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WO2017178509A1 - Procédés de prédiction de la sensibilité à un traitement avec des inhibiteurs parp chez des patients cancéreux - Google Patents

Procédés de prédiction de la sensibilité à un traitement avec des inhibiteurs parp chez des patients cancéreux Download PDF

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WO2017178509A1
WO2017178509A1 PCT/EP2017/058735 EP2017058735W WO2017178509A1 WO 2017178509 A1 WO2017178509 A1 WO 2017178509A1 EP 2017058735 W EP2017058735 W EP 2017058735W WO 2017178509 A1 WO2017178509 A1 WO 2017178509A1
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cancer
patient
genes
expression
hbcx
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Jean-Gabriel Judde
Stéfano CAIRO
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Xentech
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a molecular diagnostic test useful for predicting the antitumor effectiveness of a PARP inhibitor administered to a patient afflicted by a cancer, preferably a triple-negative breast cancer patient.
  • the invention includes the use of gene expression classifiers for prediction of tumor responsiveness to PARP inhibitors and for selection of triple-negative breast cancer patients for treatment with PARP inhibitors.
  • the present invention also relates to a product containing a DNA damage-inducing anticancer agent, preferably cyclophosphamide, and a PARP inhibitor as a combined preparation for simultaneous, separate or sequential use in cancer therapy, preferably triple-negative breast cancer therapy.
  • a DNA damage-inducing anticancer agent preferably cyclophosphamide
  • a PARP inhibitor as a combined preparation for simultaneous, separate or sequential use in cancer therapy, preferably triple-negative breast cancer therapy.
  • TNBC Triple negative breast cancer
  • TNBCs are often more undifferentiated, carry an increased risk of distant metastasis, tend to relapse early and have been associated with a short post-recurrence survival.
  • TNBCs lack hormonal receptors and Her2 overexpression and are therefore not candidate for anti-estrogen or Herceptin® therapy (Linn SC. and Van't Veer L. Clinical relevance of the triple-negative breast cancer concept: genetic basis and clinical utility of the concept. Eur. J Cancer 45, Suppl 1: 11-26, 2009).
  • TNBC tumor necrosis factor-associated cytotoxic drugs
  • anthracyclins including anthracyclins, cyclophosphamide, 5-fluorouracil and taxanes
  • 5-fluorouracil 5-fluorouracil
  • taxanes as well as local radiation therapy and surgery.
  • aggressive or advanced breast cancers of the hormone receptor-positive and Her2-overexpressing subtypes also receive cytotoxic chemotherapy in combination with anti-estrogen or anti-Her2 therapies.
  • pCR pathological complete response
  • BC breast cancer
  • OS overall survival
  • TNBC triple- negative breast cancer
  • TNBCs Besides mutation- associated BRCA inactivation occurring by loss of heterozygosity (LOH) in about 15% of the cases, frequent dysregulation in the homologous-recombination (HR)-dependent DNA-repair pathway, has been attributed to a number of mechanisms, including BRCA 1 -promoter methylation and other defects in HR pathways, providing a strong rationale for developing new agents that exploit DNA-repair defects in these cancers.
  • PARP1 poly (adenosine diphosphate-ribose) polymerase 1
  • PARP2 two important regulators of the DNA base-excision-repair pathway
  • a subset of TNBC patients are responsive to PARP inhibitors, a class of novel therapeutic agents that inhibits the function of several PARP family members, including PARP1 and PARP2.
  • Pathogenic BRCAl/2 mutations, and other genomic markers such as high scores of loss of heterozygosity (LOH), large-scale transition (LST) and allelic imbalance (AI) rearrangements in tumor cells, also called genomic scars, have been proposed as molecular markers to identify tumors with homologous recombination deficiency (HRD) that are more likely to be sensitive to PARP inhibitors (Abkevich V. et al. Pattern of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.
  • LOD homologous recombination deficiency
  • the inventors surprisingly discovered a set of genes related to genomic stress response and designated herein as GSS (for Genomic Stress Signature), whose level of expression in a tumor sample, designated herein as GSI (for Genomic Stress Index), allows predicting the responsiveness of TNBC patients to treatment with a PARP inhibitor.
  • GSS Genomic Stress Signature
  • GSI Genomic Stress Index
  • They have thus developed a method for measuring the GSI in a biological sample of a patient afflicted by a cancer, preferably TNBC, and using the GSI to predict the sensitivity of the patient to a PARP inhibitor.
  • Said prediction is sensitive and reliable, independently of the PARP inhibitor used within the class of PARP inhibitors possessing PARP DNA-trapping activity, such as niraparib or olaparib.
  • the present invention provides a method for predicting the responsiveness of a cancer patient, preferably a TNBC patient, to treatment with a PARP inhibitor, comprising (1) measuring the expression of at least TDRD7, DDX60, IFIT2, ABCA1 and DDX58 genes, expressed in a tumor sample of the patient, so as to obtain an expression profile; and further (3) comparing the obtained expression profile with cut-off value(s),
  • the present invention provides a method for predicting the responsiveness of a cancer patient, preferably a TNBC patient, to treatment with a PARP inhibitor, comprising, or consisting essentially of, (1) measuring the expression of a collection of gene product markers expressed in a tumor sample of the patient; (2) determining a score, preferably the GSI, in the tumor sample based at least on the measurements made in (1), and further (3) comparing the obtained score with cut-off value,
  • the method comprises, or consists essentially of, (1) measuring the expression of a collection of gene product markers expressed in the tumor sample; (2) determining the GSI in the tumor sample based at least in part on the measurements made in (1); and (3) comparing the obtained score with cut-off value,
  • the cancer patient is likely to be sensitive to a PARP inhibitor treatment.
  • the present invention also provides a method for identifying a molecular subtype of TNBC tumor demonstrating sensitivity to PARP inhibitors, comprising (1) measuring the expression of a collection of gene product markers expressed in a tumor sample of a TNBC patient, so as to obtain an expression profile; and further (3) comparing the obtained expression profile with cut-off value(s), wherein if said profile is greater than cut-off value(s), then the TNBC patient is likely to be sensitive to a PARP inhibitor treatment.
  • the present invention also provides a method for identifying a molecular subtype of TNBC tumor demonstrating sensitivity to PARP inhibitors, comprising, or consisting essentially of, (1) measuring the expression of a collection of gene product markers expressed in a tumor sample of a TNBC patient; (2) determining a score, preferably the GSI, in the tumor sample based at least on the measurements made in (1); and (3) comparing the obtained score with cut-off value,
  • the method comprises, or consists essentially of, (1) measuring the expression of a collection of gene product markers expressed in the tumor sample; (2) determining the GSI in the tumor sample based at least in part on the measurements made in (1); and (3) if the GSI is greater than a threshold value, then the tumor is likely to be sensitive to PARP inhibitors.
  • the present invention provides a method for predicting the responsiveness of a cancer patient, preferably a TNBC patient, to treatment with a PARP inhibitor, or for identifying a molecular subtype of TNBC demonstrating sensitivity to PARP inhibitors, comprising combining the GSI evaluation method of the invention with determination of a HRD genomic signature.
  • the method for predicting the responsiveness of a cancer patient, preferably a TNBC patient, to treatment with a PARP inhibitor comprises, or consists essentially of, (1) measuring the expression of a collection of gene product markers expressed in a tumor sample of said cancer patient; (2) determining the GSI in the tumor sample based at least in part on the measurements made in (1); (3) measuring the HRD score in a tumor sample of said cancer patient; and (4) if the GSI and the HRD score obtained in (2) and (3) respectively are both greater than their respective threshold values, then the cancer patient is likely to be sensitive to a PARP inhibitor treatment.
  • Variability of GSI values between individual tumors is not limited to a single cancer type like TNBC. Therefore, the GSI evaluation method according to the invention may be used to predict responsiveness to PARP inhibitors across different cancer types in different tissues. In a preferred embodiment of the invention, these genes or gene products are useful for evaluating breast cancer tumors, preferably TNBC tumors. Moreover, as shown in the examples, it was discovered that combining PARP inhibitors with genotoxic chemotherapy, preferably cyclophosphamide, resulted in higher antitumor efficacy than each treatment used alone only in tumors over-expressing the gene markers predicting sensitivity to PARP inhibitors (eg. classified as GSTpositive, or as both GSI-positive and HRD-positive) and showing partial or complete response to genotoxic chemotherapy.
  • genotoxic chemotherapy preferably cyclophosphamide
  • the present invention provides a method of predicting potentiation of a treatment consisting of administering a PARP inhibitor simultaneously with or subsequently to an active chemotherapy containing a range of genotoxic drugs that directly or indirectly affect DNA damage, e.g. neoadjuvant 5-fluorouracil, anthracycline and cyclophosphamide-based regimens such as AC (Adriamycin/cyclophosphamide), FEC (5-fluorouracil/epirubicin/cyclophosphamide) and FAC (5-fluorouracil/ Adriamycin/cyclophosphamide), or platinum salts.
  • AC Adriamycin/cyclophosphamide
  • FEC fluorouracil/epirubicin/cyclophosphamide
  • FAC fluorouracil/ Adriamycin/cyclophosphamide
  • the method for predicting potentiation of a treatment consisting of administering a PARP inhibitor simultaneously with or subsequently to an active chemotherapy in a cancer patient comprises, or consists essentially of, (1) assessing the GSI in a tumor sample of said patient; and (2) if the GSI is greater than a threshold value, then the cancer patient is likely to have an increased response to said treatment compared to each treatment used alone.
  • said method comprises, or consists essentially of, (1) assessing both the GSI and the HRD score in a tumor sample of said patient; and (2) if the GSI and the HRD score are both greater than their respective threshold values, then the cancer patient is likely to have an increased response to a treatment combining a PARP inhibitor with a genotoxic chemotherapy compared to each treatment alone.
  • the invention also relates to guiding conventional treatment of patients or selecting patients for clinical trials where novel drugs of the classes that directly or indirectly affect DNA damage and/or DNA damage repair, such as PARP inhibitors, are used alone or in combination with genotoxic chemotherapy.
  • an anti-cancer agent particularly cyclophosphamide, and a PARP inhibitor, as a combined preparation for simultaneous, separate or sequential use in cancer therapy, preferably triple negative breast cancer therapy.
  • PARP inhibitor refers to compounds which inhibit signalling through PARP, have PARP DNA-trapping activity, or which inhibit the expression of the PARP genes.
  • An “inhibitor of gene expression” refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce the expression of said gene. Consequently an inhibitor of PARP gene expression refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce the expression of the targeted PARP.
  • the inhibitors of PARP gene expression include, but are not limited to, antisense oligonucleotides, siRNAs, shRNAs, ribozymes and DNAzymes.
  • PARP are a family of at least 17 enzymes which encode for poly-(ADP-ribose)- polymerases. These polymerases, among which the most abundant is PARPI, are involved in DNA repair, cell cycle checkpoints and chromatin remodelling, among other known or unknown functions. DNA repair mechanisms are complex, are related to single strand and/or double strand breaks, and involve multiple pathways:
  • MMR - mismatch repair
  • NER nucleotide excision repair
  • BER base excision repair
  • HRR homologous recombination repair
  • NHEJ non-homologous end-joining
  • PARP enzymes play a role in single strand lesion repair via the BER mechanism, but also in other DNA repair pathways such as HRR or NHEJ (Beck C. et al. Poly(ADP- ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp Cell Res (2014) 329: 18-25).
  • DNA repair pathways which are BRCA-dependent homologous recombination and PARP pathway, are complementary. If one of the channels is deficient, such as by mutation of BRCA, and if the other pathway is blocked by a PARP inhibitor, it results in cell death by apoptosis, while the cell remains viable if one pathway is deficient. This double blocking is called synthetic lethality (Farmer H. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature (2005) 434:917-21. Kaelin W.G. The concept of synthetic lethality in the context of anticancer therapy, Nat. Rev. Cancer (2005) 5: 689-698).
  • PARP inhibitors are compounds which inhibit signalling through PARP.
  • PARP inhibitors include PARP1 and/or PARP2 inhibitors. Among them, one can quote nicotinamide and analogs, AZD-2281 (also called olaparib), AG014699 (also called rucaparib), ABT-888 (also called veliparib), BMN-673 (also called talazoparib), MK- 4827 (also called niraparib) or BGB-290.
  • the PARP inhibitor is chosen from those possessing a DNA trapping activity, such as olaparib, rucaparib, talazoparib and niraparib (Murai J. et al.
  • the term “cancer” refers to any type of cancer.
  • said cancer is chosen from breast cancer, more preferably triple-negative breast cancer, ovarian cancer, lung carcinoma, colorectal cancer, prostate cancer, pancreatic cancer and melanoma.
  • TNBC triple-negative breast cancer
  • the term “triple-negative breast cancer” or “TNBC” refers to any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and Her2/neu.
  • the cancer is triple-negative breast cancer.
  • the term “patient” denotes a mammal, such as a rodent, a feline, a canine, and a primate.
  • a patient according to the invention is a human.
  • said patient is not mutated on BRCA2 gene.
  • tumor sample of a patient refers to any biological sample comprising cancer cells of said patient.
  • it is a blood sample, a saliva sample, a urine sample or a tumor biopsy. More preferably it is a tumor biopsy.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of the disorder or condition to which such term applies.
  • the expression responsiveness, sensibility or sensitivity to PARP inhibitors or chemotherapeutic agents means a measurable decrease in tumor load or a shorter time to progression induced by the treatment.
  • the decrease can be partial, eg. decrease of measurable tumor load, or complete, eg. total loss of measurable tumor load.
  • Response can be assessed using different classification methods, such as overall survival, progression free survival, radiological response, as defined by RECIST, complete response, partial response, or stable disease.
  • chemotherapeutic treatment refers to the treatment of cancer (cancerous cells) with one or more cytotoxic anti-neoplastic drugs (chemotherapeutic agents) as part of a standardized regimen.
  • Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms. It is often used in conjunction with other cancer treatments, such as radiation therapy, surgery, and/or hyperthermia therapy.
  • Traditional chemotherapeutic agents act by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that chemotherapy also harms cells that divide rapidly under normal circumstances: cells in the bone marrow, digestive tract, and hair follicles. This results in the most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).
  • Some newer anticancer drugs for example various monoclonal antibodies such as monoclonal antibodies against EGF receptor or VEGF, like bevacizumab, cetuximab and panitumumab, and also bortezomib - also called PS341, and sold by Millenium Pharmaceuticals under the name Velcade
  • monoclonal antibodies such as monoclonal antibodies against EGF receptor or VEGF, like bevacizumab, cetuximab and panitumumab, and also bortezomib - also called PS341, and sold by Millenium Pharmaceuticals under the name Velcade
  • Targeted therapy as distinct from classic chemotherapy
  • traditional chemo therapeutic agents in antineoplastic treatment regimens are often used alongside traditional chemo therapeutic agents in antineoplastic treatment regimens.
  • chemotherapeutic drugs As used herein refer are:
  • Alkylating agents are the oldest group of chemotherapeutics in use today. They are so named because of their ability to alkylate many molecules, including proteins, RNA and DNA. This ability to bind covalently to DNA or RNA via their alkyl group is the primary cause for their anti-cancer effects. This leads to a form of programmed cell death called apoptosis. Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug.
  • alkylating agents are the nitrogen mustards, nitrosoureas, tetrazines, aziridines, cisplatins and derivatives, and non-classical alkylating agents.
  • Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan.
  • Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin.
  • Tetrazines include dacarbazine, mitozolomide and temozolomide.
  • Aziridines include thiotepa, mytomycin and diaziquone (AZQ).
  • Cisplatin and derivatives include cisplatin, carboplatin and oxaliplatin. They impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules.
  • Non-classical alkylating agents include procarbazine and hexamethylmelamine.
  • Mafosfamide is an oxazaphosphorine (cyclophosphamide-like) alkylating agent under investigation as a chemotherapeutic drug.
  • Anti-metabolites and "DNA synthesis and transcription inhibitors” as used herein have an interchangeable meaning and define are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. Anti-metabolites resemble either nucleobases or nucleosides, but have altered chemical groups. These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, DNA damage can occur and programmed cell death (apoptosis) is induced.
  • anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case S-phase (the DNA synthesis phase). For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses.
  • Subtypes of the antimetabolites are the anti-folates, fluoropyrimidines, deoxynucleoside analogues and thiopurines.
  • the anti-folates include methotrexate and pemetrexed.
  • the fluoropyrimidines include fluorouracil and capecitabine.
  • Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5- fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.
  • Capecitabine is a prodrug of 5- fluorouracil that is broken down in cells to produce the active drug.
  • the deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, vidaza, fludarabine, nelarabine, cladribine, clofarabine and pentostatin.
  • the thiopurines include thioguanine and mercaptopurine
  • Anti-micro tubule agents are plant-derived chemicals that block cell division by preventing microtubule function.
  • Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents.
  • the vinca alkaloids prevent the formation of the microtubules, whereas the taxanes prevent the microtubule disassembly. By doing so, they prevent the cancer cells from completing mitosis. Following this, cell cycle arrest occurs, which induces programed cell death (apoptosis).
  • Vinca alkaloids are derived from the Madagascar periwinkle, Catharanthusroseus. Taxanes are natural and semi- synthetic drugs.
  • the first drug of their class was originally extracted from the Pacific Yew tree, Taxusbrevifolia. Now this drug and another in this class, docetaxel, are produced semi-synthetically from a chemical found in the bark of another Yew tree, Taxusbaccata. These drugs promote microtubule stability, preventing their disassembly. Docetaxel exerts its effect during S-phase.
  • Topoisomerase inhibitors are drugs that affect the activity of two enzymes; topoisomerase I and topoisomerase II.
  • topoisomerase I and topoisomerase II When the DNA double stranded helix is unwound, during DNA replication or translation for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single or double strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or translation. Inhibition of topoisomerase I or II interferes with both of these processes.
  • topoisomerase I inhibitors are semi-synthetically derived from camptothecin, which is obtained from the Chinese ornamental tree Camptothecaacuminata.
  • Drugs that target topoisomerase II can be divided into two groups.
  • the topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and translation, causes DNA strand breaks, and leads to programmed cell death (apoptosis).
  • These agents include etoposide, doxorubicin, mitoxantrone and teniposide.
  • the second group, catalytic inhibitors is drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin, merbarone, and aclarubicin.
  • Cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action.
  • the group includes the anthracyclines and other drugs including actinomycin, bleomycin, plicamycin and mitomycin.
  • Doxorubicin and daunorubicin were the first two anthracyclines, and were obtained from the bacterium Streptomyces peucetius. Derivatives of these compounds include epirubicin and idarubicin.
  • Other clinically used drugs in the anthracyline group are pirarubicin, aclarubicin and mitoxantrone.
  • anthracyclines include DNA intercalation (molecules insert between the two strands of DNA), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition.
  • Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis.
  • Bleomycin a glycopeptide isolated from Streptomyces verticillus, also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion, becomes chemically reduced and reacts with oxygen.
  • Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.
  • Combination chemotherapy involves treating a patient with a number of different drugs simultaneously.
  • the drugs differ in their mechanism and side effects. The biggest advantage is minimizing the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity.
  • a prominent example is the combination of doxorubicin and cyclophosphamide (A/C).
  • the anti-cancer agent is an alkylating agent, more preferably cyclophosphamide, optionally in combination with an anthracycline such as doxorubicin or epirubicin.
  • biomarker or “marker” is widespread in the art and may broadly denote a biological molecule and/or a detectable portion thereof (e.g. a nucleic acid, a peptide or a lipid such as a glycolipid) whose qualitative and/or quantitative evaluation in an individual is predictive or informative (e.g., predictive, diagnostic and/or prognostic) with respect to one or more aspects of the individual's phenotype and/or genotype, such as, for example, with respect to the status of the individual.
  • the biomarker is predictive or informative with respect to the outcome for chemotherapeutic treatment of a cancer in an individual.
  • a biomarker is expressed ("expression of the biomarker") if the biomarker is detectable with methods known in the art. Therefore expression of biomarkers encompasses not only expression at nucleic acid level (DNA and/or RNA) and protein level but also expression (presence) of other biological structures on or in the cells such as glycolipids or the activity of a protein.
  • the present invention provides a method for predicting the responsiveness of a cancer patient, preferably a TNBC patient, to treatment with a PARP inhibitor, comprising (1) measuring the expression of at least TDRD7, DDX60, IFIT2, ABCA1 and DDX58 genes, expressed in a tumor sample of the patient, so as to obtain an expression profile; and further (3) comparing the obtained expression profile with cut-off value(s),
  • the term "expression profile” refers to quantitative expressions of at least said genes TDRD7, DDX60, IFIT2, ABCA1 and DDX58, in a tumor sample.
  • the expression profile is a repository of the expression level data that can be used to compare the expression levels of different genes, in whatever units are chosen.
  • the term "profile” is also intended to encompass manipulations of the expression level data derived from a cell, tissue or individual. For example, once relative expression levels are determined for a given set of genes, the relative expression levels for that cell, tissue or individual can be compared to a standard to determine if expression levels are higher or lower relative to the same genes in a standard.
  • Standards can include any data deemed by one of skilled in the art to be relevant for comparison, for example determined threshold value or expression profile of a positive and/or negative control.
  • the expression "comparing the expression profile” in all its grammatical forms refers to the evaluation of the quantitative difference in expressions of said genes. Typically, the person skilled in the art may compare the levels of expression of the genes to cut-off values.
  • a "control value” or “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by person skilled in the art.
  • the person skilled in the art may compare the expression profile of the genes of interest according to the invention with threshold value(s).
  • the present invention relates to a method for predicting the responsiveness of a cancer patient, preferably a TNBC patient, to treatment with a PARP inhibitor, comprising measuring a GSI (Genomic Stress Index), as defined below, in a tumor sample of said patient.
  • GSI Genetic Stress Index
  • said method comprises: (1) measuring the expression of genes expressed in a tumor sample of the patient, said genes being at least TDRD7, DDX60, IFIT2, ABCA1 and DDX58; (2) determining the GSI in the tumor sample based at least on the measurements made in (1), and further (3) comparing the obtained the GSI with a cut-off value,
  • the GSI is correlated to the sensibility of a given patient afflicted by a cancer to PARP inhibitor treatment.
  • the tumor of the patient is not sensitive (resistant) to PARP inhibitor treatment.
  • the tumor will continue its progression.
  • the method of the invention is applicable, on one hand, in case of a treatment with a PARP inhibitor as a monotherapy, as well as, on the other hand, in case of a treatment with a PARP inhibitor in combination with a chemotherapeutic agent, preferably a genotoxic, more preferably cyclophosphamide.
  • a chemotherapeutic agent preferably a genotoxic, more preferably cyclophosphamide.
  • the patient has not undergone any treatment of said cancer.
  • the method of the invention predicts the sensibility to PARP inhibitor treatment of said patient, and said PARP inhibitor may be administered as monotherapy.
  • the patient has already been treated for said cancer, preferably by genotoxic chemotherapy, and more preferably by cyclophosphamide.
  • the method of the invention predicts the sensibility to PARP inhibitor treatment of said treated patient, and said PARP inhibitor may be administered in combination with a chemotherapeutic agent.
  • the purpose of the method is to predict sensibility of the treated patient to PARP inhibitor treatment given in combination with genotoxic chemotherapy, and thus, to select patients in which the addition of a PARP inhibitor to genotoxic chemotherapy, preferably cyclophosphamide, will result in increased antitumor efficacy and prevention of metastasis and/or relapse as compared to genotoxic chemotherapy used alone.
  • genotoxic chemotherapy preferably cyclophosphamide
  • a method for preventing metastasis and/relapse of a cancer, preferably triple negative breast cancer, in a patient already treated by chemotherapy comprises, or consists essentially of the following steps:
  • genotoxic chemotherapy preferably cyclophosphamide
  • the present invention provides a method for predicting the responsiveness of a cancer patient, preferably a TNBC patient, to treatment with a PARP inhibitor, comprising (1) measuring the expression of at least one gene chosen from TDRD7, DDX60, IFIT2, ABCA1, APOL6, B2M, BST2, C1R, CIS, C3, CD68, CLDN1, DDIT3, DDR2, DDX58, DTX3L, HERC5, HERC6, HLA-E, IFI27, IFI35, IFI6, IFI44L, IFI44, TLR2, TLR3, TRIM21, TRIM22, TSPANl, IFIHl, IFITl, IFITMl, IRF9, C19orf66, USP18, SAMD9, SAMD9L, SAMHDl, SELM, SOD2, SPlOO, SPl lO, STATl, STAT2, CCL5, MUCl, MUC15, MXl, PLSCRl, OAS3, IFIT3,
  • GSI Genetic Stress Index
  • said method comprises: (1) measuring the expression of genes expressed in a tumor sample of the patient, said genes being at least TDRD7, DDX60, IFIT2, ABCA1 and DDX58; (2) determining a score, preferably the GSI, in the tumor sample based at least on the measurements made in (1), and further (3) comparing the obtained the score, preferably the GSI, with a cut-off value,
  • Step (2) is indeed optional; it may be replaced by any statistical method known in the art.
  • the expression profile may be defined in combination with corresponding scalar weights on the real scale with varying magnitude, which are further combined through linear or non-linear, algebraic, trigonometric or correlative means into a single scalar value via an algebraic, statistical learning, Bayesian, regression, or similar algorithms which together with a mathematically derived decision function on the scalar value provide a predictive model by which expression profiles from samples may be resolved into discrete classes of responder or non-responder, resistant or non-resistant, to a specified drug or drug class.
  • Such predictive models are developed by learning weights and the decision threshold, optimized for sensitivity, specificity, negative and positive predictive values, hazard ratio or any combination thereof, under cross-validation, bootstrapping or similar sampling techniques, from a set of representative expression profiles from historical patient samples with known drug response and/or resistance.
  • the expression profile is used to form a weighted sum of the genes signals, where individual weights can be positive or negative.
  • the resulting sum (“decisive function") is compared with a pre-determined cut-off value. The comparison with the cut-off value may be used to diagnose, or predict a clinical condition or outcome.
  • the genes included in the classifier provided in the table above will carry unequal weights in a classifier for responsiveness or resistance to a PARP inhibitor. Therefore, while few sequences may be used to diagnose or predict an outcome such as responsiveness to therapeutic agent, the specificity and sensitivity or diagnosis or prediction accuracy may increase using more sequences.
  • the term "weight” refers to the relative importance of an item in a statistical calculation. The weight of each gene may be determined on a data set of patient samples using analytical methods known in the art.
  • the relative expression levels of said genes in a tumor sample are measured to form the expression profile.
  • the expression profile of the set of genes from a patient tumor sample is summarized in the form of a compound decision score and compared to a score threshold that is mathematically derived from a training set of patient data.
  • the score threshold separates a patient group based on different characteristics such as, but not limited to, responsiveness/non-responsiveness to treatment.
  • the patient training set data is preferably derived from tumor tissue samples having been characterized by prognosis, likelihood of recurrence, long term survival, clinical outcome, treatment response, diagnosis, tumor classification, or personalized genomics profile.
  • Expression profiles, and corresponding decision scores from patient samples may be correlated with the characteristics of patient samples in the training set that are on the same side of the mathematically derived score decision threshold.
  • the threshold of the linear classifier scalar output is optimized to maximize the sum of sensitivity and specificity under cross-validation as observed within the training dataset.
  • the expression profile of a patient tumor sample is evaluated by a linear classifier.
  • a linear classifier refers to a weighted sum of the individual genes intensities into a compound decision score ("decision function"). The decision score is then compared to a pre-defined cut-off score, corresponding to a certain set-point in terms of sensitivity and specificity which indicates if a sample is above the score threshold (decision function positive) or below (decision function negative).
  • the data space i.e. the set of all possible combinations of gene (biomarker) expression values
  • the data space i.e. the set of all possible combinations of gene (biomarker) expression values
  • two mutually exclusive halves corresponding to different clinical classifications or predictions, e.g. one corresponding to responsiveness to a therapeutic agent and the other to resistance.
  • relative over-expression of a certain biomarker can either increase the decision score (positive weight) or reduce it (negative weight) and thus contribute to an overall decision of, for example, responsiveness or resistance to a therapeutic agent.
  • AUC area under the curve
  • ROC receiver operating characteristic
  • the feature data across the entire population e.g., the cases and controls
  • the true positive and false positive rates for the data are calculated.
  • the true positive rate is determined by counting the number of cases above the value for that feature and then dividing by the total number of cases.
  • the false positive rate is determined by counting the number of controls above the value for that feature and then dividing by the total number of controls.
  • ROC curves can be generated for a single feature as well as for other single outputs, for example, a combination of two or more features can be mathematically combined (e.g., added, subtracted, multiplied, etc.) to provide a single sum value, and this single sum value can be plotted in a ROC curve. Additionally, any combination of multiple features, in which the combination derives a single output value, can be plotted in a ROC curve. These combinations of features may comprise a test.
  • the ROC curve is the plot of the true positive rate (sensitivity) of a test against the false positive rate (1 -specificity) of the test.
  • this quantity i.e. the cut-off threshold responsiveness or resistance to a therapeutic agent
  • the interpretation of this quantity is derived in the development phase ("training") from a set of patients with known outcome.
  • the corresponding weights and the responsiveness/resistance cut-off threshold for the decision score are fixed a priori from training data by methods known to those skilled in the art.
  • Partial Least Squares Discriminant Analysis (PLS-DA) is used for determining the weights. (L. Stahle, S. Wold, J. Chemom. 1 (1987) 185-196; D. V. Nguyen, D. M. Rocke, Bioinformatics 18 (2002) 39-50).
  • step (2) comprises determining the GSI in the tumor sample based on the measurements made in (1), and may be performed as explained in the examples. Typically, it is calculated with the z-scores for each gene expression level for at least TDRD7, DDX60, IFIT2, ABCA1 and DDX58 genes. Said z-score can be calculated from the following formula:
  • z is the z-score
  • X is the value of the element
  • ⁇ is the mean of the expression level of one gene
  • ⁇ is the standard deviation
  • the GSI is obtained for the given tumor sample.
  • the minimal 5 genes necessary for the present invention are TDRD7, DDX60, IFIT2, ABCA1 and DDX58.
  • At least one of the following genes may be further used: APOL6, B2M, BST2, C1R, CIS, C3, CD68, CLDN1, DDIT3, DDR2, DTX3L, HERC5, HERC6, HLA-E, IFI27, IFI35, IFI6, IFI44L, IFI44, TLR2, TLR3, TRIM21, TRIM22, TSPAN1, IFIH1, IFIT1, IFITM1, IRF9, C19orf66, USP18, SAMD9, SAMD9L, SAMHD1, SELM, SOD2, SP100, SP110, STAT1, STAT2, CCL5, MUC1, MUC15, MX1, PLSCR1, OAS3, IFIT3, IFIT5, OAS1, OAS2, OASL, PARP12, PARP14, PARP9, LAMP3, RSAD2, UBE2L6 and/or ZNFX1.
  • At least one of the following genes may be further used: STAT2, IFI44L, DDR2, IFI44, TLR3, MX1, IFIT1, C19orf66, USP18, SAMD9L, SAMHD1, OASL, CCL5, MUC1, PLSCR1, OAS3, B2M, IFIT3, IFIT5, OAS1, LAMP3, IFITMl, TRIM22, RSAD2 and/or UBE2L6.
  • the additional genes are chosen from STAT2, IFI44L, DDR2, IFI44 and TLR3.
  • the additional genes are at least STAT2, IFI44L, DDR2, IFI44 and TLR3.
  • the additional genes are chosen from MX1, IFITl, C19orf66, USP18, SAMD9L, SAMHD1, OASL, CCL5, MUC1 and PLSCR1.
  • the additional genes are at least MX1, IFITl, C19orf66, USP18, SAMD9L, SAMHD1, OASL, CCL5, MUC1 and PLSCRl.
  • the additional genes are chosen from OAS3, B2M, IFIT3, IFIT5, OAS1, LAMP3, IFITMl, TRIM22, RSAD2 and UBE2L6.
  • the additional genes are at least OAS3, B2M, IFIT3, IFIT5, OAS1, LAMP3, IFITMl, TRIM22, RSAD2 and UBE2L6.
  • genes are used for said calculation: STAT2, IFI44L, DDR2, IFI44, TLR3, MX1, IFITl, C19orf66, USP18, SAMD9L, SAMHD1, OASL, CCL5, MUC1, PLSCR1, OAS3, B2M, IFIT3, IFIT5, OAS1, LAMP3, IFITMl, TRIM22, RSAD2 and UBE2L6.
  • gene expression level or “level of expression of a gene” refers to an amount or a concentration of a transcription product, for instance mRNA, or of a translation product, for instance a protein or polypeptide.
  • a level of mRNA expression can be expressed in units such as transcripts per cell or nanograms per microgram of tissue.
  • a level of a polypeptide can be expressed as nanograms per microgram of tissue or nanograms per milliliter of a culture medium, for example.
  • relative units can be employed to describe a gene expression level.
  • the expression of "measuring the level of expression of a gene” encompasses the step of measuring the quantity of a transcription product, preferably mRNA obtained through transcription of said gene, and/or the step of measuring the quantity of translation product, preferably the protein obtained through translation of said gene.
  • the step of measuring the expression of a gene refers to the step of measuring the quantity of mRNA obtained through transcription of said gene.
  • the step of measuring the gene expression levels may be performed according to the routine techniques, well known of the person skilled in the art.
  • the measurement comprises contacting the cancer cells of the biological sample with selective reagents such as probes, primers, ligands or antibodies, and thereby detecting the presence of nucleic acids or proteins of interest originally in the sample.
  • selective reagents such as probes, primers, ligands or antibodies
  • the expression may be measured by measuring the level of mRNA.
  • the nucleic acid contained in the samples e.g., isolated cancer cells prepared from the patient, like those included in biopsies
  • the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis) and/or amplification (e.g., RT- PCR).
  • hybridization e.g., Northern blot analysis
  • amplification e.g., RT- PCR
  • the expression of the relevant genes is measured by RT-PCR, preferably quantitative or semi-quantitative RT-PCR, even more preferably real-time quantitative or semi-quantitative RT-PCR.
  • LCR ligase chain reaction
  • TMA transcription- mediated amplification
  • SDA strand displacement amplification
  • NASBA nucleic acid sequence based amplification
  • Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization. A wide variety of appropriate indicators are known in the art including, fluorescent, radioactive, enzymatic or other ligands (e. g. avidin/biotin).
  • Probes typically comprise single- stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500.
  • Primers typically are shorter single- stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified.
  • the probes and primers are "specific" to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC.
  • SCC is a 0.15 M NaCl, 0.015 M Na-citrate).
  • the nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit.
  • a kit includes consensus primers and molecular probes.
  • a preferred kit also includes the components necessary to determine if amplification has occurred.
  • the kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.
  • the tumor samples are archived formalin fixed paraffin-embedded (FFPE) biopsy material, as well as fresh/frozen (FF) tissue, and are used for assay of all transcripts.
  • FFPE formalin fixed paraffin-embedded
  • the expression level may be determined using RNA obtained from FFPE tissue, fresh frozen tissue or fresh tissue that has been stored in solutions such as RNAlater.
  • the gene expression levels of the GSI may also be measured by using standard immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
  • immunoassays such as competition, direct reaction, or sandwich type assays.
  • cancers cells are purified from the isolated tumor sample.
  • assays include, but are not limited to, microarray; qPCR; agglutination tests; enzyme-labelled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; Immunoelectrophoresis; immunoprecipitation .
  • the threshold may be comprised between 1.81 and 1.87, preferably is around 1.83.
  • the threshold may be comprised between 3.40 and 4.30, preferably is around 3.66.
  • the threshold may be comprised between 3.40 and 4.30, preferably is around 3.66.
  • the threshold may be comprised between 7.50 and 11.40, preferably is around 8.66.
  • Said method for predicting the sensibility of a patient afflicted by a cancer to a PARP inhibitor according to the invention may be combined with the HRD assay developed by Myriad (Myriad Genetics Inc. US Patent Application US 2014/0363521). Indeed, as shown in the examples, the combination of the HRD assay and the GSI assay of the invention shows a better prediction than each method alone, with a lower rate of false positives.
  • the HRD assay comprises, or consists essentially of, (a) detecting, in a sample or DNA derived therefrom, chromosomal aberrations regions (CA Regions) in at least one pair of human chromosomes or DNA derived therefrom; and (b) determining the number, size (e.g., length), and/or character of said CA Regions.
  • chromosomal aberration or "CA” means a somatic change in a cell's chromosomal DNA that falls into at least one of three overlapping categories: LOH (loss of heterozygosity), TAI (telomeric allelic imbalance), or LST (large scale transition).
  • Polymorphic loci within the human genome are generally heterozygous within an individual's germline since that individual typically receives one copy from the biological father and one copy from the biological mother. Somatically, however, this heterozygosity can change (via mutation) to homozygosity. This change from heterozygosity to homozygosity is called loss of heterozygosity (LOH). LOH may result from several mechanisms. For example, in some cases, a locus of one chromosome can be deleted in a somatic cell.
  • the locus that remains present on the other chromosome is an LOH locus as there is only one copy (instead of two copies) of that locus present within the genome of the affected cells. This type of LOH event results in a copy number reduction.
  • a locus of one chromosome e.g., one non-sex chromosome for males
  • the locus that remains present on each chromosome is an LOH locus and can be referred to as a copy neutral LOH locus. LOH and its use in determining HRD is described in detail in WO2011/160063.
  • allelic imbalance occurs when the relative copy number (i.e., copy proportion) at a particular locus in somatic cells differs from the germline. For example, if the germline has one copy of allele A and one copy of allele B at a particular locus, and a somatic cell has two copies of A and one copy of B, there is allelic imbalance at the locus because the copy proportion of the somatic cell (2:1) differs from the germline (1:1). LOH is an example of allelic imbalance since the somatic cell has a copy proportion (1:0 or 2:0) that differs from the germline (1:1).
  • allelic imbalance encompasses more types of chromosomal aberration, e.g., 2:1 germline going to 1:1 somatic; 1:0 germline going to 1:1 somatic; 1:1 germline going to 2:1 somatic, etc.
  • Analysis of regions of allelic imbalance encompassing the telomeres of chromosomes is particularly useful in the invention.
  • a "telomeric allelic imbalance region" or "TAI Region” is defined as a region with allelic imbalance that (a) extends to one of the subtelomeres and (b) does not cross the centromere. TAI and its use in determining HRD is described in detail in WO2012/027224.
  • LST large scale transition
  • LST refers to any somatic copy number transition (i.e., breakpoint) along the length of a chromosome where it is between two regions of at least some minimum length (e.g., at least 3, 4, 5, 6, 7, 8 9, 10, 11 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more megabases) after filtering out regions shorter than some maximum length (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4 or more megabases).
  • the method for predicting the responsiveness of a cancer patient to treatment with a PARP inhibitor is used in combination with a method comprising (a) detecting, in a tumor sample of the patient (which may be the same or different from the tumor sample used in the method of the invention), chromosomal aberrations regions in at least one pair of human chromosomes or DNA derived therefrom; and (b) determining the number, size, and/or character of said chromosomal aberrations regions.
  • the present invention also relates to a product containing a genotoxic anti-cancer agent, preferably cyclophosphamide and a PARP inhibitor as a combined preparation for simultaneous, separate or sequential use in cancer therapy, preferably triple-negative breast cancer therapy.
  • a product containing a genotoxic anti-cancer agent, preferably cyclophosphamide and a PARP inhibitor as a combined preparation for simultaneous, separate or sequential use in cancer therapy, preferably triple-negative breast cancer therapy.
  • said combined preparation is administered to TNBC patients having a positive GSI.
  • the present invention also relates to a PARP inhibitor for use for potentiating the effects of chemotherapy in cancer patients, preferably in TNBC patients, having a positive GSI.
  • a PARP inhibitor potentiates the therapeutic effects of chemotherapy.
  • said chemotherapy is cyclophosphamide, optionally in combination with doxorubicin.
  • potentiation it is meant that the effects of chemotherapy are increased by the PARP inhibitor. This contributes to inhibiting tumor regrowth, and/or to induce partial or complete tumor regression.
  • Figure 1 Example of tumor response to genotoxic chemotherapy.
  • mice with subcutaneously growing tumors HBCx-7, HBCx-23, HBCx- 17 or HBCx-6) were treated with saline vehicle (Control) or with cyclophosphamide at 100 mg/kg by ip route at DO (Treated).
  • Graphs represent the evolution of the mean tumor volume in mm3 (y axis) over time in days (x axis) for each group.
  • Figure 2 Comparative analysis of GSI, HRD-score and BRCA status classifiers, alone or combined, as predictors of niraparib efficacy.
  • Figure 3 Effect on tumor growth of cyclophosphamide and PARP inhibitor treatment in the human breast tumor xenograft HBCx-6.
  • Cyclophosphamide was administered i.p once at 100 mg/kg at day 0.
  • PARPl inhibitor niraparib was administered at 75 mg/kg i.p qdx28 from day 15 to day 35.
  • PARPl inhibitor olaparib was administered at 100 mg/kg i.p qdx28 from day 15 to day 35.
  • Data are expressed as median tumor volume (mm ).
  • Figure 4 Effect on tumor growth of cyclophosphamide and PARP inhibitor treatment in the human breast tumor xenograft HBCx-14.
  • Cyclophosphamide was administered i.p once at 100 mg/kg at day 0.
  • PARPl inhibitor niraparib was administered at 75 mg/kg i.p qdx28 from day 15 to day 35.
  • PARPl inhibitor olaparib was administered at 100 mg/kg i.p qdx28 from day 15 to day 35.
  • Data are expressed as median tumor volume (mm ).
  • Figure 5 Effect on tumor growth of cyclophosphamide and PARP inhibitor treatment in the human breast tumor xenograft HBCx-1.
  • Cyclophosphamide was administered i.p once at 100 mg/kg at day 0.
  • PARPl inhibitor niraparib was administered at 75 mg/kg i.p qdx28 from day 15 to day 35.
  • PARPl inhibitor olaparib was administered at 100 mg/kg i.p qdx28 from day 15 to day 35.
  • Data are expressed as median tumor volume (mm ).
  • Figure 6 Effect on tumor growth of cyclophosphamide and PARP inhibitor treatment in the human breast tumor xenograft HBCx-8.
  • Cyclophosphamide was administered i.p once at 100 mg/kg at day 0.
  • PARPl inhibitor niraparib was administered at 75 mg/kg i.p qdx28 from day 15 to day 28.
  • PARPl inhibitor olaparib was administered at 100 mg/kg i.p qdx28 from day 15 to day 28.
  • Data are expressed as median tumor volume (mm ).
  • Figure 7 Effect on tumor growth of cyclophosphamide and PARP inhibitor treatment in the human breast tumor xenograft HBCx-33.
  • Cyclophosphamide was administered i.p once at 100 mg/kg at day 0.
  • PARPl inhibitor niraparib was administered at 75 mg/kg i.p qdx28 from day 15 to day 28.
  • PARPl inhibitor olaparib was administered at 100 mg/kg i.p qdx28 from day 15 to day 28.
  • Data are expressed as median tumor volume (mm ).
  • Tumor xenografts were generated by direct subcutaneous grafting into immunodeficient mice of human tumor surgical samples with informed written consent of the patients and maintained by serial transplantation.
  • the tumor xenografts have been studied for histology, cytogenetics, genetic and other biological markers, and for their response to a number of anticancer agents, alone and in combination.
  • These studies have shown that tumor xenografts are biologically similar to the patient's tumors from which they derive, in term of both molecular characteristics and response to therapy. They are thus clinically relevant tumor models, as opposed to xenografts produced from tumor cell lines that have been obtained by in vitro culture and often passaged for many years (Fiebig, H.H. et al. Eur J Cancer 40, 802-820, 2004; Marangoni E., Vincent- Salomon A., Auger N. et al. Clin Cancer Res. 2007 Jul l;13:3989-98).
  • Chemotherapeutic drugs were administered by intraperitoneal or per os route as indicated according to the following doses and schedules: adriamycin, 2 mg/kg, q3wk (Doxorubicin®, Teva Pharmaceuticals, France) and cyclophosphamide, 100 mg/kg, q3wk (Endoxan®, Baxter, France).
  • PARP inhibitor olaparib (AZD2281, Sequoia Research Products, UK) at 50 or 100 mg/kg (po; qd).
  • PARP inhibitor niraparib MK- 4827, Tesaro, US) at 50 or 75 mg/kg (po; qd).
  • the formula TV (mm3) [length (mm) x width (mm) 2 ]/2 was used, where the length and the width were the longest and the shortest diameters of the tumor, respectively. All animals were observed daily for clinical symptoms and weighted biweekly during the treatment period and the follow-up period. Mice were ethically sacrificed when the tumor volume reached 2000 mm3. Response to treatment was evaluated as follows:
  • Stabilization stable tumor volume for at least two consecutive measurements
  • Progression Progression
  • Time to progression time between beginning of treatment and progression
  • Median time since beginning of treatment at which half of the mice in a treated group show tumor progression.
  • Gene expression data of were obtained by running total RNA extracted from 28 TNBC PDXs on Affymetrix U133.2 plus gene chips. Data were normalized by using the PLIER algorithm, available in the Affymetrix Expression Console.
  • the genomic stress signature used for PDX classification was identified as described in previous studies (US Patent Application 13/463,129 Markers for Cancer Prognosis and Therapy and Methods of use, May 3, 2012 to Judde JG et al.; Legrier et al, Activation of JEN/STAT signaling predicts response to chemotherapy in estrogen receptor-negative breast cancer. Br J Cancer (2016) 114: 177-187). Probesets corresponding to the 62 genes with the most significant p value selected from this list were identified in the microarray. Probesets containing suffix "x" were removed as unique hybridization is not guaranteed for these probesets, and when multiple probesets were assigned to the same gene a mean value was calculated and used in the analysis. Gene intensity in the dataset was expressed as log 2 values .
  • a mean z-score was calculated for the niraparib- sensitive and niraparib-resistant group of PDXs, and the ratio between the two mean values was used to rank genes. In the analysis, the sum of gene expression values from the top 5, 10, 20 and 30 genes with decreasing responder/non-responder ratio were used to calculate a score for each PDX.
  • EXAMPLE 1 Assay for predicting breast cancer sensitivity to PARP inhibitors Identification of a gene expression signature as indicator of tumor genomic stress
  • Genomic Stress Signature 62 genes with the lowest p-values, overexpressed in residual tumor foci from TNBC PDXs treated with AC compared to their untreated counterparts, analyzed by GeneChip Human Exon ST Array (Affymetrix).
  • the overexpression of GSS genes in tumor cells following genotoxic treatment is associated with DNA damage and repair, activation of the DNA-damage checkpoints.
  • Overexpression of GSS genes is transient and reverts to normal levels upon tumor regrowth (Legrier et al, Activation of IFN/STAT signaling predicts response to chemotherapy in estrogen receptor-negative breast cancer. Br J Cancer (2016) 114: 177- 187).
  • Replicative/genomic stress is common in tumors and may have various tumor- specific sources that have yet to be fully identified (Luo J. et al. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell (2009) 136: 823-837; Dobbelstein M. and Sorensen CS. Exploiting replicative stress to treat cancer. Nat. Review Drug Discovery (2015) 14: 405-423).
  • GSS chronic replicative/genomic stress
  • PARP inhibitors are a family of compounds that block PARP-mediated DNA repair and work particularly well in tumors with impaired homologous recombination (HR)- mediated DNA repair such as those with inactivated BRCA genes. So far, the most accepted biomarker to predict tumor sensitivity to PARP inhibitor is mutation of BRCA1/BRCA2 genes. Another candidate biomarker to identify PARP inhibitor- sensitive tumors is the HRD genomic scar assay, in which the detection of genomic rearrangements signals a tumor with homologous recombination deficiency (HRD). The HRD assay identifies the majority of BRCA-mutated tumors, but also other tumors with putative alterations in other DNA repair pathways.
  • HRD homologous recombination deficiency
  • the inventors tested the efficacy of niraparib (provided by Tesaro) and of olaparib in a series of TNBC PDXs. The predictive value of the GSS was compared to that of BRCA mutation and of HRD status.
  • TNBC PDXs were tested for their response to niraparib.
  • Several PDXs showed very similar response to olaparib, another PARP inhibitor, thus indicating that in the tested experimental conditions the two drugs efficacy is very similar.
  • Tumor response to the standard of care combination adryamicin/cyclophosphamide (AC) was also evaluated for 27 out of 28 PDXs. The results obtained are shown in Table 2.
  • DDX58 3.5 -0,5 0,4 -1,4 -0,2 1,0 -0,1 0,5
  • IFI44L 2.0 -0,6 1,8 0,6 0,5 1,0 -1,2 l,l
  • SAMD9L 2.4 -1,1 1,1 0,9 -0,6 0,1 -0,2 -0,4 1,3 0,6 -0,7 -0,8 1,0 0,6 -0,2 0,5 -2,0 0,4 0,9 0,6 -1,3 -0,9 0,2 -1,4 0,3 -0,7 1,0 1,0 0,3 -0,1 0,4
  • SAMHD1 1.8 -0,1 1,8 0,3 -1,7 1,0 -0,6 -0,6 0,9 -0,4 -1,2 -1,0 -0,7 -1,0 1,4 -1,0 -1,7 0,7 -0,1 0,1 0,1 0,5 0,9 1,4 -0,5 0,0 -1,1 0,5 0,3 -0,1 0,4
  • OAS3 2.5 -1,0 0,6 0,9 -0,4 0,3 -1,4 0,2 0,8 -0,1 0,5 -0,2 0,4 -1,4 -0,4 -0,7 -0,8 1,1 -0,3 0,9 0,4 0,9 -0,9 -0,8 0,6 -2,1 1,5 0,5 0,2 -0,1 0,3
  • IFIT3 1.9 -0,6 0,9 0,5 -0,8 0,0 -1,7 1,2 1.1 -0,2 0,9 0,1 -0,4 -1,0 0,0 -0,7 -0,6 1,1 -1,0 1,4 0,3 -0,1 -0,5 0,6 0,4 -0,9 1,9 -1,9 0,2 -0,1 0,3
  • OAS1 1.4 -0,3 0,6 0,3 -0,7 0,3 -0,1 0,0 0,5 0,6 1,1 0,5 0,0 -1,9 -0,3 -0,4 -1,6 1,3 0,0 1,1 -0,2 0,9 -1,2 -0,6 0,2 -2,6 1,4 0,8 0,2 -0,1 0,2
  • LAMP3 1.8 -0,8 0,6 0,2 0,3 0,5 -1,3 0,2 0,1 -0,7 0,4 0,3 -0,3 -0,6 -0,7 -1,1 0,8 1,2 0,3 1,0 -0,2 -0,9 -1,5 -2,8 1,0 0,4 1,1 1,0 0,2 -0,1 0,2
  • TRIM22 2.1 -0,5 0,2 1,3 -1,2 0,2 -1,5 0,6 0,8 -0,4 1,2 -0,3 -0,1 0,9 -2,1 -0,8 -1,1 1,1 0,7 0,5 0,5 -0,6 -1,2 -0,5 0,2 -0,5 1,3 0,7 0,1 -0,1 0,2
  • IFI27 1.8 -0,2 1,3 -0,6 0,6 0,2 -2,5 -0,4 1,0 0,0 1,5 -0,5 -1,1 -0,5 -0,3 -1,0 -0,7 0,7 -0,1 0,6 0,7 0,5 -0,7 -0,1 0,9 -1,6 1,3 1,0 0,0 ⁇ , ⁇ o,i
  • APOL6 1.4 -1,4 0,2 0,6 -0,8 1,4 -1,6 0,4 0,0 0,4 -0,7 -1,9 1,1 -0,4 1,2 -1,3 -0,9 1,2 0,0 1,0 0,5 -1,4 -0,4 1,3 0,2 -0,7 0,8 -0,2 0,0 0,0
  • BST2 1.5 0,2 0,7 1,1 0,5 -0,4 -3,2 -0,. 1.6 0,4 0,6 0,5 0,5 -1,2 0,9 -1,5 -0,3 0,9 -0,2 0,6 0,8 -0,1 -0,7 -0,8 0,3 -0,6 0,9 0,9 0,0 0,0
  • IRF9 1,6 -0,1 1,1 -0,1 0,3 -0,6 -1,6 -0 1.2 -0,5 0,4 -0,2 -0,4 0,0 0,0 -0,7 1,1 1,5 -1,2 2,3 1,0 -0,8 0,1 -0,4 0,6 -1,4 1,3 -1,3 0,0 0,0
  • TRIM21 1.6 -1,2 0,7 1,3 -0,6 0,0 -1,3 -0,9 1.5 0,9 0,9 -1,1 0,5 0,3 -0,2 -1,3 -1,0 1,5 -0,2 0,0 0,9 1,2 -0,5 -0,8 0,8 -1,6 1,0 0,5 0,0 ⁇ 0,1
  • HLA-E 1,9 -0,8 0,6 -0,4 0,6 -0,5 -1,8 -2,1 0,1 -0,1 1,8 0,9 1,4 0,2 -0,2 0,2 0,1 -0,1 -0,3 1,4 0,1 -0,6 -0,6 -0,6 0,3 -1,9 0,8 -0,6 -0,3 0,1 -0,4
  • Genomic Stress Index To generate a Genomic Stress Index, the sum of the mean values of the top 5, 10, 20 or 30 genes of Table 3 in term of R/NR ratio value was calculated for each PDX, and the values obtained were used to rank the models.
  • the top 5 genes were: TDRD7, DDX60, IFIT2, ABCA1 and DDX58.
  • the top 10 genes were: TDRD7, DDX60, IFIT2, ABCA1, DDX58, STAT2, IFI44L, DDR2, IFI44 and TLR3.
  • the top 20 genes were: TDRD7, DDX60, IFIT2, ABCA1, DDX58, STAT2, IFI44L, DDR2, IFI44, TLR3, MX1, IFIT1, C19orf66, USP18, SAMD9L, SAMHD1, OASL, CCL5, MUC1 and PLSCR1.
  • the top 30 genes were: TDRD7, DDX60, IFIT2, ABCA1, DDX58, STAT2, IFI44L, DDR2, IFI44, TLR3, MX1, IFIT1, C19orf66, USP18, SAMD9L, SAMHD1, OASL, CCL5, MUC1, PLSCR1, OAS3, B2M, IFIT3, IFIT5, OAS1, LAMP3, IFITM1, TRIM22, RSAD2 and UBE2L6.
  • T311 3,51 T311R 6,59 HBCx-24 14,35 T311R 25,32
  • HBCx-15 1,80 HBCx-27 2,02 T174 2,85 T174 6,51
  • HBCx-27 0,26 HBCx-33 0,50 HBCx-27 0,67 HBCx-27 1,83 HBCx-33 0,23 HBCx7 -0,17 HBCx7 0,32 HBCx-2 -4,23
  • HBCx-30 -2,50 -4,09 HBCx-1 -9,63 HBCX-12B -14,14
  • HBCx-8 -2,81 HBCx-9 -5,73 HBCx-10 -10,16 HBCx-11 -17,39
  • Table 4 GSI calculated by increasing number of genes listed in Table 3. PDXs with GSI above the cut-off value indicated by the 70 percentile are predicted as sensitive to PARP inhibitors; PDXs that showed sensitivity to niraparib are labeled in green: dark green: complete or partial tumor regression; light green: tumor stabilization.
  • DDR DNA damage response
  • EXAMPLE 2 Biomarker for selecting TNBC patients likely to benefit from combination of genotoxic chemotherapy and PARP inhibitors
  • the inventors therefore tested if PARP inhibitors could potentiate the antitumor effect of cyclophosphamide-based chemotherapy (C) in several of the tested TNBC models.
  • Treatments were given at full doses, with PARP inhibitor treatment being initiated 14 days after a single active dose of C.
  • Out of 5 tested TNBC models that are responsive to C two responded to the sequential combination treatment with PARP inhibitors, with a significant increase in TTP over C alone (HBCx-6 and HBCx-14; Figs. 3 & 4 and Table 5).
  • Three other tumors did not respond at all to combination of PARP inhibitor and cyclophosphamide, with no change in TTP over each agent alone (HBCx-1, HBCx-8 and HBCx-33; Figs. 5, 6, 7 and Table 5).
  • Table 5 Median TTP values from experiments shown in Figures 6 to 10, and GSI and HRD scores of the corresponding tumor models. Groups of 8-10 mice received the indicated treatments.
  • C cyclophosphamide. *>228: means that less than half of the mice had their tumor progressing 228 days after treatment start (3/5 tumor-free mice in the C+niraparib group and 8/8 tumor-free mice in the C/olaparib group).
  • red positive GSI and HRD scores.
  • the GSI assay is therefore useful to identify TNBC patients who are more likely to benefit from PARP inhibitors given in combination with cyclophosphamide-based chemotherapy, either in the neoadjuvant setting, or as maintenance therapy following completion of neoadjuvant chemotherapy.

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Abstract

La présente invention concerne un procédé de prédiction de la sensibilité d'un patient atteint d'un cancer à un inhibiteur PARP, comprenant la mesure du GSI dans un échantillon biologique dudit patient. L'invention concerne également un produit contenant un agent anticancéreux et un inhibiteur PARP comme préparation combinée pour l'utilisation simultanée, séparée ou séquentielle dans la thérapie cancéreuse, préférablement la thérapie du cancer du sein triple négatif.
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WO2021119311A1 (fr) * 2019-12-10 2021-06-17 Tempus Labs, Inc. Systèmes et méthodes de prédiction de l'état d'une déficience de recombinaison homologue d'un spécimen
WO2021175236A1 (fr) * 2020-03-03 2021-09-10 上海善准生物科技有限公司 Groupe de gènes liés à la voie de signalisation de l'interféron, produit de diagnostic et application
CN113512587A (zh) * 2021-04-21 2021-10-19 华中科技大学同济医学院附属同济医院 癌细胞耐药性的标志物、逆转癌细胞耐药性的制剂组合及其应用
WO2023224488A1 (fr) * 2022-05-19 2023-11-23 Agendia N.V. Signature de réparation d'adn et prédiction de réponse après une cancérothérapie
CN118621012A (zh) * 2024-06-07 2024-09-10 华中科技大学同济医学院附属同济医院 Treg细胞作为HRD肿瘤的标记物及靶点的应用

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CN110302383A (zh) * 2019-07-29 2019-10-08 深圳先进技术研究院 Trim11基因和蛋白靶点以及抑制剂在乳腺癌中的用途
WO2021119311A1 (fr) * 2019-12-10 2021-06-17 Tempus Labs, Inc. Systèmes et méthodes de prédiction de l'état d'une déficience de recombinaison homologue d'un spécimen
US11164655B2 (en) 2019-12-10 2021-11-02 Tempus Labs, Inc. Systems and methods for predicting homologous recombination deficiency status of a specimen
WO2021175236A1 (fr) * 2020-03-03 2021-09-10 上海善准生物科技有限公司 Groupe de gènes liés à la voie de signalisation de l'interféron, produit de diagnostic et application
CN115279923A (zh) * 2020-03-03 2022-11-01 上海善准医疗科技有限公司 干扰素信号通路相关基因群及诊断产品和应用
CN113512587A (zh) * 2021-04-21 2021-10-19 华中科技大学同济医学院附属同济医院 癌细胞耐药性的标志物、逆转癌细胞耐药性的制剂组合及其应用
CN113512587B (zh) * 2021-04-21 2022-03-18 华中科技大学同济医学院附属同济医院 癌细胞耐药性的标志物、逆转癌细胞耐药性的制剂组合及其应用
WO2023224488A1 (fr) * 2022-05-19 2023-11-23 Agendia N.V. Signature de réparation d'adn et prédiction de réponse après une cancérothérapie
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