性及其他肉瘤、卵巢瘤、嗜铬细胞瘤、真性红血球增多症、原发性脑瘤、小细胞肺癌、溃疡型及乳头型二者的鳞状细胞癌、增生、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病灶、网状细胞肉瘤及威尔姆氏肿瘤。
PARP是一种酶，全称叫聚腺苷酸二磷酸核糖基聚合酶(Poly ADP-ribose Polymerase，P ARP)。PARP是一种DNA修复酶，在DNA修复通路中起关键作用。DNA损伤断裂时会激活P ARP，它作为DNA损伤的一种分子感受器，具有识别、结合到DNA断裂位置的功能，进而激活、催化受体蛋白的聚ADP核糖基化作用，参与DNA的修复过程。
PARP抑制剂通过抑制PARP酶的工作，让这些相当于“修理工”的PARP酶没法正常工作，DNA的损伤得不到修复，细胞就会死亡。
因为细胞并不是只有PARP这一个“修理工”，所以即使PARP出问题，细胞的DNA损伤被带到下一个工序中，还有另一个“修理工”在等着，仍然可以把DNA修复。BRCA基因负责产生的蛋白正是这另一个“修理工”的重要成员。正常细胞拥有这套双重保险机制，即使PARP抑制剂破坏了其中一重保险，另一重仍然可以工作，所以细胞不会死亡。
但是在具有BRCA基因突变的卵巢癌或乳腺癌细胞中，BRCA这个“修理工”已经不能正常工作。当然，由于PARP班组还在继续工作，所以癌细胞还不会死。
如果用PARP抑制剂特异性进入癌细胞，让PARP酶活性被抑制无法正常发挥作用，癌细胞的DNA就无法被修复。这样，PARP抑制剂就实现了只杀死癌细胞而不杀正常细胞的作用。
PARP抑制剂+BRCA基因突变同时发生，就会导致所谓的“合成致死(Synthetic Lethality)”，合成致死即当两种不同的基因(BRCA)或蛋白(PRAP)同时发生变化时会导致细胞死亡，而这两种基因/蛋白中如果只有一种异常则不会导致细胞死亡。
PARP抑制剂就是对PARP酶有抑制作用的化合物，即凡是能抑制PARP酶活性的物质均是PARP抑制剂。
选自已经上市销售的5个药物即奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Nirap arib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib以及进入临床三期的药物帕米帕利Pamip arib，显然此处的PARP抑制剂实质是指含有PARP抑制剂活性成分的药物。
Figure PCTCN2022115284-appb-000011
他拉唑帕利Talazoparib，适用于有害或疑似有害种系BRCA突变(gBRCAm)HER2阴性局部晚期或转移性乳腺癌的成人。市售剂型为0.25mg/1mg的他拉唑帕利甲苯磺酸盐胶囊，口服一次1毫克，每天1次，在不良反应的情况下考虑治疗中断或剂量减少：
首次出现不良反应，口服剂量减少到0.75mg(三个0.25mg胶囊)，每天1次；
第二次出现不良反应，口服剂量减少到0.5mg(两个0.25mg胶囊)，每天1次；
第三次出现不良反应，口服剂量减少到0.25mg(一个0.25mg胶囊)，每天1次。
尼拉帕利Niraparib，用于铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗。市售剂型为100mg的尼拉帕利甲苯磺酸盐胶囊，每天一次口服300mg,直至出现疾病进展或不可耐受的不良反应，在不良反应的情况下考虑治疗中断或剂量减少：
剂量下调首先从每天3粒胶囊(300mg)减少至每天2粒胶囊(200mg)；
如果需要进一步下调剂量，可第二次下调剂量，从每天2粒胶囊(200mg)减少至每天1粒胶囊(100mg)；
如果暂停给药和下调剂量无法控制不良反应，建议停药。
芦卡帕利Rucaparib，用于肿瘤携带一种特定基因突变(有害的BRCA)，且已使用两种或多种化疗药物治疗过的晚期卵巢癌女性。市售剂型为片剂：200mg，250mg和300mg， 三种规格。推荐剂量为600毫克，每日口服两次，含或不含食物。继续治疗直至疾病进展或不可接受的毒性。对于不良反应，考虑中断治疗或减少剂量。
奥拉帕利Olaparib，用于携带胚系或体细胞BRCA突变的(gBRCAm或sBRCAm)晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌初治成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗；铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗。市售剂型为片剂：150mg和100mg，两种规格。推荐剂量为300mg(2片150mg片剂)，每日2次，相当于每日总剂量为600mg。100mg片剂用于剂量减少时使用：
为处理不良事件，比如恶心、呕吐、腹泻、贫血等，可考虑中断治疗或减量；
如果需要减量，推荐剂量减至250mg(1片150mg片剂，1片100mg片剂)，每日服用2次(相当于每日总剂量为500mg)；
如果需要进一步减量，则推荐剂量减至200mg(2片100mg片剂)，每日服用2次(相当于每日总剂量为400mg)。
氟唑帕利Fluzoparib，用于既往经过二线及以上化疗的伴有胚系BRCA突变(gBRCAm)的铂敏感复发性卵巢癌、输卵管癌或原发性腹膜癌患者的治疗。市售剂型胶囊剂：50mg规格。
其他在研的进入临床的PARPi候选药物参见网页链接https://www.selleckchem.com/PARP.html及相关学术综述文献。
TH-302或其类似化合物
Figure PCTCN2022115284-appb-000012
治疗癌症的推荐剂量可以参考Thres hold公司及其他制药公司的专利申请文本中(比如WO2016011195A2、WO2004087075A1、WO2007002931A1、WO2008151253A2、WO2009018163A1、WO2009033165A2、WO2010048330A2、WO2012142520A1、WO2008083101A2、WO2020007106A1、WO2020118251A1、WO2014169035A1、WO2013116385A1、WO2019173799A2、WO2016081547A1、WO2014062856A1、WO2015069489A1、WO2012006032A2、WO2018026606A2、WO2010048330A2、WO2015171647A1、WO2013096687A1、WO2013126539A2、WO2013096684A2、WO2012009288A2、WO2012145684A2、WO2016014390A2、WO2019055786A2、WO2012135757A2、WO2015013448A2、WO2016011328A2、WO2013177633A2、WO2016011195A2、WO2015051921A2)以及FDA登记的临床试验中(NCT02402062、NCT02020226、NCT02076230、NCT01381822、NCT02093962、NCT01440088、NCT02255110、NCT02342379、NCT01864538、NCT01149915、NCT02433639、NCT00743379、NCT01485042、NCT01721941、NCT02047500、NCT00742963、NCT01497444、NCT00495144、NCT01746979、NCT01144455、NCT01403610、NCT01522872、NCT01833546、NCT02598687、NCT03098160、NCT02496832、NCT02712567)中的剂量：
120mg/m 2至460mg/m 2的日剂量来静脉注射给药；
480mg/m 2至大约670mg/m 2或者例如575mg/m 2的周剂量来静脉注射给药。
用于临床试验的TH-302(用于施用溶液的浓缩物)是TH-302的无菌液体制剂。用70％无水乙醇、25％二甲基乙酰胺和5％聚山梨酯80配制TH-302。它由发起人提供，在具有橡胶塞和flip-off封口的10mL玻璃小瓶中。TH-302药物产品是澄清的、无色至淡黄色的溶液，基本上不含可见颗粒。对于标称总量为650mg的TH-302，每个单次使用的小瓶含有标称填充体积为6.5mL的TH-302药物产品(相当于100mg/mL)，并且被清楚地贴上标签，其公开 了批号、施用途径、所需的储存条件、发起人的名称和适用的规定所要求的适宜的预警标记。在施用前需要按照药房手册进行稀释。
在施用前用可商购获得的5％葡萄糖水溶液稀释至总体积为500mL(对于≥1000mg的总剂量为1000mL)施用，以获得所需的终浓度。用不含邻苯二甲酸二(2-乙基己基)酯(无DEHP)的5％葡萄糖水溶液制备每剂TH-302，并使用不含DEHP的静脉输液施用装置静脉滴注。
当然也可以使用Threshold公司开发的冻干制剂：
将TH-302(100mg)和蔗糖(1g)的溶液(20mL)加入冻干小瓶中并冻干以产生TH-302的冻干单位剂型，载药量不到5mg/cm 3。为了人类施用的目的，将单位剂型溶解在的5％葡萄糖注射液中，并向患者施用适量的该溶液；
后续人类患者TH-302的I期临床试验给药方案使用冻干制剂，在100mL玻璃小瓶中制备注射用TH-302冻干制剂，载药量为100mg/100ml，在2-8℃°的受控条件下储存，使用时注射到冻干制剂瓶中250mL的5％葡萄糖注射液，并通过输注泵在30分钟内静脉滴注。
单药，即单药治疗。联用，即联合用药治疗。单药治疗是指在一个疗程中仅使用一种抗癌药物。联合治疗是指在一个疗程中同时或先后使用两种或两种以上的抗癌药物。
一般而言，联合治疗需要根据病情特点、联用药物种类探索不同的给药剂量、给药周期，只有根据上述情况，探索得到的联合用药治疗方案才可能取得较单一用药治疗好的治疗效果。
单药和联用治疗方案的药物给药剂量、给药周期均需要在参考上述TH-302及其类似化合物和PARPi的剂量、给药方案通过临床试验探索得到。
进一步的，所述患者的DNA修复酶受损。
根据相关研究文献，DNA修复酶受损选自：
同源重组DNA修复酶(homologous recombination repair)受损、
核苷酸切除修复酶(nucleotide excision repair)受损、
非同源末端连接酶受损(nonhomologous end joining)、
碱基切除修复酶(base excision repair)受损、
错配修复酶(mismatch repair)受损、
范康尼贫血(Fanconi’s anemia)途径修复酶受损中的一种或更多种。
优选为同源重组DNA修复酶受损、核苷酸切除修复酶受损、碱基切除修复酶受损中的任意一种或更多种，更优选为单独的同源重组DNA修复酶受损或同时具有同源重组DNA修复酶受损与核苷酸切除修复酶受损。
进一步，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变可以通过市售的(伴随)诊断试剂盒检测得到：
奥拉帕利Olaparib伴侣检测试剂盒BRACAnalysisCDx，该基因检测用于发现卵巢癌患者血样中BRCA基因突变；
BRCA1/2基因突变检测试剂盒(联合探针锚定聚合测序法)，用于对临床确诊为卵巢癌及乳腺癌患者的BRCA1/2基因外显子区以及邻近内含子区的胚系变异进行定性检测；
人类BRCA1基因和BRCA2基因突变检测试剂盒(可逆末端终止测序法)，可用于PARP抑制剂奥拉帕利片的相关用药指导。
BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变。
式(1)的乏氧激活化合物选自以下结构的化合物：
Figure PCTCN2022115284-appb-000013
即TH-302，以及
Figure PCTCN2022115284-appb-000014
特别的，优选TH-302。
进一步，所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肺癌、肝癌、结肠癌、直肠癌、膀胱癌等，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
治疗方法，其使用含有下式的乏氧激活化合物的药物单药治疗奥拉帕利Olaparib耐药的卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌、膀胱癌患者：
Figure PCTCN2022115284-appb-000015
其中，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
治疗方法，其使用含有下式的乏氧激活化合物的药物联用奥拉帕利Olaparib治疗奥拉帕利Olaparib耐药的卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌、膀胱癌患者：
Figure PCTCN2022115284-appb-000016
其中，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
治疗方法，包括以下步骤：
检测PARP抑制剂耐药的癌症、肿瘤患者的BRCA1、BRCA2基因突变情况；
如该患者具有BRCA1、BRCA2基因突变，则使用含有式(1)的乏氧激活化合物的药物单药或联用PARP抑制剂进行治疗：
Figure PCTCN2022115284-appb-000017
其中，R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离 去官能团。
优选的，所述的基因突变的TMB(肿瘤基因突变负荷)水平为中。
式(1)的乏氧激活化合物在制备用于单药或联用PARP抑制剂治疗患者癌症的药物中用途：
Figure PCTCN2022115284-appb-000018
其中，所述患者为PARP抑制剂耐药的患者；
R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
上述的制药用途，所述患者的DNA修复酶受损；或
所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或
所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变。
上述的制药用途，所述式(I)的乏氧激活化合物选自以下结构的化合物：
Figure PCTCN2022115284-appb-000019
所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；或
所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌、膀胱癌；或
所述的基因突变的TMB(肿瘤基因突变负荷)水平为中。
由于不同瘤种之间TMB(Tumor mutation load(burden)即肿瘤基因突变负荷)高低不同：一般认为，TMB超过20个突变/Mb(Mb代表的就是每百万个碱基)，就是高；低于10个突变/Mb，就是低，处于中间的就是中。2017年世界肺癌大会上，施贵宝公司(BMS)公布过一项名为CheckMate-032的临床试验结果。这是一项纳入了401名一线治疗失败的晚期肺癌患者的II期临床试验，接受PD-1抑制剂单独或联合伊匹木治疗。按照TMB高低划分成TMB高、TMB中、TMB低三类病人，那么在接受联合治疗的人群中，三组的有效率分别为62％、20％、23％，TMB高的人群有效率高3倍；而三组的中位总生存期，分别为：22.0个月、3.6个月、3.4个月——22.0个月与3.4个月，相差6倍！该试验证明，对于不同的癌症治疗药物，不同的TMB水平对于药物的疗效有很大的影响。
本发明还提供了一种治疗PARP抑制剂耐药的癌症、肿瘤患者的药物，该药物含有式(I)的乏氧激活化合物，该药物可以单药或联用治疗PARP抑制剂耐药的癌症、肿瘤患者：
Figure PCTCN2022115284-appb-000020
其中，R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
优选的，所述患者的DNA修复酶受损；或
所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或
所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
优选的，BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变。
特别地，上述药物中，所述式(1)的乏氧激活化合物选自以下结构的化合物：
Figure PCTCN2022115284-appb-000021
所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；或
所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌、膀胱癌；或
所述的基因突变的TMB(肿瘤基因突变负荷)水平为中。
上述药物除含有式(1)的乏氧激活化合物外，还应根据药品、药物、制剂的特点，添加药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
上述药物在使用时，可以单用上述药物或联合PARPi药物进行治疗。
附图说明
图1为化合物TH-302和替拉扎明(tirapazamine)在常氧和缺氧条件下对Capan-1细胞系的抑制率曲线，其中，con.Log(nM)表示nmol/L单位下浓度数值的以10为底数的对数值，inhib ition表示抑制率；
图2为化合物TH-302和替拉扎明(tirapazamine)在常氧和缺氧条件下对Capan-1细胞系的抑制率曲线，其中，con.Log(nM)表示nmol/L单位下浓度数值的以10为底数的对数值，inhib ition表示抑制率；
图3为人源胰腺癌Capan-1皮下模型中各组小鼠肿瘤体积的生长曲线图；
图4为人源胰腺癌Capan-1皮下模型中各组小鼠相对肿瘤抑制率曲线图；
图5为人源胰腺癌Capan-1皮下模型中各组小鼠体重曲线图；
图6为人源胰腺癌Capan-1皮下模型中各组小鼠体重变化百分比曲线图；
图7为胰腺癌Capan-1CDX模型中各组小鼠肿瘤体积的生长曲线图；
图8为胰腺癌Capan-1CDX模型中各治疗组体重随时间变化曲线图；
图9为肺癌LU6429 PDX模型中各组小鼠肿瘤体积的生长曲线图；
图10为肺癌LU6429 PDX模型中各治疗组体重随时间变化曲线图；
图11为膀胱癌BL3325 PDX模型中各组小鼠肿瘤体积的生长曲线图；
图12为膀胱癌BL3325 PDX模型中各治疗组体重随时间变化曲线图。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
“患者”及“个体”可互换使用，是指需要癌症治疗的哺乳动物。通常，患者是人类。通常，患者是诊断患有癌症的人类。在某些实施例中，“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物，例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物，前药以使其相对于药物活性较低或无活性的方式化学修饰，但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味。前药可使用除相应药物以外的反应物来合成。
“治疗”或“治疗患者”是指向患者投与、使用或施用本发明相关的治疗有效量的药物。
向患者“投与”或“施用”“使用”药物是指直接投与或施用(其可由医学专业人士向患者投与或施用或者可自投与或施用)及/或间接投与或施用，其可是开处药物的行为。举例而言，指示患者自投与或施用药物及/或将药物的处方提供给患者的医师是向患者投与或施用药物。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用、使用时，将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现，且可仅在投与或施用一系列剂量后出现。因此，治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的，有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善；疾病程度的减弱；疾病进展的延迟或减缓；疾病状态的改善、缓解或稳定；或其他有益结果。在一些情形下，癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如，哺乳动物，例如鼠类、犬、猫、马或人类)的肿瘤细胞。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
以下提供本发明的具体实验。
本发明披露的试验过程中动物实验的试验方案、任何修改、动物福利和使用均通过所在CRO(合同研究组织)IACUC委员会审核并批准通过。试验过程中，动物福利和实验操作均符合AAALAC的要求。
一、化合物TH-302在BRCA敲除和野生型的肿瘤细胞中的体外细胞毒性比较
TH-302是一种在乏氧条件下能够被激活，并释放出细胞毒素，进而杀伤肿瘤细胞和肿瘤 组织的小分子前药。为了评价在体外细胞水平TH-302与BRCA致病突变的相关性，我们选用人源结肠癌细胞系DLD1和敲除BRCA2蛋白的DLD1-BRCA2-/-肿瘤细胞系，检测在乏氧条件下，TH-302对上述两种有或者无BRCA2蛋白表达的肿瘤细胞系的杀伤能力是否有区别。
该克隆形成实验使用IC 90(90％抑制浓度)值作为评价化合物TH-302对细胞杀伤的能力。具体实验方法如下：
(1)细胞培养
a)DLD1和DLD1-BRCA2-/-细胞培养于RPMI培养基中，加10％FBS和1％双抗，置于37℃、5％CO 2条件下培养。
(2)细胞铺板
a)细胞常规培养至细胞饱和度为80％-90％，数量到达要求时，收取细胞。
b)用相应的培养基重悬，计数，配制成合适密度的细胞悬液。
c)将细胞悬液加入10 cm玻璃皿中，DLD1-BRCA2 -/-细胞密度为3.0 x 10 5/皿、DLD1细胞密度为300/皿。
d)细胞在37℃，5％CO 2培养箱中培养2天。
(3)化合物的准备
化合物按照实验要求准备。
(4)化合物处理细胞
a)化合物在氧气含量<0.01％(乏氧)的条件下处理细胞3小时。
b)使用1 x PBS洗细胞一次，利用胰酶消化细胞后，进行细胞计数。
c)用3mL培养基重悬细胞，接种于6孔培养板中，其中DLD1-BRCA2-/-细胞密度为2000/孔、DLD1细胞密度为300/孔。
d)将细胞板放置培养箱10天。
e)弃掉培养基，将细胞固定后，利用结晶紫染色40min。
f)使用Colony Counter(VWR)进行细胞克隆计数并根据CalcuSyn软件(http://www.biosoft.com/w/calcusyn.htm)计算IC 90值。
经过上述实验方法测得的待测化合物TH-302在两种细胞中的IC 90值列示于下表1中。
表1：乏氧条件下化合物TH-302对2株肿瘤细胞抑制作用IC 90数据
Figure PCTCN2022115284-appb-000022
实验结论：化合物TH-302在被乏氧激活以后，对DLD1野生型和BRCA2缺失的DLD1-BRCA2-/-细胞的体外细胞毒性有显著差异。与DLD1-BRCA2-/-细胞相比较，野生型DLD1的体外IC 90值增加了70倍。上述结果说明，在乏氧条件下，BRCA2蛋白的缺失，造成DLD1的细胞对TH-302的敏感程度显著增强。
二、化合物TH-302/tirapazamine(替拉扎明)对Capan-1/BxPc-3体外细胞增殖的影响实验
申请人专门研究了缺氧活化抗癌前药TH-302和替拉扎明分别在常氧和缺氧条件下、在Capan-1和BxPc-3细胞系的体外细胞增殖抑制实验。Capan-1细胞系为BRCA突变型细胞系，BxPc-3细胞系为BRCA野生型，即非BRCA突变型细胞系。通过该实验来验证同为缺氧活化抗癌前药的TH-302与替拉扎明对BRCA突变的敏感性差异。
实验方法与实验数据、结论如下所述。
实验方法
1)将Capan-1/BxPc-3细胞悬液加入两类24孔板中，每孔495μL，细胞密度为6×10 4/孔。插有玻璃插板(glass inserts)的24孔板用于乏氧实验，普通塑料24孔板用于常氧实 验。
2)细胞在37℃，5％CO 2培养箱中培养过夜。
3)化合物处理
低氧条件：
调节低氧工作站至乏氧环境(O 2<0.01％)，并利用氧气指示剂确认工作站中的乏氧情况。
细胞铺板24小时以后，将带有玻璃插板(glass inserts)的24孔板送入低氧工作站。
将24孔板放至在螺旋振荡器上，打开孔板盖振荡，进行气体交换5分钟。
单药组每孔直接加入100倍测试浓度的化合物溶液。
常氧条件：
细胞铺板24小时以后，每孔加入5μL 100倍测试浓度的化合物溶液，每个实验组3个复孔。
单药组每孔直接加入100倍测试浓度的化合物溶液。
4)化合物处理3小时后，所有24孔板用完全培养基洗2次，每孔、每次500μL。
5)Capan-1细胞培养板中每孔加入1000μL完全培养基，BxPc-3细胞培养板中每孔加入500μL完全培养基。
6)放置37℃，5％CO 2培养箱72小时。
7)Capan-1细胞每孔弃去800μL培养基，BxPc-3细胞每孔弃去300μL培养基，加入50μL CTG，震荡混匀2min，室温避光放置15分钟。
8)将培养基从24孔板中，每孔转移100μL至96孔白板中。
9)用多功能酶标仪读取化学发光信号值，读值时间1000ms。
10)用GraphPad Prism 5 software计算IC 50，得到化合物的IC 50值(半数抑制浓度)。
实验数据
TH-302和替拉扎明在BRCA突变型Capan-1细胞系中，常氧与缺氧条件下的细胞增殖抑制实验数据如表2和表3所示，IC 50曲线如图1所示。
表2：TH-302在BRCA突变型Capan-1细胞系中的细胞增殖抑制实验数据
化合物 IC50(μM) 比率(21％O 2/0.01％O 2)
TH-302，21％O 2 93.45 -
TH-302，＜0.01％O 2 0.82 113.96
表3：替拉扎明在BRCA突变型Capan-1细胞系中的细胞增殖抑制实验数据
化合物 IC50(μM) 比率(21％O 2/0.01％O 2)
替拉扎明，21％O 2 ＞2000 -
替拉扎明，＜0.01％O 2 29.06 ＞68.82
TH-302和替拉扎明在BRCA野生型BxPc-3细胞系中，常氧与缺氧条件下的细胞增殖抑制实验数据如表4和表5所示，IC 50曲线如图2所示。
表4：TH-302在BRCA野生型BxPc-3细胞系中的细胞增殖抑制实验数据
化合物 IC50(μM) 比率(21％O 2/0.01％O 2)
TH-302，21％O 2 423.50 -
TH-302，＜0.01％O 2 3.07 137.95
表5：替拉扎明在BRCA野生型BxPc-3细胞系中的细胞增殖抑制实验数据
化合物 IC50(μM) 比率(21％O 2/0.01％O 2)
替拉扎明，21％O 2 ＞2000 -
替拉扎明，＜0.01％O 2 33.23 ＞60.19
实验结论
上述实验数据中，TH-302在乏氧条件下，在BRCA突变的Capan-1细胞系中的IC 50为0.82μM，在BRCA野生型的BxPc-3细胞系中IC 50为3.07μM，两者相差3.7倍，说明BRCA突变使得TH-302对肿瘤细胞系具有更强的增殖抑制活性，即BRCA突变将增强肿瘤细胞对TH-302药物的敏感性。
而同为乏氧活化抗癌前药的替拉扎明，在乏氧条件下，在BRCA突变的Capan-1细胞系中的IC 50为29.06μM，在BRCA野生型的BxPc-3细胞系中IC 50为33.23μM，相差1.1倍，无明显的差异，这说明替拉扎明与BRCA突变无相关性，即BRCA突变并不明显影响替拉扎明对肿瘤细胞系的增殖抑制活性，即BRCA突变并不能增强肿瘤细胞对替拉扎明药物的敏感性。
三、TH-302在奥拉帕利Olaparib耐受的动物CDX、PDX模型中的药效及安全性实验
3.1 TH-302在Olaparib耐受的胰腺癌Capan-1 CDX模型中的药效及安全性评价
Capan-1 CDX模型是带有BRCA2致病突变的Olaparib耐受模型。
每只BALB/c雌性裸鼠右侧背部下方皮下接种5×10 5 Capan-1细胞，细胞重悬在1:1的PBS和基质胶中(0.1ml/只)，共接种64只雌性小鼠。接种日期为2021年06月23日,待肿瘤平均体积140mm 3时，根据肿瘤大小随机分组。试验分为测试药Olaparib 100mg/kg单药组(Group 2)、TH-302 75mg/kg和Olaparib 100mg/kg联合给药组(Group 5)、TH-302 75mg/kg单药组(Group 7)以及10％无水乙醇+10％聚氧乙烯(35)蓖麻油+80％葡萄糖注射液D5W(pH7.4)溶媒对照组，共7组，每组6只小鼠。溶媒对照组、TH-302单药及联合用药组均为尾静脉给药，每周给药一次，共计给药三周；测试药Olaparib组，口服灌胃给药，每天给药一次，共给药30天。根据相对肿瘤抑制率TGI(％)进行疗效评价，根据动物体重变化和死亡情况进行安全性评价。
测试药Olaparib 100mg/kg(Group 2)治疗组在肿瘤细胞接种后的第35天没有抑瘤作用，相对肿瘤抑制率TGI(％)为-7.1％，相较对照组统计学上没有显著性差异(p>0.05)。Olaparib100mg/kg和TH-302 75mg/kg的联合治疗组(Group 5)，在肿瘤细胞接种后的第35天有显著的抑瘤作用，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为84.47％。TH-302 75mg/kg单药治疗组(Group 7)在肿瘤细胞接种后的第35天(Day 35)表现出显著的抑瘤作用，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为87.66％。TH-302单药组与Olaparib和TH-302的联合治疗组相比，抑瘤效果没有显著性差异(p>0.05)。测试药Olaparib 100mg/kg、TH-302 75mg/kg单药组与Olaparib 100mg/kg和TH-302 75mg/kg联合给药组小鼠体重均没有明显下降，耐受良好。
具体每一组的给药方案下表6所示。
表6：药物在人源胰腺癌Capan-1皮下动物治疗模型实验中各组别的给药方案
Figure PCTCN2022115284-appb-000023
分别在不同天数对不同组别的小鼠的肿瘤体积进行测量，并取得平均值，其结果如下表7 所示。
表7：人胰腺癌Capan-1模型中各组小鼠肿瘤体积随治疗时间的变化(单位mm 3)
Figure PCTCN2022115284-appb-000024
各治疗组和对照组肿瘤生长情况见表7和图3。药效评估见表8。
表8：在人源胰腺癌Capan-1皮下模型中各组药效分析表
Figure PCTCN2022115284-appb-000025
表8：相对肿瘤增殖率，T/C％，即在某一时间点，治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下：
T/C％＝TRTV/CRTV×100％(TRTV：治疗组平均RTV；CRTV：溶媒对照组平均RTV；RTV＝Vt/V0，V0为分组时该动物的瘤体积，Vt为治疗后该动物的瘤体积)；
相对肿瘤抑制率，TGI(％)，计算公式如下：TGI％＝(1-T/C)×100％。(T和C分别为治疗组和对照组在某一特定时间点的平均相对肿瘤体积(RTV)。
表9：在人源胰腺癌Capan-1皮下模型中各组肿瘤的相对肿瘤抑制率
Figure PCTCN2022115284-appb-000026
将上表制作为曲线图，可以得到图4。
分别在不同天数对不同组别的小鼠的体重进行测量，并取得平均值，其结果如下表10所示。
表10：药物在人源胰腺癌Capan-1皮下动物治疗模型实验中不同接种天数小鼠的体重
Figure PCTCN2022115284-appb-000027
将上表制作为曲线图，可以得到图5，即人源胰腺癌Capan-1皮下模型中各组小鼠体重曲线。
同理对表10的数据进行处理可以得到下表11。
表11：药物在人源胰腺癌Capan-1皮下动物治疗模型实验中不同接种天数小鼠的体重变化百分比(％Group Mean Change＝mean((T-T0)/T0)*100，T表示current value，T0表示initial value)
Figure PCTCN2022115284-appb-000028
将上表制作为曲线图，可以得到图6。
分析实验数据可知，疗效方面：
1、Capan-1 CDX模型确实是Olaparib抵抗模型，Olaparib对该模型的肿瘤增长无抑制作用，即对Olaparib具有耐药性；
2、TH-302单药对Olaparib抵抗的胰腺癌有较好的治疗效果(TGI为82.67％)；
3、TH-302联用Olaparib对Olaparib抵抗的胰腺癌有较好的治疗效果(TGI为87.43％)；
4、TH-302单药组与Olaparib和TH-302的联合治疗组相比，抑瘤效果稍好，但没有显著性差异(p>0.05)；
分析实验数据可知，测试药Olaparib 100mg/kg、TH-302 75mg/kg单药组与Olaparib 100mg/kg和TH-302 75mg/kg联合给药组小鼠体重均没有明显下降，耐受良好。
发明人对TH-302在Olaparib耐受的胰腺癌Capan-1 CDX模型进一步进行了深入的研究，发现：①TH-302单药治疗组表现出药物抑瘤作用的剂量依赖性；②Olaparib与TH-302联用的特定剂量组合可以显示出抑瘤效果的协同作用。
发明人同时对TH-302在Olaparib耐受的肺癌LU6429 PDX模型、膀胱癌BL3325 PDX模型中的药效和安全性进行了研究。
进一步的研究方案与实验数据如下文所述。
3.2进一步研究TH-302在Olaparib耐受的胰腺癌Capan-1 CDX模型中的药效及安全性
方案：BALB/c裸小鼠皮下接种人源胰腺癌Capan-1细胞，建立人源胰腺癌皮下移植模型。试验分为测试药Olaparib 100mg/kg单药组(Group 2)、TH-302 50mg/kg单药组(Group 3，QD)、TH-302 100mg/kg单药组(Group 4)、TH-302 50mg/kg单药组(Group 5，QW)、TH-302 25mg/kg单药组(Group 6)、TH-302 25mg/kg和Olaparib 100mg/kg联合给药组(Group 7)以及10％无水乙醇+10％聚氧乙烯(35)蓖麻油+80％葡萄糖注射液D5W(pH7.4)溶媒对照组(Group 1)，共7组，每组6只小鼠。溶媒对照组、TH-302各测试药均为尾静脉注射给药。其中TH-302 50mg/kg单药组(Group 3，QD)每天给药一次，连续给药3天，休息4天，再休息两周；再每天给药，连续给药3天。TH-302 100mg/kg(Group 4，QW)、50mg/kg(Group 5，QW)、25mg/kg(Group 6，QW)单药组以及TH-302 25mg/kg和Olaparib 100mg/kg联合给药组(Group 7)中的TH-302，均为每周给药一次，共给药三周。各组中测试药Olaparib均为口服灌胃给药，每天给药一次，共给药30天。具体人源胰腺癌Capan-1动物模型中的给药途径、剂量及方案如表12所示。
表12：人源胰腺癌Capan-1动物模型中的给药途径、剂量及方案
Figure PCTCN2022115284-appb-000029
注：给药体积为10μL/g。
在试验不同天数记录各治疗组和对照组肿瘤生长情况，如表13所示，相应地各组小鼠肿瘤体积的生长曲线如图7所示。根据相对肿瘤增殖率和相对肿瘤抑制率对疗效进行评价，各组药效分析如表14所示。记录治疗组和对照组给药后体重变化，研究人源胰腺癌Capan-1皮下模型中各组的安全性，第43天小鼠体重变化率结果如表15所示，各治疗组体重随时间变化曲线图如图8所示。
相对肿瘤增殖率，T/C％，即在某一时间点，治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下：
T/C％＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：溶媒对照组平均RTV；RTV＝V t/V 0，V 0为分组时该动物的瘤体积，V t为治疗后该动物的瘤体积)；
或T/C％＝T TW/C TW×100％(T TW：治疗组实验终结时平均瘤重；C TW：溶媒对照组实验终结时平均瘤重)。
相对肿瘤抑制率，TGI(％)，计算公式如下：TGI％＝(1-T/C)×100％。(T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)或瘤重(TW))。
表13：人胰腺癌Capan-1模型中各组小鼠肿瘤体积随治疗时间的变化(mm 3)
Figure PCTCN2022115284-appb-000030
Figure PCTCN2022115284-appb-000031
表14：在人源胰腺癌Capan-1皮下模型中各组药效分析表
Figure PCTCN2022115284-appb-000032
注：1.数据以“平均值±标准误差”表示；2.T/C％＝T RTV/C RTV×100％；3.CR：肿瘤完全缓解，肿瘤消退到0。
表15：在人源胰腺癌Capan-1皮下模型中各组体重变化情况
Figure PCTCN2022115284-appb-000033
Figure PCTCN2022115284-appb-000034
上述数据表明：
溶媒对照组小鼠在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为1301.38mm 3。测试药Olaparib 100mg/kg(Group 2)治疗组在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为846.86mm 3，相对肿瘤抑制率TGI(％)为37.43％，相较对照组统计学上没有显著性差异(p>0.05)。
测试药TH-302 50mg/kg治疗组(Group 3，QD)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为146.99mm 3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为89.17％。测试药TH-302 100mg/kg治疗组(Group 4)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为124.68mm 3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为90.89％。测试药TH-302 50mg/kg治疗组(Group 5，QW)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为263.45mm 3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为80.18％，肿瘤完全抑制率为33.3％。测试药TH-302 25mg/kg治疗组(Group 6)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为1521.33mm 3，相较对照组统计学上没有显著性差异(p>0.05)，相对肿瘤抑制率TGI(％)为-21.59％。Olaparib 100mg/kg和TH-302 25mg/kg的联合治疗组(Group 7)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为378.56mm 3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为74.36％。
TH-302 100mg/kg(Group 4)、50mg/kg(Group 5，QW)和25mg/kg(Group 6)单药治疗组表现出药物抑瘤作用的剂量依赖性。TH-302 100mg/kg(Group 4，QW)、50mg/kg(Group 5，QW)单药治疗组相较TH-302 25mg/kg单药治疗组(Group 6，QW)统计学上均有显著性差异(p均<0.001)。
Olaparib 100mg/kg与TH-302 25mg/kg的联合治疗组(Group 7)抗肿瘤作用优于Olap arib 100mg/kg(Group 2)以及TH-302 25mg/kg单药组(Group 6)，统计学上有显著性差异(p<0.05以及p<0.001)，Olaparib与TH-302联用的特定剂量组合可以显示出抑瘤效果的协同作用。
测试药Olaparib 100mg/kg(Group 2)、TH-302 25mg/kg(Group 6)、TH-302 50mg/kg(Group 3，QD)、TH-302 50mg/kg(Group 5，QW)、TH-302 100mg/kg(Group 4)、Olaparib 100mg/kg和TH-302 25mg/kg联合给药组(Group 7)、溶媒对照组(Group 1)小鼠体重均没有明显下降，耐受良好。
3.3 TH-302在Olaparib耐受的肺癌LU6429 PDX模型中的药效及安全性评价
LU6429 PDX模型是带有BRCA2致病突变的Olaparib耐受模型。
方案：Balb/c nude雌性小鼠皮下接种
Figure PCTCN2022115284-appb-000035
肺癌LU6429瘤块，建立人肺癌皮下移植肿瘤模型。试验分为测试药Olaparib 50mg/kg单药组(Group 02)，TH-302 80mg/kg单药组(Group 03)，TH-302 40mg/kg单药组(Group 04)，TH-302 20mg/kg单药组(Group 05)，TH-302 40mg/kg和Olaparib 50mg/kg联合给药组(Group 06)，以及葡萄糖注射液 溶媒对照组(Group 01)。该研究共6组，每组6只小鼠，其中溶媒对照组和TH-302均为尾静脉给药，每周给药1次，共计给药3周；Olaparib为灌胃给药，每天给药1次，共计给药28天。具体的
Figure PCTCN2022115284-appb-000036
肺癌LU6429动物模型中的给药途径、剂量及方案如表16所示。
表16：
Figure PCTCN2022115284-appb-000037
肺癌LU6429动物模型中的给药途径、剂量及方案
Figure PCTCN2022115284-appb-000038
注：1.给药体积为10μL/g；2.QD×28：每天给药一次，连续给药28天；3.QW×3:每周给药1次，连续给药3周。
在试验不同天数记录各治疗组和对照组肿瘤生长情况，如表17所示，相应地各组小鼠肿瘤体积的生长曲线如图9所示。根据相对肿瘤增殖率和相对肿瘤抑制率对疗效进行评价，各组药效分析如表18所示。记录治疗组和对照组给药后体重变化，研究在
Figure PCTCN2022115284-appb-000039
肺癌LU6429皮下模型中各组的安全性，第25天小鼠体重变化结果如表19所示，各治疗组体重随时间变化曲线图如图10所示。
表17：在
Figure PCTCN2022115284-appb-000040
肺癌LU6429模型中各组小鼠肿瘤体积随治疗时间的变化(mm 3)
Figure PCTCN2022115284-appb-000041
表18：在
Figure PCTCN2022115284-appb-000042
肺癌LU6429皮下模型中各组药效分析表
Figure PCTCN2022115284-appb-000043
Figure PCTCN2022115284-appb-000044
注：数据以“平均值±标准误差”表示。
表19：在
Figure PCTCN2022115284-appb-000045
肺癌LU6429皮下模型中各组体重变化情况
Figure PCTCN2022115284-appb-000046
上述数据表明：
Olaparib单独给药组未产生抑瘤作用，显示出肺癌LU6429 PDX模型对Olaparib的耐受。测试药TH-302在80mg/kg，40mg/kg，20mg/kg剂量单独治疗组，以及TH-302在40mg/kg与Olaparib在50mg/kg剂量下的联合治疗组，在本研究中，对
Figure PCTCN2022115284-appb-000047
肺癌LU6429皮下模型均具有显著的抗肿瘤增殖作用。其中TH-302 80mg/kg(Group 03)剂量治疗组有1只小鼠的肿瘤被完全清除，清除率为16.7％。测试药TH-302 80mg/kg，40mg/kg以及20mg/kg治疗组之间，统计学上有显著差异(p<0.05)，显示出剂量依赖性。TH-302 40mg/kg与Olaparib 50mg/kg的联合治疗效果显著优于Olaparib 50mg/kg单独治疗组，但与TH-302 40mg/kg单独治疗组相比稍好，但差异较小不显著。
各测试药治疗组小鼠在治疗期间小鼠体重均没有下降，耐受良好。
3.4 TH-302在Olaparib耐受的膀胱癌BL3325 PDX模型中的药效及安全性评价
BL3325 PDX模型是带有BRCA2致病突变的Olaparib耐受模型。
方案：Balb/c nude雌性小鼠皮下接种
Figure PCTCN2022115284-appb-000048
膀胱癌BL3325瘤块，建立人膀胱癌皮下移植肿瘤模型。试验分为测试药Olaparib 50mg/kg单药组(Group 02)，TH-302 80mg/kg单药组(Group 03)，TH-302 40mg/kg单药组(Group 04)，TH-302 20mg/kg单药组(Group 05)，TH-302 40mg/kg和Olaparib 50mg/kg联合给药组(Group 06)，以及葡萄糖注射液溶媒对照组(Group 01)。该研究共6组，每组6只小鼠，其中溶媒对照组和TH-302均为尾静脉给药，每周给药1次，共计给药3周；Olaparib为灌胃给药，每天给药1次，共计给药30天。具体的
Figure PCTCN2022115284-appb-000049
膀胱癌BL3325动物模型中的给药途径、剂量及方案如表20所示。
表20：
Figure PCTCN2022115284-appb-000050
膀胱癌BL3325动物模型中的给药途径、剂量及方案
Figure PCTCN2022115284-appb-000051
Figure PCTCN2022115284-appb-000052
注：1.给药体积为10μL/g；2.QD×30：每天给药一次，连续给药30天；3.QW×3：每周给药1次，连续给药3周；4.i.v.为尾静脉给药，p.o.为灌胃给药。
在试验不同天数记录各治疗组和对照组肿瘤生长情况，如表21所示，相应地各组小鼠肿瘤体积的生长曲线如图11所示。根据相对肿瘤增殖率和相对肿瘤抑制率对疗效进行评价，各组药效分析如表22所示。记录治疗组和对照组给药后体重变化，研究
Figure PCTCN2022115284-appb-000053
膀胱癌BL3325皮下模型中各组的安全性，第35天小鼠体重变化结果如表23所示，各治疗组体重随时间变化曲线图如图12所示。
表21：在
Figure PCTCN2022115284-appb-000054
膀胱癌BL3325模型中各组小鼠肿瘤体积随治疗时间的变化(mm 3)
Figure PCTCN2022115284-appb-000055
表22：在
Figure PCTCN2022115284-appb-000056
膀胱癌BL3325皮下模型中各组药效分析表
Figure PCTCN2022115284-appb-000057
注：1.数据以“平均值±标准误差”表示；2.T/C％＝T RTV/C RTV*100％。
表23：在
Figure PCTCN2022115284-appb-000058
膀胱癌BL3325皮下模型中各组体重变化情况
Figure PCTCN2022115284-appb-000059
Figure PCTCN2022115284-appb-000060
注：1.数据以“平均值±标准误差”表示。
上述数据表明：
测试药TH-302在80mg/kg、40mg/kg、20mg/kg剂量单独治疗组，以及TH-302 40mg/kg与Olaparib 50mg/kg联合治疗组对
Figure PCTCN2022115284-appb-000061
膀胱癌BL3325皮下模型均具有显著的抗肿瘤增殖作用，Olaparib 50mg/kg单独治疗没有显著抑瘤作用。TH-302 80mg/kg较20mg/kg剂量组抑瘤作用存在统计学差异，表明TH-302抑制BL3325肿瘤生长具有剂量依赖性。其中TH-302 80mg/kg治疗组(Group 03)有1只小鼠肿瘤被完全清除，清除率为16.7％。TH-302 40mg/kg与Olaparib 50mg/kg的联合治疗效果显著优于Olaparib 50mg/kg单独治疗组，与TH-302 40mg/kg单独治疗组相比更好，且差异显著。
各测试药治疗组小鼠在治疗期间小鼠体重均没有下降，耐受良好。
虽然本申请实施例中选用的PARP抑制剂为奥拉帕利Olaparib，但芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib等同样属于PARP抑制剂，作用机理与奥拉帕利Olaparib类似，均是阻断参与修复受损DNA酶发挥作用，因此，可以推定，芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib等PARPi具有与上述实验中的奥拉帕利Olaparib类似的肿瘤抑制疗效。
TH-302为乏氧活化的DNA烷化剂，权利要求1的通式化合物：
Figure PCTCN2022115284-appb-000062
在相关专利申请中已被证明是与TH-302类似的机理，因此这类化合物具有与TH-302类似的效果是完全可以预测的。

Claims (16)

  1. 治疗方法，其使用含有式(I)的乏氧激活化合物的药物单药或联用治疗PARP抑制剂耐药的癌症、肿瘤患者：
    Figure PCTCN2022115284-appb-100001
    其中，R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
  2. 根据权利要求1所述的治疗方法，其使用含有式(I)的乏氧激活化合物的药物联用PARP抑制剂治疗PARP抑制剂耐药的癌症、肿瘤患者。
  3. 根据权利要求1或2所述的治疗方法，其中，
    所述患者的DNA修复酶受损；或
    所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或
    所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
  4. 根据权利要求3所述的治疗方法，其中，BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变。
  5. 根据权利要求1或2所述的治疗方法，其中，
    所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；
    所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
  6. 根据权利要求1或2所述的治疗方法，其中，式(I)的乏氧激活化合物选自以下结构的化合物：
    Figure PCTCN2022115284-appb-100002
  7. 治疗方法，其使用含有下式的乏氧激活化合物的药物单药治疗奥拉帕利Olaparib耐药的卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌、膀胱癌患者：
    Figure PCTCN2022115284-appb-100003
    其中，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
  8. 治疗方法，其使用含有下式的乏氧激活化合物的药物联用奥拉帕利Olaparib治疗奥拉帕利Olaparib耐药的卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌、膀胱癌患者：
    Figure PCTCN2022115284-appb-100004
    其中，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
  9. 治疗方法，包括以下步骤：
    检测对PARP抑制剂耐药的癌症、肿瘤患者的BRCA1、BRCA2基因突变情况；
    如该患者具有BRCA1、BRCA2基因突变，则使用含有式(I)的乏氧激活化合物的药物单药或联用PARP抑制剂进行治疗：
    Figure PCTCN2022115284-appb-100005
    其中，R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
  10. 根据权利要求3或4或7或8或9任一项所述的治疗方法，其中，所述的基因突变的TMB(肿瘤基因突变负荷)水平为中。
  11. 式(I)的乏氧激活化合物在制备用于单药或联用PARP抑制剂治疗患者癌症的药物中的用途：
    Figure PCTCN2022115284-appb-100006
    其中，所述患者为对PARP抑制剂耐药的患者；
    R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
  12. 根据权利要求11所述的用途，其中，
    所述患者的DNA修复酶受损；或
    所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或
    所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变。
  13. 根据权利要求12所述的用途，其中，
    所述BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变；
    所述基因突变的TMB(肿瘤基因突变负荷)水平为中。
  14. 根据权利要求11所述的用途，其中，式(I)的乏氧激活化合物选自以下结构的化合物：
    Figure PCTCN2022115284-appb-100007
    或
    所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；或
    所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌、膀胱癌。
  15. 治疗对PARP抑制剂耐药的癌症、肿瘤患者的药物，该药物含有式(I)的乏氧激活化合物：
    Figure PCTCN2022115284-appb-100008
    其中，R各自独立地选自H、-CH 3、-CH 2CH 3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
  16. 根据权利要求15所述的药物，其中，
    所述患者的DNA修复酶受损；或
    所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变；或
    所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变，优先的，BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变。
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