WO2024058252A1 - Procédé pour prédire l'effet thérapeutique d'une pharmacothérapie dans le traitement d'un sujet atteint d'un cancer de la prostate métastatique, kit, réseau et biomarqueur - Google Patents

Procédé pour prédire l'effet thérapeutique d'une pharmacothérapie dans le traitement d'un sujet atteint d'un cancer de la prostate métastatique, kit, réseau et biomarqueur Download PDF

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WO2024058252A1
WO2024058252A1 PCT/JP2023/033598 JP2023033598W WO2024058252A1 WO 2024058252 A1 WO2024058252 A1 WO 2024058252A1 JP 2023033598 W JP2023033598 W JP 2023033598W WO 2024058252 A1 WO2024058252 A1 WO 2024058252A1
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single nucleotide
therapy
prognosis
nucleotide polymorphisms
prostate cancer
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真己 塩田
正俊 江藤
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国立大学法人九州大学
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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    • A61P35/00—Antineoplastic agents
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Definitions

  • the present invention relates to methods, kits, arrays, and biomarkers for predicting the therapeutic efficacy of drug therapy in the treatment of subjects with metastatic prostate cancer.
  • Prostate cancer is likely to metastasize to lymph nodes and bones, and may also metastasize to multiple organs such as the lungs and liver.
  • the disease progresses to androgen-insensitive castration-resistant prostate cancer (CRPC) several years after starting initial treatment.
  • CRPC castration-resistant prostate cancer
  • Drug treatment is the first choice for metastatic prostate cancer.
  • Known drug treatments for prostate cancer include androgen deprivation therapy (ADT; also referred to as “castration therapy”), androgen receptor (AR) blockade therapy (ARPI; also referred to as “AR target drug”), and treatment with anticancer drugs.
  • ADT androgen deprivation therapy
  • ARPI androgen receptor blockade therapy
  • anticancer drugs treatment with anticancer drugs.
  • the prognosis particularly with castration therapy which is the fundamental treatment, varies greatly depending on the individual patient.
  • the patient's sensitivity to drugs is important. Therefore, there is a need for a method for predicting the effectiveness and prognosis of each therapy and a biomarker for the prediction in individual patients.
  • SNP Single Nucleotide Polymorphism
  • ADT androgen deprivation therapy
  • AR androgen receptor
  • SNPs that correlate with the therapeutic effects of the anticancer drug docetaxel We disclosed the SNP that
  • the present invention aims to provide a biomarker for predicting the therapeutic effect of drug therapy in the treatment of subjects with metastatic prostate cancer, a prediction method using the biomarker, a kit and an array for prediction. do.
  • the present inventors have identified multiple single nucleotide polymorphisms that are correlated with the therapeutic effect of drug therapy in the treatment of subjects with metastatic prostate cancer.
  • the present invention is based on this novel finding.
  • the present invention relates to, for example, the inventions according to [1] to [19] below.
  • [1] A method for predicting the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer, wherein the drug therapy includes at least one selected from androgen blockade therapy, androgen receptor blockade therapy, and an anticancer drug. , a method comprising the step of detecting the presence or absence of one or more single nucleotide polymorphisms in the subject.
  • One or more of the above single nucleotide polymorphisms are rs76237622, rs117573572, rs2455473, rs13098845, rs76353787, rs7789551, rs117508236, rs78802177, rs77712131, rs80255163, rs19
  • One or more single nucleotide polymorphisms selected from the group consisting of 45293 and rs6478199 The method according to [1], wherein when the presence of the one or more single nucleotide polymorphisms is detected, it is predicted that the metastatic prostate cancer subject will have a good prognosis with androgen deprivation therapy.
  • the one or more single nucleotide polymorphisms include one or more single nucleotide polymorphisms selected from the group consisting of rs1045642, rs1856888, rs523349, rs34550074, and rs4149117, and the presence of the one or more single nucleotide polymorphisms If detected, the method according to [1] is predicted to have a better prognosis with androgen receptor blockade therapy than with anticancer drugs for the subject with metastatic prostate cancer.
  • the one or more single nucleotide polymorphisms include one or more single nucleotide polymorphisms selected from the group consisting of rs1128503, rs1077858, and rs4775936, and the presence of the one or more single nucleotide polymorphisms is detected.
  • the method according to [1] wherein among androgen receptor blockade therapy for the subject with metastatic prostate cancer, a CYP17 inhibitor is predicted to have a better prognosis than an anti-androgen.
  • a kit comprising a reagent for detecting the presence or absence of a single nucleotide polymorphism.
  • One or more of the above single nucleotide polymorphisms are rs76237622, rs117573572, rs2455473, rs13098845, rs76353787, rs7789551, rs117508236, rs78802177, rs77712131, rs80255163, rs19
  • One or more single nucleotide polymorphisms selected from the group consisting of 45293 and rs6478199
  • the kit according to [6] wherein when the presence of the one or more single nucleotide polymorphisms is detected, it is predicted that the metastatic prostate cancer subject will have a good prognosis with androgen deprivation therapy.
  • the one or more single nucleotide polymorphisms include one or more single nucleotide polymorphisms selected from the group consisting of rs1045642, rs1856888, rs523349, rs34550074, and rs4149117, and the presence of the one or more single nucleotide polymorphisms If detected, the kit according to [6] is predicted to have a better prognosis with anticancer drugs than with androgen receptor blockade therapy for the subject with metastatic prostate cancer.
  • the one or more single nucleotide polymorphisms include one or more single nucleotide polymorphisms selected from the group consisting of rs1128503, rs1077858, and rs4775936, and the presence of the one or more single nucleotide polymorphisms is detected.
  • the kit according to [6] which is predicted to have a better prognosis with a CYP17 inhibitor than with an anti-androgen agent among androgen receptor blockade therapy for the subject with metastatic prostate cancer.
  • the above-mentioned one or more single nucleotide polymorphisms include rs78445514 and the presence of rs78445514 is detected, treatment with androgen deprivation therapy, androgen receptor blockade therapy, or anticancer drugs is recommended for patients with metastatic prostate cancer.
  • the kit according to [6] which is predicted to have a poor prognosis.
  • An array comprising a probe for detecting the presence or absence of a single nucleotide polymorphism.
  • One or more of the above single nucleotide polymorphisms are rs76237622, rs117573572, rs2455473, rs13098845, rs76353787, rs7789551, rs117508236, rs78802177, rs77712131, rs80255163, rs19
  • One or more single nucleotide polymorphisms selected from the group consisting of 45293 and rs6478199 The array according to [11], wherein when the presence of the one or more single nucleotide polymorphisms is detected, it is predicted that the metastatic prostate cancer subject will have a good prognosis with androgen deprivation therapy.
  • the one or more single nucleotide polymorphisms include one or more single nucleotide polymorphisms selected from the group consisting of rs1045642, rs1856888, rs523349, rs34550074, and rs4149117, and the presence of the one or more single nucleotide polymorphisms When detected, the array according to [11] is predicted to have a better prognosis with anticancer drugs than with androgen receptor blockade therapy for the subject with metastatic prostate cancer.
  • the one or more single nucleotide polymorphisms include one or more single nucleotide polymorphisms selected from the group consisting of rs1128503, rs1077858, and rs4775936, and the presence of the one or more single nucleotide polymorphisms is detected.
  • the array according to [11] wherein the prognosis is predicted to be better with CYP17 inhibitors than with anti-androgens among androgen receptor blockade therapies for the subject with metastatic prostate cancer.
  • a biomarker for predicting the therapeutic effect of drug therapy in particular, androgen deprivation therapy, androgen receptor blockade therapy, or anticancer drugs in the treatment of subjects with metastatic prostate cancer.
  • the present invention also provides arrays and kits for predicting the therapeutic effects of drug therapy, particularly androgen deprivation therapy, androgen receptor blockade therapy, or anticancer drugs in the treatment of subjects with metastatic prostate cancer; Additionally, a method for predicting the therapeutic effect of drug therapy, particularly androgen blockade therapy, androgen receptor blockade therapy, or an anticancer drug in the treatment of subjects with metastatic prostate cancer can be provided.
  • Example 1 the results of identification of SNPs correlated with progression-free survival rate based on image diagnosis after one year in the development set are shown.
  • Metastatic prostate cancer is prostate cancer in which cancer has metastasized to extraregional lymph nodes, bones, internal organs, etc. Metastatic prostate cancer is clinically diagnosed by imaging tests such as CT and bone scintigraphy.
  • Metastatic prostate cancer is mainly treated with drugs.
  • drugs There are three treatment options for drug therapy for metastatic prostate cancer: androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs, and a combination of these is often used.
  • ADT Androgen Deprivation Therapy
  • ADT is also called castration treatment or hormone therapy, and may be ADT alone or Combined Androgen Blockade (CAB).
  • ADT is performed by administering a luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) that reduces testosterone from the testes, and CAB combines ADT with bicalutamide, a first-generation antiandrogen (androgen inhibitor). , flutamide, etc.
  • LHRH luteinizing hormone-releasing hormone
  • CAB combines ADT with bicalutamide, a first-generation antiandrogen (androgen inhibitor).
  • flutamide etc.
  • Androgen receptor (AR) blockade therapy is performed by administering an AR targeting drug.
  • AR target drugs include CYP17 inhibitors such as abiraterone, second generation anti-androgens such as enzalutamide and apalutamide, bicalutamide, flutamide, and the like.
  • Anticancer drugs used for prostate cancer include taxane anticancer drugs such as docetaxel and cabazitaxel.
  • ADT + AR target drug or ADT + anticancer drug e.g. docetaxel
  • treatment options include ADT +/- abiraterone, ADT +/- enzalutamide, ADT +/- docetaxel, etc. .
  • the biomarker of this embodiment is a biomarker used for predicting the therapeutic effect of drug therapy in the treatment of metastatic prostate cancer, and here, the drug therapy is androgen blockade therapy, androgen receptor blockade therapy, and anticancer therapy.
  • the drug therapy is androgen blockade therapy, androgen receptor blockade therapy, and anticancer therapy.
  • Single nucleotide polymorphism is a type of genetic polymorphism, and refers to a single nucleotide difference between individuals in the genomic DNA of a population of biological species. It is a genetic polymorphism caused by single nucleotide substitution due to mutation. The frequency of single nucleotide polymorphisms is said to be more than 1% of the population, and depending on their function, there are rSNPs (regulatory SNPs) that cause mutations in the promoter region, cSNPs (coding SNPs) that cause mutations in the exon region, and cSNPs (coding SNPs) that cause mutations in the exon region.
  • rSNPs regulatory SNPs
  • cSNPs coding SNPs
  • cSNPs coding SNPs
  • sSNPs small SNPs
  • iSNPs intron SNPs
  • gSNPs geneomics SNPs
  • Medical treatment that aims to avoid side effects and obtain efficient therapeutic effects by testing the patient's SNP before taking medication and determining the appropriate dosage based on the genotype, that is, genetic More appropriate medical care based on information based on each patient's constitution is called "personalized medicine.”
  • the rs number is a number that refers to the SNP, and indicates the registration number of the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP/) of the National Center for Biotechnology Information (NCBI).
  • the sample used for single nucleotide polymorphism analysis is not particularly limited as long as it contains genomic DNA, and may be, for example, blood, tissue cells such as oral mucosal cells, body hair such as hair, urine, etc., and is preferably Whole blood, plasma or serum. Analysis of single nucleotide polymorphisms can be performed, for example, by sequence analysis, TaqMan PCR method, invader method, etc. Examples of the devices used include a sequencer, a real-time PCR device, and a fluorescence spectrophotometer.
  • the biomarker is a biomarker for predicting the prognosis of androgen deprivation therapy (ADT) for subjects with metastatic prostate cancer.
  • the biomarkers of this embodiment include rs76237622, rs117573572, rs2455473, rs13098845, rs76353787, rs7789551, rs117508236, rs78802177, rs77712131, rs80255163, rs1945 It may consist of a single nucleotide polymorphism selected from the group consisting of 293 and rs6478199, Among these 12 SNPs, it is particularly preferable that the SNP consists of a single nucleotide polymorphism selected from the group consisting of rs76237622, rs117573572, rs2455473, rs117508236,
  • the 12 biomarkers according to this embodiment are single nucleotide polymorphisms that are significantly detected in a group of patients with good prognosis in metastatic prostate cancer subjects who have undergone androgen deprivation therapy (ADT) in genome-wide SNP analysis. be. Since these single nucleotide polymorphisms have a high correlation with ADT, they can be used as a biomarker for predicting the therapeutic effect of ADT. In the genomic DNA analysis, if at least one of the 12 biomarker SNPs according to this embodiment is detected, it can be predicted that treatment with ADT will bring about a good prognosis.
  • the 12 biomarkers according to this embodiment may be used alone, or in order to further improve prediction accuracy, multiple (2 or more, 3 or more, or 4 or more) markers may be used in combination. good.
  • rs76237622 exists 5787 bp upstream of the PRR27 gene.
  • the PRR27 gene is located on human chromosome 4.
  • the PRR27 gene is secreted extracellularly from salivary glands as exosomes, but its function is not well known.
  • rs117573572 exists in the intron region of the MTAP gene.
  • the MTAP gene is located on human chromosome 9.
  • the MTAP gene is an enzyme that controls polyamine metabolism, and its expression has been reported to be defective in many cancers.
  • rs2455473 is present near the ICE1 gene and 152353 bp downstream of the ICE1 gene.
  • the ICE1 gene is located on human chromosome 5.
  • the ICE1 gene is known to be involved in processes such as control of intracellular protein transport, control of transcription by RNA polymerase III, and snRNA transcription through protein-polymer adapter activity.
  • rs13098845 is present near the TPRG1 gene and 73861 bp downstream of the TPRG1 gene.
  • the TPRG1 gene is present on human chromosome 3. Although the function of the TPRG1 gene is unknown, it has been reported that the expression of the TPRG1 gene is altered in various cancers.
  • rs76353787 is present near the NEB gene and 17155 bp upstream of the NEB gene.
  • the NEB gene is located on human chromosome 2.
  • the NEB gene is a constituent protein of striated muscle myofibrils, and is known to play an important role in the formation of myofibrils.
  • rs7789551 exists in the intron region of a gene on human chromosome 7.
  • rs117508236 exists in the intron region of the FAF1 gene.
  • the FAF1 gene is present on human chromosome 1.
  • the FAF1 gene binds to the FAS antigen, which is an apoptosis regulator, and has the function of promoting apoptosis, and has been reported to be malfunctioning in cancer.
  • rs78802177 exists in the intron region of the CNTN6 gene.
  • the CNTN6 gene is located on human chromosome 3.
  • the CNTN6 gene is a glycosylphosphatidylinositol (GPI)-anchored nerve cell membrane protein and is known to function as a cell adhesion molecule.
  • GPI glycosylphosphatidylinositol
  • rs77712131 exists in the intron region of the TBX15 gene.
  • the TBX15 gene is present on human chromosome 1.
  • the TBX15 gene is a member of the T-box family and is known to function as a transcription factor that controls developmental processes.
  • rs80255163 exists near the LOC101927838 gene and 43699 bp upstream of the LOC101927838 gene.
  • the LOC101927838 gene exists on human chromosome 5. The function of the LOC101927838 gene is unknown.
  • rs1945293 is present near the KRT85 gene and 26845 bp downstream of the KRT85 gene.
  • the KRT85 gene is located on human chromosome 12.
  • the KRT85 gene is a member of the keratin family and is known to function as a constituent protein of keratin, which forms hair and nails.
  • rs6478199 is present near the DEC1 gene and 240514 bp downstream of the DEC1 gene.
  • the DEC1 gene is present on human chromosome 9. Although the function of the DEC1 gene is unknown, deletion or decreased expression has been reported in esophageal squamous cell carcinoma.
  • the 12 biomarkers according to this embodiment can be used, for example, in a method, kit, or array for predicting the therapeutic effect of androgen deprivation therapy (ADT) on a subject with metastatic prostate cancer.
  • ADT androgen deprivation therapy
  • the biomarker of one embodiment is a biomarker for predicting whether the prognosis is better with androgen receptor blockade therapy or anticancer drugs for subjects with metastatic prostate cancer.
  • the biomarker of this embodiment may consist of a single nucleotide polymorphism selected from the group consisting of rs1045642, rs1856888, rs523349, rs34550074, and rs4149117, and in particular, the AG/GG allele of rs1045642, the CC/CT of rs1856888 It may consist of a single nucleotide polymorphism selected from the group consisting of the GG allele of rs523349, and the TT allele of rs34550074.
  • the five biomarkers according to this embodiment are significantly detected in a patient group with a better prognosis due to androgen receptor blockade therapy (AR target drug) than anticancer drugs (e.g. docetaxel) for metastatic prostate cancer subjects.
  • AR target drug e.g. anticancer drugs
  • This is a single nucleotide polymorphism. Depending on the presence or absence of detection of these single nucleotide polymorphisms, it is possible to predict which patients are expected to benefit from anticancer drug therapy and which patients are expected to benefit from AR target drugs.
  • at least one of the five biomarker SNPs according to this embodiment is detected in genomic DNA analysis, androgen receptor blockade therapy has a better prognosis than anticancer drugs for patients with metastatic prostate cancer. can be predicted to be good.
  • the five biomarkers according to this embodiment may be used alone, or may be used in combination of multiple (2 or more, 3 or more, or 4 or more) markers to further improve prediction accuracy. good.
  • rs1045642 exists in the exon region of the ABCB1 gene and causes a silent mutation.
  • the ABCB1 gene is located on human chromosome 7.
  • the ABCB1 gene is a member of the ABC transporter family and functions as a drug efflux pump. It is known that the excretion of anticancer drugs from within cancer cells causes resistance to various anticancer drugs.
  • rs1856888 is present near the HSD3B1 gene and 13048 bp upstream of the HSD3B1 gene.
  • the HSD3B1 gene is present on human chromosome 1.
  • the HSD3B1 gene is known to be an essential enzyme for the synthesis of steroids including androgens.
  • rs523349 exists in the exon region of the SRD5A2 gene and causes a missense mutation.
  • the SRD5A2 gene is located on human chromosome 2.
  • the SRD5A2 gene is expressed in tissues such as the prostate, and is known to metabolize testosterone to dihydrotestosterone, which is more active.
  • rs34550074 exists in the exon region of the SLCO2A1 gene and causes a missense mutation.
  • the SLCO2A1 gene is located on human chromosome 3.
  • the SLCO2A1 gene is known to function as a prostaglandin transporter.
  • rs4149117 exists in the exon region of the SLCO1B3 gene and causes a missense mutation.
  • the SLCO1B3 gene is located on human chromosome 12.
  • the SLCO1B3 gene is known to function as an organic anion transporter.
  • a method, kit, or array for predicting a comparison between the prognosis due to anticancer drugs and the prognosis due to androgen receptor blockade therapy for a subject with metastatic prostate cancer can be used.
  • a method, kit, or array for predicting a comparison between the prognosis due to anticancer drugs and the prognosis due to androgen receptor blockade therapy for a subject with metastatic prostate cancer can be used. can be used.
  • the biomarker is a biomarker for predicting whether anti-androgen agents or CYP17 inhibitors have a better prognosis among androgen receptor blockade therapy for subjects with metastatic prostate cancer.
  • the biomarker of this embodiment may consist of one or more single nucleotide polymorphisms selected from the group consisting of rs1128503, rs1077858, and rs4775936, and in particular, the AA/AG allele of rs1128503, the GG allele of rs1077858, and a single nucleotide polymorphism selected from the group consisting of the CT/TT allele of rs4775936.
  • the three biomarkers according to this embodiment are used to treat patients with metastatic prostate cancer using a CYP17 inhibitor (e.g. This is a single nucleotide polymorphism that is significantly detected in patients with a good prognosis due to abiraterone. These single nucleotide polymorphisms are highly correlated with the difference in the therapeutic effects of anti-androgens and CYP17 inhibitors.
  • a CYP17 inhibitor e.g. This is a single nucleotide polymorphism that is significantly detected in patients with a good prognosis due to abiraterone.
  • the three biomarkers according to this embodiment may be used alone, or a plurality of (two, three) markers may be used in combination to further improve prediction accuracy.
  • rs1128503 exists in the exon region of the ABCB1 gene and causes a silent mutation.
  • the ABCB1 gene is located on human chromosome 7.
  • the ABCB1 gene is a member of the ABC transporter family and functions as a drug efflux pump. It is known that the excretion of anticancer drugs from within cancer cells causes resistance to various anticancer drugs.
  • rs1077858 is present in the intron region of the SLCO2B1 gene.
  • the SLCO2B1 gene is present on human chromosome 11.
  • the SLCO2B1 gene is known to function as an organic anion transporter, including sulfated steroids.
  • rs4775936 exists in the intron region of the CYP19A1 gene.
  • the CYP19A1 gene is located on human chromosome 15.
  • the CYP19A1 gene is known to function as a variety of monooxygenases, including the metabolism of androgens to estrogens.
  • a method for comparing the prognosis with an anti-androgen agent and the prognosis with a CYP17 inhibitor in androgen receptor blockade therapy for a subject with metastatic prostate cancer can be used in kits or arrays.
  • the biomarker is a biomarker for predicting a poor prognosis of treatment with any of androgen deprivation therapy, androgen receptor deprivation therapy, and anticancer drugs for a subject with metastatic prostate cancer.
  • the biomarker of this embodiment consists of rs78445514.
  • the biomarker according to the present embodiment is one that is significantly detected in a patient group with poor prognosis when treated with androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs for patients with metastatic prostate cancer. It is a nucleotide polymorphism. This single nucleotide polymorphism has a high correlation with the therapeutic effects of androgen deprivation therapy, androgen receptor blockade therapy, and anticancer drugs. On the other hand, the prognosis of androgen blockade therapy, androgen receptor blockade therapy, and treatment with anticancer drugs can be predicted.
  • rs78445514 exists in the intron region of the AR gene.
  • the AR gene is present on the human X chromosome.
  • the AR gene is a member of the nuclear hormone receptor superfamily and is known to function as a transcription factor activated by androgens.
  • biomarker for example, a method for predicting that the prognosis of treatment with androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs is poor for a subject with metastatic prostate cancer; It can be used in kits or arrays.
  • a method for predicting the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer includes detecting the presence or absence of one or more single nucleotide polymorphisms in the subject, wherein the method comprises:
  • the drug therapy includes at least one selected from androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs.
  • the single nucleotide polymorphism used in the prediction method of this embodiment may be the above-mentioned biomarker.
  • a method for predicting the therapeutic effect of drug therapy in treating a subject with metastatic prostate cancer is a method for predicting prognosis by androgen deprivation therapy, and the method for predicting prognosis by androgen deprivation therapy includes rs76237622, rs117573572, rs2455473, rs13098845, rs76353787, rs7789551, rs117508236, rs78802177, rs77712131, rs80255163, rs1945293 and rs6478199; more than one base If the presence of the polymorphism is detected, this method predicts that the prognosis of androgen deprivation therapy will be good for the subject with metastatic prostate cancer.
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the 12 biomarkers according to this embodiment.
  • the 12 biomarkers according to this embodiment are single bases that are significantly detected in a group of patients with good prognosis in metastatic prostate cancer subjects who have undergone androgen deprivation therapy (ADT) in genome-wide SNP analysis. It is polymorphic. Since these single nucleotide polymorphisms have a high correlation with ADT, according to the method for predicting the prognosis based on androgen deprivation therapy according to the present embodiment, it is possible to predict the prognosis based on androgen deprivation therapy for each patient.
  • the single nucleotide polymorphism to be detected is one or more types selected from the group consisting of 12 biomarkers according to the present embodiment, preferably two or more types, three or more types, four or more types, five or more types, and six types. Single nucleotide polymorphisms of more than one species, seven or more types, eight or more types, nine or more types, ten or more types, eleven or more types, or all 12 types.
  • Preferred single nucleotide polymorphisms include one or more, two or more, three or more, four or more, five or more, and six selected from the group consisting of rs76237622, rs117573572, rs2455473, rs117508236, rs77712131, rs80255163, and rs6478199. Examples include more than one species, or all seven types, particularly rs76237622 and/or rs117573572, and more particularly a SNP panel consisting of a plurality of single nucleotide polymorphisms.
  • the step of detecting the presence or absence of a single nucleotide polymorphism includes a step capable of detecting the presence or absence of a single nucleotide polymorphism (SNP), which is the 12 biomarkers according to the present embodiment, there are no particular limitations. Not done.
  • SNP single nucleotide polymorphism
  • the operations in the detection step and the devices and reagents used vary depending on the detection method, but can be appropriately selected by those skilled in the art.
  • the method for detecting SNPs is not particularly limited, and for example, the RFLP method (Restriction Fragment Length Polymorphism), single-stranded DNA is subjected to RFLP PCR, electrophoresis is performed while maintaining the three-dimensional structure, and the SSCP method (Single Examples include conventional SNP analysis methods such as Strand Conformation Polymorphism). Also included are SNP analysis methods such as TaqMan PCR method, SNaP shot method, Invander method, mass spectrometry, and DNA chip method, and DNA microarray method.
  • the method for predicting the prognosis by androgen deprivation therapy includes, after the detection step, a step of predicting the prognosis by androgen deprivation therapy based on the detection result of the presence or absence of the one or more single nucleotide polymorphisms. include. In the prediction step, if even one of the one or more single nucleotide polymorphisms to be detected is detected, it is possible to predict that the prognosis of androgen deprivation therapy for a subject with metastatic prostate cancer is good.
  • the prediction accuracy is thought to be, but if even one type is detected, there is a possibility that androgen deprivation therapy will have a better prognosis for patients with metastatic prostate cancer.
  • the method for predicting prognosis using androgen deprivation therapy according to this embodiment is preferably performed before performing androgen deprivation therapy. Since human SNPs are thought to remain unchanged throughout life, the prognosis prediction method using androgen deprivation therapy according to this embodiment only needs to be performed once in a lifetime; however, it may be performed two or more times to further improve prediction accuracy. Good too. Another embodiment is to apply androgen deprivation therapy (e.g., surgical castration, gonadotropin therapy, The present invention provides a therapeutic method using degarelix, a releasing hormone (GnRH) antagonist, or therapy using a GnRH agonist (leuprorelin or goserelin).
  • GnRH releasing hormone
  • a method for predicting the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer is a method for predicting whether the prognosis is better with either androgen receptor blockade therapy or anticancer drugs, and the prediction method includes: , rs1045642, rs1856888, rs523349, rs34550074 and rs4149117. This is a method in which androgen receptor blockade therapy is predicted to have a better prognosis than anticancer drugs for patients with metastatic prostate cancer.
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the five biomarkers according to this embodiment.
  • the five biomarkers according to this embodiment are single nucleotide polymorphisms that are significantly detected in patients with metastatic prostate cancer who have a better prognosis with androgen receptor blockade therapy than with anticancer drugs. It is.
  • These single nucleotide polymorphisms are highly correlated with the difference in prognosis between anticancer drugs and androgen receptor blockade therapy. According to the method of predicting the difference between cancer and cancer, it is possible to predict whether or not the prognosis of androgen receptor blockade therapy will be better than that of anticancer drugs for individual patients.
  • the single nucleotide polymorphism to be detected is one or more types selected from the group consisting of five biomarkers according to this embodiment, preferably two or more types, three or more types, four or more types, or all five types. It is a nucleotide polymorphism.
  • Preferred single nucleotide polymorphisms include one or more, two or more, three or more selected from the group consisting of the AG/GG allele of rs1045642, the CC/CT allele of rs1856888, the GG allele of rs523349, and the TT allele of rs34550074. , or all four types, particularly SNP panels consisting of two or more types, three or more types, or all four types.
  • the step of detecting the presence or absence of a single nucleotide polymorphism includes a step of detecting the presence or absence of a single nucleotide polymorphism (SNP), which is the five biomarkers according to this embodiment, there are no particular limitations. Not done.
  • SNP single nucleotide polymorphism
  • the prediction method according to the present embodiment is based on the detection result of the presence or absence of the one or more single nucleotide polymorphisms after the detection step, and the prediction method is based on the detection result of the presence or absence of the one or more single nucleotide polymorphisms, and the prediction method is based on the detection result of the presence or absence of the one or more single nucleotide polymorphisms.
  • the target patient in whom two or more, three or more, four or more, and more preferably all of the one or more single nucleotide polymorphisms to be detected are detected will receive androgen receptor blockade rather than anticancer drugs. It is possible to predict a good prognosis with therapy.
  • the prediction method of the present embodiment is for presenting the possibility that androgen receptor blockade therapy has a better prognosis than anticancer drugs, and does not include diagnosis or treatment (medical treatment) by a doctor.
  • the prediction method according to this embodiment is preferably performed before treatment with anticancer drugs and androgen receptor blockade therapy. Since it is thought that human SNPs do not change over a lifetime, the prediction method according to this embodiment may be performed once in a lifetime, but may be performed two or more times to further improve prediction accuracy.
  • Another embodiment uses the method of predicting whether the prognosis is better with androgen receptor blockade therapy or an anticancer drug according to the present embodiment, and uses the method of predicting whether the prognosis is better with androgen receptor blockade therapy than with anticancer drugs.
  • the present invention provides a treatment method for treating patients with metastatic prostate cancer who are predicted to have a good condition with androgen deprivation therapy.
  • a method for predicting the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer is a method for predicting whether the prognosis is good for either an antiandrogen agent or a CYP17 inhibitor, and the prediction method includes rs1128503, the step of detecting the presence or absence of one or more single nucleotide polymorphisms selected from the group consisting of rs1077858 and rs4775936, and when the presence of the one or more single nucleotide polymorphisms is detected, the metastatic prostate gland Among androgen receptor blockade therapy for cancer subjects, it is predicted that a CYP17 inhibitor will have a better prognosis than an anti-androgen.
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the three biomarkers according to this embodiment.
  • the three biomarkers according to this embodiment are single nucleotide polymorphisms that are significantly detected in patients with metastatic prostate cancer who have a better prognosis with CYP17 inhibitors than with anti-androgens. be.
  • the single nucleotide polymorphism to be detected is one or more types, preferably two or more or three types of single nucleotide polymorphisms selected from the group consisting of three biomarkers according to this embodiment.
  • Preferred single nucleotide polymorphisms include one or more, two or more, or three selected from the group consisting of the AA/AG allele of rs1128503, the GG allele of rs1077858, and the CT/TT allele of rs4775936, and particularly Examples include SNP panels consisting of two or three or more types.
  • the step of detecting the presence or absence of a single nucleotide polymorphism includes a step capable of detecting the presence or absence of a single nucleotide polymorphism (SNP), which is the three biomarkers according to this embodiment, there are no particular limitations. Not done.
  • SNP single nucleotide polymorphism
  • the prediction method predicts the difference between the prognosis caused by an anti-androgen agent and the prognosis caused by a CYP17 inhibitor based on the detection result of the presence or absence of the one or more single nucleotide polymorphisms after the detection step. including steps to In the prediction step, if even one of the one or more single nucleotide polymorphisms to be detected is detected, CYP17 inhibition is preferred to anti-androgen drugs in androgen receptor blockade therapy for patients with metastatic prostate cancer. It can be predicted that the prognosis will be good depending on the drug. The more types of single nucleotide polymorphisms that are detected, the higher the prediction accuracy is thought to be.
  • target patients in whom two or three of the one or more single nucleotide polymorphisms to be detected are detected are treated with androgen receptor blockade therapy for patients with metastatic prostate cancer, rather than anti-androgen drugs. It can be predicted that the prognosis will be better with CYP17 inhibitors.
  • the prediction method of the present embodiment is intended to present the possibility that a CYP17 inhibitor may have a better prognosis than an anti-androgen agent among androgen receptor blockade therapy for patients with metastatic prostate cancer. does not include diagnosis or treatment (medical treatment).
  • the prediction method according to this embodiment is preferably performed before treatment with an anti-androgen and a CYP17 inhibitor. Since it is thought that human SNPs do not change over a lifetime, the prediction method according to this embodiment may be performed once in a lifetime, but may be performed two or more times to further improve prediction accuracy. Another embodiment is to use the prediction method according to the present embodiment to treat patients with metastatic prostate cancer who are predicted to have a better prognosis with a CYP17 inhibitor than with an anti-androgen in androgen receptor blockade therapy.
  • a method of treatment is provided that involves treatment with a CYP17 inhibitor (eg, abiraterone).
  • a method for predicting the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer is a method for predicting the prognosis of androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs; If the presence of rs78445514 is detected, the prognosis of treatment with any of androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs for metastatic prostate cancer subjects is determined. This method is predicted to be defective.
  • the single nucleotide polymorphism rs78445514 which is the target of detection, is used in patients with metastatic prostate cancer who have a poor prognosis when treated with androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs.
  • This is a significantly detected single nucleotide polymorphism.
  • This single nucleotide polymorphism has a high correlation with the therapeutic effects of androgen deprivation therapy, androgen receptor blockade therapy, and anticancer drugs. It is possible to predict whether a patient with metastatic prostate cancer will have a poor prognosis when treated with androgen blockade therapy, androgen receptor blockade therapy, or an anticancer drug.
  • the step of detecting the presence or absence of a single nucleotide polymorphism is not particularly limited as long as it includes a step that can detect the presence or absence of a single nucleotide polymorphism (SNP), which is a biomarker according to this embodiment.
  • SNP single nucleotide polymorphism
  • the specific detection method is as described above.
  • the prediction method includes, after the detection step, a step of predicting the prognosis due to androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs based on the detection result of the presence or absence of rs78445514.
  • a step of predicting the prognosis due to androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs based on the detection result of the presence or absence of rs78445514.
  • rs78445514 which is the detection target, it can be predicted that the prognosis for metastatic prostate cancer subjects is poor regardless of androgen blockade therapy, androgen receptor blockade therapy, or anticancer drugs.
  • the prediction method of the present embodiment is intended to present the possibility that the prognosis of treatment with androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs will be poor for patients with metastatic prostate cancer. Yes, and does not include diagnosis or treatment (medical treatment) by a doctor.
  • the prediction method according to this embodiment is preferably performed before androgen blockade therapy, androgen receptor blockade therapy, and treatment with anticancer drugs. Since it is thought that human SNPs do not change over a lifetime, the prediction method according to this embodiment may be performed once in a lifetime, but may be performed two or more times to further improve prediction accuracy.
  • Another embodiment is metastatic prostate cancer that is predicted to have a poor prognosis after treatment with androgen deprivation therapy, androgen receptor deprivation therapy, and anticancer drugs, using the prediction method according to the present embodiment.
  • a therapeutic method is provided in which a subject is treated with a therapy other than androgen blockade therapy, androgen receptor blockade therapy, and therapy using an anticancer drug (eg, radium-223 or a molecular target drug).
  • an anticancer drug eg, radium-223 or a molecular target drug
  • a kit for predicting the therapeutic effect of drug therapy in treating a subject with metastatic prostate cancer includes a reagent for detecting the presence or absence of one or more single nucleotide polymorphisms in the subject;
  • Drug therapy includes androgen deprivation therapy, androgen receptor blockade therapy, and anticancer drugs.
  • the single nucleotide polymorphism to be detected by the prediction kit of this embodiment may be the above-mentioned biomarker.
  • kits for predicting the therapeutic effect of drug therapy in treating a subject with metastatic prostate cancer is a kit for predicting the prognosis by androgen deprivation therapy, and the kit for predicting the prognosis by androgen deprivation therapy includes rs76237622, rs117573572, rs2455473, A reagent for detecting the presence or absence of one or more single nucleotide polymorphisms selected from the group consisting of rs13098845, rs76353787, rs7789551, rs117508236, rs78802177, rs77712131, rs80255163, rs1945293 and rs6478199, One or more of the above If the presence of a single nucleotide polymorphism is detected, this kit predicts a good prognosis for the above-mentioned meta
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the 12 biomarkers according to this embodiment.
  • the 12 biomarkers according to this embodiment are single bases that are significantly detected in a group of patients with good prognosis in metastatic prostate cancer subjects who have undergone androgen deprivation therapy (ADT) in genome-wide SNP analysis. It is polymorphic. Since these single nucleotide polymorphisms have a high correlation with ADT, the kit for predicting the prognosis due to androgen deprivation therapy according to the present embodiment can predict the prognosis due to androgen deprivation therapy for each patient.
  • the single nucleotide polymorphism to be detected is one or more, preferably two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or all twelve types of single nucleotide polymorphisms selected from the group consisting of the twelve biomarkers according to this embodiment.
  • Preferred single nucleotide polymorphisms include one or more, two or more, three or more, four or more, five or more, six or more, or all seven types selected from the group consisting of rs76237622, rs117573572, rs2455473, rs117508236, rs77712131, rs80255163, and rs6478199, particularly rs76237622 and/or rs117573572, and more particularly an SNP panel consisting of a plurality of single nucleotide polymorphisms.
  • the kit for predicting prognosis by androgen deprivation therapy includes one or more biomarkers selected from the group consisting of 12 biomarkers according to this embodiment, preferably two or more, three or more, four or more, Including reagents for detecting the presence or absence of 5 or more types, 6 or more types, 7 or more types, 8 or more types, 9 or more types, 10 or more types, 11 or more types, or all 12 types of single nucleotide polymorphisms.
  • such reagents may include, for example, primers or probes corresponding to single nucleotide polymorphisms, and may further include restriction enzymes, polymerases, dNTPs, ddNTPs, etc., and further include buffers, instruction manuals, etc. It may be included.
  • Primers are preferably designed to amplify a region containing a single nucleotide polymorphism and have restriction enzyme sites at appropriate locations, and probes are designed to be able to hybridize with single nucleotide polymorphisms. It is preferable to do so.
  • the primers, probes, and ddNTPs may be labeled with a fluorescent label or the like in order to be detected.
  • Reagents included in the kit may vary depending on the SNP analysis method. For example, in the case of conventional SNP analysis methods such as RFLP method and SSCP method, it is sufficient to include primers corresponding to single nucleotide polymorphisms, and in addition, reagents necessary for PCR reaction, such as polymerase, polynucleotide, and restriction enzymes. etc. may be included. In the case of the SNaP shot method, a primer and a fluorescently labeled ddNTP may be included, and a single base extension reaction is performed using these and analyzed by capillary electrophoresis. In the case of a comprehensive SNP analysis method using a probe, a fluorescently labeled probe may be included, and a reagent for labeling the genomic DNA of the test subject may also be included.
  • kits for predicting the therapeutic effect of drug therapy in treating a subject with metastatic prostate cancer is a kit for predicting whether the prognosis is better with either androgen receptor blockade therapy or anticancer drugs, and the prediction kit is , rs1045642, rs1856888, rs523349, rs34550074 and rs4149117. If detected, this kit predicts that the prognosis of the metastatic prostate cancer subject will be better with anticancer drugs than with androgen receptor blockade therapy.
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the five biomarkers according to this embodiment.
  • the five biomarkers according to this embodiment are single nucleotide polymorphisms that are significantly detected in patients with metastatic prostate cancer who have a better prognosis with androgen receptor blockade therapy than with anticancer drugs. It is.
  • These single nucleotide polymorphisms are highly correlated with the difference in prognosis between anticancer drugs and androgen receptor blockade therapy. According to the Difference Prediction Kit, it is possible to predict for individual patients whether or not the prognosis will be better with androgen receptor blockade therapy than with anticancer drugs.
  • the single nucleotide polymorphism to be detected is one or more types selected from the group consisting of five biomarkers according to this embodiment, preferably two or more types, three or more types, four or more types, or all five types. It is a nucleotide polymorphism.
  • Preferred single nucleotide polymorphisms include one or more, two or more, three or more selected from the group consisting of the AG/GG allele of rs1045642, the CC/CT allele of rs1856888, the GG allele of rs523349, and the TT allele of rs34550074. , or all four types, particularly SNP panels consisting of two or more types, three or more types, or all four types.
  • the kit for predicting the difference between the prognosis due to anticancer drugs and the prognosis due to androgen receptor blockade therapy according to the present embodiment is preferably one or more biomarkers selected from the group consisting of five biomarkers according to the present embodiment. It is sufficient to include a reagent for detecting the presence or absence of two or more types, three or more types, four or more types, or all five types of single nucleotide polymorphisms, and such reagents include, for example, primers corresponding to single nucleotide polymorphisms.
  • it may contain a probe, and may further contain restriction enzymes, polymerases, dNTPs, ddNTPs, etc., and may further contain buffers, instruction manuals, and the like.
  • Primers are preferably designed to amplify a region containing a single nucleotide polymorphism and have restriction enzyme sites at appropriate locations, and probes are designed to be able to hybridize with single nucleotide polymorphisms. It is preferable to do so.
  • the primers, probes, and ddNTPs may be labeled with a fluorescent label or the like in order to be detected.
  • Reagents included in the kit may vary depending on the SNP analysis method.
  • primers corresponding to single nucleotide polymorphisms it is sufficient to include primers corresponding to single nucleotide polymorphisms, and in addition, reagents necessary for PCR reaction, such as polymerase, polynucleotide, and restriction enzymes. etc. may be included.
  • reagents necessary for PCR reaction such as polymerase, polynucleotide, and restriction enzymes. etc.
  • a primer and a fluorescently labeled ddNTP may be included, and a single base extension reaction is performed using these and analyzed by capillary electrophoresis.
  • a fluorescently labeled probe may be included, and a reagent for labeling the genomic DNA of the test subject may also be included.
  • kits for predicting the therapeutic effect of drug therapy in treating a subject with metastatic prostate cancer is a kit for predicting whether the prognosis is good for either an anti-androgen agent or a CYP17 inhibitor, and the prediction kit includes rs1128503, It includes a reagent for detecting the presence or absence of one or more single nucleotide polymorphisms selected from the group consisting of rs1077858 and rs4775936, and when the presence of the one or more single nucleotide polymorphisms is detected, the above metastasis
  • This kit is predicted to provide a better prognosis with a CYP17 inhibitor than with an anti-androgen agent among androgen receptor blockade therapy for men with prostate cancer.
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the three biomarkers according to this embodiment.
  • the three biomarkers according to this embodiment are single nucleotide polymorphisms that are significantly detected in patients with metastatic prostate cancer who have a better prognosis with CYP17 inhibitors than with anti-androgens. be.
  • the single nucleotide polymorphism to be detected is one or more types, preferably two or more or three types of single nucleotide polymorphisms selected from the group consisting of three biomarkers according to this embodiment.
  • Preferred single nucleotide polymorphisms include one or more, two or more, or three selected from the group consisting of the AA/AG allele of rs1128503, the GG allele of rs1077858, and the CT/TT allele of rs4775936, and particularly Examples include SNP panels consisting of two or three or more types.
  • the kit for predicting the difference between the prognosis due to an anti-androgen agent and the prognosis due to a CYP17 inhibitor includes one or more, preferably two or three biomarkers selected from the group consisting of three biomarkers according to the present embodiment. It is sufficient to include a reagent for detecting the presence or absence of a single nucleotide polymorphism in a species, and such a reagent may include, for example, a primer or probe corresponding to the single nucleotide polymorphism, and furthermore, a restriction enzyme, a polymerase, a dNTP, etc. , ddNTP, etc., and may further contain a buffer, an instruction manual, etc.
  • Primers are preferably designed to amplify a region containing a single nucleotide polymorphism and have restriction enzyme sites at appropriate locations, and probes are designed to be able to hybridize with single nucleotide polymorphisms. It is preferable to do so.
  • the primers, probes, and ddNTPs may be labeled with a fluorescent label or the like in order to be detected.
  • Reagents included in the kit may vary depending on the SNP analysis method.
  • primers corresponding to single nucleotide polymorphisms it is sufficient to include primers corresponding to single nucleotide polymorphisms, and in addition, reagents necessary for PCR reaction, such as polymerase, polynucleotide, and restriction enzymes. etc. may be included.
  • reagents necessary for PCR reaction such as polymerase, polynucleotide, and restriction enzymes. etc.
  • a primer and a fluorescently labeled ddNTP may be included, and a single base extension reaction is performed using these and analyzed by capillary electrophoresis.
  • a fluorescently labeled probe may be included, and a reagent for labeling the genomic DNA of the test subject may also be included.
  • kits for predicting the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer is a kit for predicting the prognosis of androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs; contains a reagent for detecting the presence or absence of rs78445514, and if the presence of rs78445514 is detected, the above-mentioned metastatic prostate cancer subject is treated with any of androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs. This method also predicts a poor prognosis.
  • the single nucleotide polymorphism rs78445514 which is the target of detection, is used in patients with metastatic prostate cancer who have a poor prognosis when treated with androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs.
  • This is a significantly detected single nucleotide polymorphism.
  • This single nucleotide polymorphism has a high correlation with the therapeutic effects of androgen deprivation therapy, androgen receptor blockade therapy, and anticancer drugs. It is possible to predict whether a patient with metastatic prostate cancer will have a poor prognosis when treated with androgen blockade therapy, androgen receptor blockade therapy, or an anticancer drug.
  • the kit for predicting prognosis using androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs may include a reagent for detecting the presence or absence of rs78445514, and such a reagent may include, for example, a single base. It may contain primers or probes corresponding to the polymorphism, and may further contain restriction enzymes, polymerases, dNTPs, ddNTPs, etc., and may further contain buffers, instruction manuals, and the like.
  • Primers are preferably designed to amplify a region containing a single nucleotide polymorphism and have restriction enzyme sites at appropriate locations, and probes are designed to be able to hybridize with single nucleotide polymorphisms. It is preferable to do so.
  • the primers, probes, and ddNTPs may be labeled with a fluorescent label or the like in order to be detected.
  • Reagents included in the kit may vary depending on the SNP analysis method.
  • primers corresponding to single nucleotide polymorphisms it is sufficient to include primers corresponding to single nucleotide polymorphisms, and in addition, reagents necessary for PCR reaction, such as polymerase, polynucleotide, and restriction enzymes. etc. may be included.
  • reagents necessary for PCR reaction such as polymerase, polynucleotide, and restriction enzymes. etc.
  • a primer and a fluorescently labeled ddNTP may be included, and a single base extension reaction is performed using these and analyzed by capillary electrophoresis.
  • a fluorescently labeled probe may be included, and a reagent for labeling the genomic DNA of the test subject may also be included.
  • an array for predicting the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer comprises a probe for detecting the presence or absence of one or more single nucleotide polymorphisms in the subject;
  • the drug therapy includes androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs.
  • the single nucleotide polymorphism to be detected by the prediction array of this embodiment may be the above-mentioned biomarker.
  • the predictive array for the therapeutic effect of drug therapy in treating a subject with metastatic prostate cancer is a predictive array for prognosis by androgen deprivation therapy
  • the predictive array for prognosis by androgen deprivation therapy includes rs76237622, rs117573572, rs2455473, A probe for detecting the presence or absence of one or more single nucleotide polymorphisms selected from the group consisting of rs13098845, rs76353787, rs7789551, rs117508236, rs78802177, rs77712131, rs80255163, rs1945293 and rs6478199, one or more types If the presence of a single nucleotide polymorphism is detected, this array is predicted to have a good prognosis with androgen deprivation therapy for the subject with meta
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the 12 biomarkers according to this embodiment.
  • the 12 biomarkers according to this embodiment are single bases that are significantly detected in a group of patients with good prognosis in metastatic prostate cancer subjects who have undergone androgen deprivation therapy (ADT) in genome-wide SNP analysis. It is polymorphic. Since these single nucleotide polymorphisms have a high correlation with ADT, the array for predicting the prognosis due to androgen deprivation therapy according to the present embodiment can predict the prognosis due to androgen deprivation therapy for each patient.
  • the single nucleotide polymorphism to be detected is one or more types selected from the group consisting of 12 biomarkers according to the present embodiment, preferably two or more types, three or more types, four or more types, five or more types, and six types. Single nucleotide polymorphisms of more than one species, seven or more types, eight or more types, nine or more types, ten or more types, eleven or more types, or all 12 types.
  • Preferred single nucleotide polymorphisms include one or more, two or more, three or more, four or more, five or more, and six selected from the group consisting of rs76237622, rs117573572, rs2455473, rs117508236, rs77712131, rs80255163, and rs6478199. Examples include more than one species, or all seven types, particularly rs76237622 and/or rs117573572, and more particularly a SNP panel consisting of a plurality of single nucleotide polymorphisms.
  • the array for predicting prognosis by androgen deprivation therapy is an array mainly used in the DNA chip method (microarray method), and may be a microarray. It may be a device that is aligned and arranged in spots or the like on a substrate such as glass, and is preferably immobilized.
  • the prognosis prediction array according to androgen deprivation therapy according to the present embodiment includes one or more biomarkers selected from the group consisting of 12 biomarkers according to the present embodiment, preferably two or more, three or more, four or more, Equipped with a probe for detecting the presence or absence of 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or all 12 types of single nucleotide polymorphisms.
  • the DNA probe may be one that hybridizes with the single nucleotide polymorphism to be detected.
  • genomic DNA or chromosomal DNA is extracted and purified from a sample derived from a target patient, fluorescently labeled for detection, and then applied to the array. do.
  • the presence or absence of hybridization between the DNA probes provided in the array and the DNA of the target patient is detected using a fluorescent substance.
  • the predictive array for the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer is a predictive array for predicting whether the prognosis is good for either androgen receptor blockade therapy or an anticancer drug
  • the predictive array for the difference between the prognosis caused by the drug and the prognosis caused by androgen receptor blockade therapy detects the presence or absence of one or more single nucleotide polymorphisms selected from the group consisting of rs1045642, rs1856888, rs523349, rs34550074, and rs4149117. If the presence of one or more single nucleotide polymorphisms is detected, it is predicted that anticancer drugs will have a better prognosis than androgen receptor blockade therapy for patients with metastatic prostate cancer. This is an array that
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the five biomarkers according to this embodiment.
  • the five biomarkers according to this embodiment are single nucleotide polymorphisms that are significantly detected in patients with metastatic prostate cancer who have a better prognosis with androgen receptor blockade therapy than with anticancer drugs. It is.
  • These single nucleotide polymorphisms are highly correlated with the difference in prognosis between anticancer drugs and androgen receptor blockade therapy. According to the predictive array of differences, it is possible to predict whether an individual patient will have a better prognosis with androgen receptor blockade therapy than with anticancer drugs.
  • the single nucleotide polymorphism to be detected is one or more types selected from the group consisting of five biomarkers according to this embodiment, preferably two or more types, three or more types, four or more types, or all five types. It is a nucleotide polymorphism.
  • Preferred single nucleotide polymorphisms include one or more, two or more, three or more selected from the group consisting of the AG/GG allele of rs1045642, the CC/CT allele of rs1856888, the GG allele of rs523349, and the TT allele of rs34550074. , or all four types, particularly SNP panels consisting of two or more types, three or more types, or all four types.
  • the array for predicting the difference between the prognosis due to anticancer drugs and the prognosis due to androgen receptor blockade therapy is an array mainly used in the DNA chip method (microarray method), and may be a microarray.
  • Such an array may be a device in which, for example, DNA probes are arranged in spots on a substrate such as a slide glass, and are preferably immobilized.
  • the prognosis prediction array based on androgen deprivation therapy includes one or more biomarkers selected from the group consisting of five biomarkers according to the present embodiment, preferably two or more, three or more, four or more, or It is sufficient to include a probe for detecting the presence or absence of all five types of single nucleotide polymorphisms, and the DNA probe may be one that hybridizes with the single nucleotide polymorphism to be detected.
  • genomic DNA or chromosomal DNA is extracted and purified from a sample derived from a target patient, and detected. After fluorescent labeling is applied to the array. The presence or absence of hybridization between the DNA probes provided in the array and the DNA of the target patient is detected using a fluorescent substance.
  • the predictive array for the therapeutic effect of drug therapy in treating a subject with metastatic prostate cancer is a predictive array for predicting whether the prognosis is better with either an anti-androgen agent or a CYP17 inhibitor;
  • the predictive array for the difference in prognosis due to a CYP17 inhibitor comprises a probe for detecting the presence or absence of one or more single nucleotide polymorphisms selected from the group consisting of rs1128503, rs1077858 and rs4775936, If the presence of a single nucleotide polymorphism is detected, this array is predicted to have a better prognosis with a CYP17 inhibitor than with an anti-androgen agent in androgen receptor blockade therapy for the subject with metastatic prostate cancer.
  • the single nucleotide polymorphism to be detected is one or more types of single nucleotide polymorphisms selected from the three biomarkers according to this embodiment.
  • the three biomarkers according to this embodiment are single nucleotide polymorphisms that are significantly detected in patients with metastatic prostate cancer who have a better prognosis with CYP17 inhibitors than with anti-androgens. be.
  • the single nucleotide polymorphism to be detected is one or more types, preferably two or more or three types of single nucleotide polymorphisms selected from the group consisting of three biomarkers according to this embodiment.
  • Preferred single nucleotide polymorphisms include one or more, two or more, or three selected from the group consisting of the AA/AG allele of rs1128503, the GG allele of rs1077858, and the CT/TT allele of rs4775936, and particularly Examples include SNP panels consisting of two or three or more types.
  • the array for predicting the difference between the prognosis due to an anti-androgen agent and the prognosis due to a CYP17 inhibitor according to the present embodiment is an array mainly used in the DNA chip method (microarray method), and may be a microarray.
  • the array may be a device in which, for example, DNA probes are arranged in spots or the like on a substrate such as a slide glass, and are preferably immobilized.
  • the array for predicting prognosis due to androgen deprivation therapy according to the present embodiment detects the presence or absence of preferably two or more or three types of single nucleotide polymorphisms selected from the group consisting of three biomarkers according to the present embodiment. It is sufficient to have a probe for detection, and the DNA probe may be one that hybridizes with the single nucleotide polymorphism to be detected.
  • genomic DNA or chromosomal DNA is extracted and purified from a sample derived from a target patient and detected. is fluorescently labeled and then applied to the array. The presence or absence of hybridization between the DNA probes provided in the array and the DNA of the target patient is detected using a fluorescent substance.
  • the predictive array of the therapeutic effect of drug therapy in the treatment of a subject with metastatic prostate cancer is a predictive array of the difference between prognosis due to an anti-androgen and a prognosis due to a CYP17 inhibitor, wherein the prognosis due to the anti-androgen and the prognosis due to CYP17
  • the predictive array for a difference in prognosis due to an inhibitor comprises a probe for detecting the presence or absence of rs78445514, and when the presence of rs78445514 is detected, the metastatic prostate cancer subject is treated with androgen deprivation therapy, androgen This array is predicted to have a poor prognosis when treated with both receptor blockade therapy and anticancer drugs.
  • the single nucleotide polymorphism rs78445514 which is the target of detection, is used in patients with metastatic prostate cancer who have a poor prognosis when treated with androgen blockade therapy, androgen receptor blockade therapy, and anticancer drugs.
  • This is a significantly detected single nucleotide polymorphism.
  • This single nucleotide polymorphism has a high correlation with the therapeutic effects of androgen deprivation therapy, androgen receptor blockade therapy, and anticancer drugs. It is possible to predict whether a patient with metastatic prostate cancer will have a poor prognosis when treated with androgen blockade therapy, androgen receptor blockade therapy, or an anticancer drug.
  • the array for predicting the difference between the prognosis due to an anti-androgen agent and the prognosis due to a CYP17 inhibitor according to the present embodiment is an array mainly used in the DNA chip method (microarray method), and may be a microarray.
  • the array may be a device in which, for example, DNA probes are arranged in spots or the like on a substrate such as a slide glass, and are preferably immobilized.
  • the array for predicting prognosis due to androgen deprivation therapy according to the present embodiment detects the presence or absence of preferably two or more or three types of single nucleotide polymorphisms selected from the group consisting of three biomarkers according to the present embodiment. It is sufficient to have a probe for detection, and the DNA probe may be one that hybridizes with the single nucleotide polymorphism to be detected.
  • genomic DNA or chromosomal DNA is extracted and purified from a sample derived from a target patient, and the detected After fluorescent labeling, it is applied to the array.
  • the presence or absence of hybridization between the DNA probes provided in the array and the target patient's DNA is detected using a fluorescent substance.
  • Radiographic progression was periodically assessed by computed tomography and bone scans and was defined as regrowth of a known tumor or development of new lesions.
  • Soft tissue lesions and bone lesions were evaluated according to RECIST 1.1 and Prostate Cancer Working Group 2, respectively.
  • rPFS radiographic progression-free survival
  • CCS cancer-specific survival
  • OS overall survival
  • End events were defined as death from any cause, death from prostate cancer, and death from any cause. Patients without these events were censored at the last follow-up visit. For survival analysis, the number of days from enrollment to the earliest event or censoring date was calculated.
  • ⁇ Serum sample collection and GWAS> The development set consisted of 127 cases for which genomic DNA could be recovered.
  • This software created a PED format file containing the individual's genotype information that was used for further statistical analysis.
  • GWAS was performed using PLINK software v1.07 applying a chi-square test for each SNP to 1-year rPFS or each AE.
  • markers that deviated from Hardy-Weinberg equilibrium (P ⁇ 0.001) were excluded.
  • P values were plotted on a Manhattan plot.
  • the significance threshold was P ⁇ 5.0 ⁇ 10 ⁇ 8 .
  • Blood was collected from 358 patients with prostate cancer (metastatic or castration-resistant prostate cancer (CRPC)) with regional lymph node or distant metastasis treated at Akita University, Kyushu University, University of Occupational and Environmental Health, University of Miyazaki, and Kyoto University. N0 and M0 patients, or patients who had been treated with chemotherapy or novel androgen receptor pathway inhibitors (ARPIs) such as abiraterone and enzalutamide before being diagnosed with CRPC, were excluded. All patients underwent ADT (medical or surgical castration with GnRH agonists/blockers [goserelin acetate, leuprorelin acetate, degarelix acetate]).
  • ADT medical or surgical castration with GnRH agonists/blockers [goserelin acetate, leuprorelin acetate, degarelix acetate]).
  • Progression was defined essentially according to the criteria of Prostate Cancer Working Group 2 (PCWG2).
  • PCWG2 Prostate Cancer Working Group 2
  • progression or death from any cause, and death from any cause were defined as end events, respectively.
  • Patients without these events were censored at the last follow-up visit.
  • survival analysis the number of days from ADT initiation to the earliest event or censoring date was calculated.
  • Written informed consent was obtained from all patients, and the study was conducted in accordance with the principles stated in the Declaration of Helsinki and the ethical guidelines for epidemiological research established by the Japanese government. This study was approved by each institution's review board.
  • Treatment failure was defined as discontinuation of each treatment. Treatment was discontinued at the discretion of the physician based on deterioration of the patient's condition, including disease progression, adverse events, patient refusal, and death. The majority of discontinuations were due to disease progression, which was essentially determined by Prostate Cancer Working Group 2 criteria.
  • TFFS treatment-failure free survival
  • Genotyping of target genes Genetic variants were genotyped using a multiplex PCR-based targeted sequencing method previously reported by the inventors. Sequenced reads were aligned to the human reference sequence (hg19) using Burrows-Wheeler Aligner (ver. 0.7.17). For quality control, only individuals with 20 or more sequence reads covering 98% or more of the target gene variants were used. Next, variants for each individual were called separately using HaplotypeCaller and Unified Genotyper from GATK (ver. 3.7-0). The genotype of all individuals was determined for each variant based on the sequencing read ratio of the reference allele and the alternative allele. Custom scripts were deposited at https://github.com/Laboratory-for-Genotyping-Development/TargetSequence.git.
  • rs1045642 (ABCB1), rs1856888 (HSD3B1), rs523349 (SRD5A2), rs34550074 (SLCO2A1), rs4149117 (SLCO 1B3) was identified (Table 3, P value for interaction between docetaxel and ARPI). It is presumed that by using a SNP panel that combines these SNPs, it is possible to effectively predict patients who are expected to receive a therapeutic effect from anticancer drug therapy and patients who are expected to receive a therapeutic effect from an AR target drug.
  • rs1128503 (ABCB1), rs1077858 (SLCO2B1), and rs4775936 (CYP19A1) were identified as biomarkers that predict the difference in therapeutic efficacy between abiraterone, a CYP17 inhibitor, and enzalutamide, an antiandrogen (Table 3). P value for enzalutamide interaction). It is presumed that by using a SNP panel combining these SNPs, it is possible to predict which patients are expected to effectively benefit from abiraterone treatment and which patients are expected to benefit from enzalutamide among AR target drugs.
  • AR target drug predicted alleles include the AG/GG allele of rs1045642 (ABCB1), the CC/CT allele of rs1856888 (HSD3B1), the GG allele of rs523349 (SRD5A2), and the TT allele of rs34550074 (SLCO2A1).
  • the correlation between the favorable prognosis of docetaxel (DOC or docetaxel) and the favorable prognosis of ARPI and the treatment continuation rate was analyzed. The results are shown in Figure 2. As expected from Figure 2, the SNP panel combining these SNPs can predict which patients will effectively benefit from docetaxel treatment and which patients will benefit from AR-targeted drugs. Ta. Furthermore, it was found that as the number of alleles increased, the accuracy of predicting prognosis increased.
  • the SNP panel combining these SNPs could effectively predict patients for whom the therapeutic effect of abiraterone treatment was expected and patients for whom the therapeutic effect of enzalutamide was expected. Furthermore, it was found that as the number of alleles increased, the accuracy of predicting prognosis increased.
  • rs78445514 the correlation with treatment duration was further analyzed using the validation set. The results are shown in Table 5. Table 5 shows that rs78445514 is correlated with the duration of treatment of docetaxel treatment and AR target drug treatment, in addition to the time until progression in ADT, similar to the development set.

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Abstract

Selon la présente invention, un procédé permet de prédire l'effet thérapeutique d'une pharmacothérapie dans le traitement d'un sujet atteint d'un cancer de la prostate métastatique, la pharmacothérapie comprenant au moins un médicament choisi parmi une thérapie de privation androgénique, une thérapie de privation des récepteurs androgéniques et un médicament anticancéreux, et ledit procédé comprend une étape de détection de la présence ou de l'absence d'au moins un polymorphisme mononucléotidique chez le sujet.
PCT/JP2023/033598 2022-09-15 2023-09-14 Procédé pour prédire l'effet thérapeutique d'une pharmacothérapie dans le traitement d'un sujet atteint d'un cancer de la prostate métastatique, kit, réseau et biomarqueur WO2024058252A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013048561A (ja) * 2011-08-30 2013-03-14 Akita Univ 前立腺癌の予後の予測方法
US20130095481A1 (en) * 2010-02-11 2013-04-18 Dana-Farber Cancer Institute, Inc. Methods for predicting likelihood of responding to treatment
US20130149703A1 (en) * 2010-06-01 2013-06-13 Universite Laval "markers for prostate cancer progression"
US20130171647A1 (en) * 2010-09-08 2013-07-04 Mayo Foundation For Medical Education And Research Predicting responses to androgen deprivation therapy
US20130338027A1 (en) * 2012-06-15 2013-12-19 Nuclea Biotechnologies, Inc. Predictive Markers For Cancer and Metabolic Syndrome

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Publication number Priority date Publication date Assignee Title
US20130095481A1 (en) * 2010-02-11 2013-04-18 Dana-Farber Cancer Institute, Inc. Methods for predicting likelihood of responding to treatment
US20130149703A1 (en) * 2010-06-01 2013-06-13 Universite Laval "markers for prostate cancer progression"
US20130171647A1 (en) * 2010-09-08 2013-07-04 Mayo Foundation For Medical Education And Research Predicting responses to androgen deprivation therapy
JP2013048561A (ja) * 2011-08-30 2013-03-14 Akita Univ 前立腺癌の予後の予測方法
US20130338027A1 (en) * 2012-06-15 2013-12-19 Nuclea Biotechnologies, Inc. Predictive Markers For Cancer and Metabolic Syndrome

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SHIOTA MASAKI, AKAMATSU SHUSUKE, NARITA SHINTARO, TERADA NAOKI, FUJIMOTO NAOHIRO, ETO MASATOSHI: "Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer", JMA JOURNAL, vol. 4, no. 2, 15 April 2021 (2021-04-15), pages 99 - 111, XP093150216, ISSN: 2433-328X, DOI: 10.31662/jmaj.2021-0004 *

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