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WO2025028789A1 - Composition de biomarqueur pour prédire la réactivité thérapeutique ou le pronostic du cancer de la prostate - Google Patents

Composition de biomarqueur pour prédire la réactivité thérapeutique ou le pronostic du cancer de la prostate Download PDF

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Publication number
WO2025028789A1
WO2025028789A1 PCT/KR2024/008332 KR2024008332W WO2025028789A1 WO 2025028789 A1 WO2025028789 A1 WO 2025028789A1 KR 2024008332 W KR2024008332 W KR 2024008332W WO 2025028789 A1 WO2025028789 A1 WO 2025028789A1
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Prior art keywords
prostate cancer
prognosis
prostate
psa
group
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Korean (ko)
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정재승
한기호
조형석
변석수
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Industry Academic Cooperation Foundation of Inje University
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Industry Academic Cooperation Foundation of Inje University
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Priority claimed from KR1020230101138A external-priority patent/KR20250021154A/ko
Priority claimed from KR1020230101139A external-priority patent/KR20250021155A/ko
Application filed by Industry Academic Cooperation Foundation of Inje University filed Critical Industry Academic Cooperation Foundation of Inje University
Publication of WO2025028789A1 publication Critical patent/WO2025028789A1/fr
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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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

Definitions

  • the present invention relates to a biomarker composition capable of predicting whether prostate cancer is resistant to anticancer drugs or androgen deprivation therapy, or the prognosis after anticancer drugs or androgen deprivation therapy treatment.
  • the prostate is an organ that exists only in men, and it produces part of the semen. It is located below the bladder and adjacent to the rectum. Most prostate cancers are cancers of the gland cells in the prostate, and easily spread to lymph nodes and bones. About 90% of prostate cancers proliferate due to male hormones produced in the body.
  • Prostate cancer is the 6th most common cancer in Korean men, and is the second most common urological cancer after bladder cancer.
  • 10 to 50% of clinically localized prostate cancers are found to be advanced prostate cancer.
  • HRPC hormone-refractory prostate cancer
  • cancer cells that progress despite lowering hormone levels to the level of castration have been found to be metastatic castrate-resistant prostate cancer (mCRPC).
  • the previous survival period for mCRPC was only 1 year and 6 months to 2 years, but with the recent introduction of new secondary hormone drugs, the survival period has increased to 4 to 5 years.
  • Secondary hormone drugs selectively bind to androgen receptors and inhibit the signaling mechanism of androgen receptors in multiple stages. It does not affect the production of androgens or their blood concentrations, but binds to androgen receptors to cause androgens to lose their function.
  • hormone-independent cancer cells are produced among mCRPCs, and in these cases, androgen receptor inhibitors are not effective, resulting in significantly lower survival rates.
  • chemotherapy or targeted therapy is applied, but if it is possible to diagnose in advance that mCRPC patients have genetic characteristics that are resistant to secondary hormones, more diverse preemptive treatment methods can be applied, and this can help extend the patient's lifespan.
  • cytotoxic chemotherapy has no choice but to be used.
  • docetaxel-based chemotherapy is known to be effective.
  • taxane drugs including docetaxel and paclitaxel, have also been reported to have resistance, and resistance problems are particularly serious in prostate cancer, breast cancer, and ovarian cancer.
  • Biomarker is an indicator that can detect changes induced inside a living organism due to external influences, and is actively being studied for the purpose of diagnosing various diseases or predicting or monitoring the efficacy of specific treatments.
  • Biomarkers include pharmacodynamic markers (PD markers) that confirm whether a drug works in the body, and predictive markers that can predict the drug's responsiveness before administration in the body. The use of these markers is helpful in establishing clinical strategies for drugs.
  • PD markers pharmacodynamic markers
  • the efficacy verification marker can be used as an indicator for calculating the appropriate drug dosage by monitoring the degree of drug response according to the administered concentration.
  • the purpose of the present invention is to provide a biomarker composition for predicting treatment responsiveness or prognosis of prostate cancer.
  • Another object of the present invention is to provide a composition for predicting treatment responsiveness or prognosis of prostate cancer.
  • Another object of the present invention is to provide a kit for predicting treatment responsiveness or prognosis of prostate cancer.
  • Another object of the present invention is to provide a kit for screening prostate cancer therapeutic agents.
  • Another object of the present invention is to provide a method for providing information necessary for predicting treatment responsiveness or prognosis of prostate cancer.
  • Another object of the present invention is to provide a method for screening a prostate cancer treatment agent.
  • the present invention provides a biomarker composition for predicting treatment response or prognosis of prostate cancer, comprising at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTC isolated circulating tumor cells
  • the present invention provides a composition for predicting anticancer treatment response or prognosis of prostate cancer, comprising an agent for measuring at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTC isolated circulating tumor cells
  • the present invention provides a kit for predicting treatment response or prognosis of prostate cancer, comprising an agent for measuring at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTC isolated circulating tumor cells
  • the present invention provides a kit for screening a prostate cancer treatment agent, comprising an agent for measuring at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTC isolated circulating tumor cells
  • the present invention provides a method for providing information necessary for predicting the treatment responsiveness or prognosis of prostate cancer, including the steps of: a) identifying the expression level of at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), the expression level of a protein encoded by the gene, or the concentration of isolated circulating tumor cells (CTCs) in a sample isolated from a test subject; and b) comparing the result with the corresponding result of the corresponding gene in a normal control sample.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • the present invention provides a method for screening a prostate cancer treatment agent, comprising the step of treating a sample with a candidate substance and selecting a candidate substance that inhibits the expression or activity of at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), or inhibits at least one gene selected from the group consisting of growth, proliferation, and metastasis of CTCs.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • the present invention relates to a biomarker composition for predicting the treatment responsiveness or prognosis of prostate cancer, and it has been confirmed that the expression levels of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), and epithelial cell adhesion molecule (EpCAM) in circulating tumor cells (CTCs) isolated from a patient are related to prostate cancer resistant to anticancer drugs.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • the concentration of CTCs isolated from a patient and/or the expression levels of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), and AR-V7 (Androgen receptor variant 7) in the CTCs are related to prostate cancer resistant to androgen deprivation therapy (ADT), and thus the above genes are provided as biomarkers for predicting the treatment responsiveness of prostate cancer to anticancer drugs or ADT, or the prognosis of prostate cancer.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • AR-V7 Androgen receptor variant 7
  • Figure 1 shows the results of classifying the experimental group of mCRPC patients with a good prognosis after treatment and the experimental group of mCRPC patients with a poor prognosis after treatment through analysis of the best PSA response in mCRPC patients treated with docetaxel, and comparing the cases showing high expression of each gene (PSMA, PSA, AR, AR-V7, EpCAM, KRT19, and CTC#).
  • Figure 2 shows the results of analyzing the genes of each experimental group using a heatmap, categorizing mCRPC patients treated with docetaxel into a group with a good prognosis and a group with a poor prognosis, and showing the number of CTCs isolated from each experimental group.
  • Figure 3 shows the results of analyzing the correlation between the survival of an experimental group of mCRPC patients with a good prognosis after docetaxel treatment and an experimental group of mCRPC patients with a poor prognosis after docetaxel treatment and the expression of PSMA, PSA or EpCAM mRNA, which are biomarker genes according to the present invention, using a Kaplan-Meier curve.
  • Figure 4 shows the results of analyzing the association between survival and the expression of known prostate cancer biomarkers AR, AR-V7, KRT19, or CTC# in the experimental group of mCRPC patients with a good prognosis after docetaxel treatment and the experimental group of mCRPC patients with a poor prognosis after docetaxel treatment using Kaplan Meier curves.
  • Figure 5 shows the results of analyzing the association between the survival of an experimental group of mCRPC patients with a good prognosis after docetaxel treatment and an experimental group of mCRPC patients with a poor prognosis after docetaxel treatment and the expression of PSMA, PSA or EpCAM, which are biomarker genes according to the present invention, using a Cox proportional-hazards model.
  • Figure 6 shows the results of classifying the experimental group of mCRPC patients with a good prognosis after treatment and the experimental group of mCRPC patients with a poor prognosis after treatment through analysis of the best PSA response in mCRPC patients who received secondary hormone therapy, and comparing the cases showing high expression of each gene (PSMA, PSA, AR, AR-V7, EpCAM, KRT19, and CTC#).
  • Figure 7 shows the results of analyzing the genes of each experimental group using a heatmap, categorizing mCRPC patients who received secondary hormone therapy into a good prognosis group and a poor prognosis group, and showing the number of CTCs isolated from each experimental group.
  • Figure 8 shows the results of analyzing the correlation between the survival of a group of mCRPC patients with a good prognosis and a group of mCRPC patients with a poor prognosis who received secondary hormone therapy and the expression of PSMA, PSA, AR-V7 mRNA, or the number of CTCs, which are biomarkers according to the present invention, using a Kaplan-Meier curve.
  • Figure 9 shows the results of analyzing the association between survival and the expression of AR, EpCAM, or KRT19, known prostate cancer biomarkers, in the experimental group of mCRPC patients with a good prognosis and the experimental group of mCRPC patients with a poor prognosis who received secondary hormone therapy, using Kaplan Meier curves.
  • Figure 10 shows the results of analyzing the association between the survival of a group of mCRPC patients with a good prognosis and a group of mCRPC patients with a poor prognosis who received secondary hormone therapy and the expression of PSMA, PSA, AR-V7 mRNA, or the number of CTCs, which are biomarkers according to the present invention, using the Cox proportional-hazards model.
  • the present invention provides a biomarker composition for predicting treatment response or prognosis of prostate cancer, comprising at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTC isolated circulating tumor cells
  • the prostate cancer may be metastatic cancer, and more preferably, metastatic castrate-resistant prostate cancer (mCRPC).
  • mCRPC metastatic castrate-resistant prostate cancer
  • the above treatment may be chemotherapy or androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • biomarker for predicting treatment responsiveness refers to a substance capable of predicting/diagnosing the responsiveness of a subject to an anticancer drug or ADT treatment in prostate cancer treated with an anticancer drug or ADT, and includes organic biomolecules such as polypeptides or nucleic acids (e.g., mRNA, etc.), lipids, glycolipids, glycoproteins, sugars (monosaccharides, disaccharides, oligosaccharides, etc.), whose expression pattern significantly correlates with symptoms/diseases that do not improve after anticancer drug or ADT treatment.
  • organic biomolecules such as polypeptides or nucleic acids (e.g., mRNA, etc.), lipids, glycolipids, glycoproteins, sugars (monosaccharides, disaccharides, oligosaccharides, etc.), whose expression pattern significantly correlates with symptoms/diseases that do not improve after anticancer drug or ADT treatment.
  • the biomarker for predicting the responsiveness to anticancer drug treatment or prognosis of prostate cancer is a gene PSMA, PSA, EpCAM, AR-V7 or an isolated CTC, wherein the mRNA or protein expression level of the gene increases or the number of the CTC increases in prostate cancer resistant to an anticancer drug or ADT.
  • markers include not only genes but also DNA or mRNA complementary to any one marker, and may be a composite marker including these markers together.
  • the anticancer agent may be a taxane series anticancer agent.
  • it may be at least one selected from the group consisting of docetaxel, paclitaxel, and cabazitaxel. More preferably, it may be docetaxel, but not limited to this.
  • docetaxel is a compound having a structure represented by the following chemical formula 1, and its anticancer activity is derived from targeting the microtubules of the mitotic spindle, thereby preventing the spindle from aligning and separating chromosomes, blocking cell cycle progression, and activating the cell death pathway.
  • Docetaxel is a more potent anticancer agent than paclitaxel, but the pathway involved in its cytotoxicity is not well defined, and many cancers often develop resistance to it, which often reduces the effectiveness of the treatment.
  • Patients with mCRPC are also sometimes treated with docetaxel prior to second-line hormonal agents. However, since it is not possible to confirm whether mCRPC patients are resistant to docetaxel, the targeted therapeutic effect may not be achieved in some cases.
  • At least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), and epithelial cell adhesion molecule (EpCAM), or a protein encoded by the at least one gene is characterized in that it can predict the anticancer treatment responsiveness or prognosis of prostate cancer.
  • biomarker composition according to the present invention can predict whether the patient has resistance to docetaxel or the prognosis according to the treatment, thereby contributing to increasing the patient's survival.
  • the ADT may be a secondary hormone agent.
  • the secondary hormone agent is a substance that can selectively bind to the androgen receptor and inhibit the signal transduction mechanism of the androgen receptor in several stages, and refers to a substance that eliminates the function of androgen without affecting the production and blood concentration of androgen.
  • the secondary hormone agent may be used without limitation as long as it is a secondary hormone agent known in the art, and preferably, it may be at least one selected from the group consisting of enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, ARN-509, ODM-201, and galeterone, and more preferably, it may be enzalutamide or abiratarone, but is not limited thereto.
  • At least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC) are characterized in that they can predict the ADT treatment responsiveness or prognosis of prostate cancer.
  • biomarker composition according to the present invention can predict whether the patient has resistance to secondary hormonal agents or the prognosis according to treatment, thereby contributing to increasing the patient's survival.
  • the separated circulating tumor cells may have a cut-off concentration value of 10.2 to 10.8 CTCs/ml.
  • the cut-off may preferably be 10.4 to 10.8 CTCs/ml, and more preferably may be 10.6 CTCs/ml.
  • the CTC concentration of the sample is higher than the cut-off concentration, it can be determined to be resistant to secondary hormone therapy.
  • the present invention provides a composition for predicting anticancer treatment response or prognosis of prostate cancer, comprising an agent for measuring at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTC isolated circulating tumor cells
  • the above formulation is a formulation capable of being measured at the mRNA level, and may be at least one selected from the group consisting of antisense oligonucleotides, primers and probes that specifically bind to any one or more genes selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and AR-V7 (Androgen receptor variant 7), but is not limited thereto.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 Androgen receptor variant 7
  • the above primer or probe may be labeled with a fluorescent substance, wherein the fluorescent substance is selected from the group consisting of a biotin receptor peptide, a lipoic acid receptor peptide, a fluorescent protein, a green fluorescent protein (GFP), a red fluorescent protein (RFP), a yellow fluorescent protein (YFP), an enhanced green fluorescent protein (EGFP), an enhanced yellow fluorescent protein (EYFP), a cysteine-containing peptide for ligation of an arsenic dye or for conjugating metastable technetium, 4',5'-bis(1,3,2-dithioasolan-2-yl)fluorescein (FlAsH), a peptide for conjugating europium clathrate for fluorescence resonance energy transfer (FRET)-based proximity assay, and any combination thereof.
  • the fluorescent substance is selected from the group consisting of a biotin receptor peptide, a lipoic acid receptor peptide, a fluorescent protein, a green fluorescent protein (GFP), a
  • the above measurement can be performed by one or more methods selected from the group consisting of polymerase chain reaction, real-time RT-PCR, reverse transcription polymerase chain reaction, competitive polymerase chain reaction (Competitive RT-PCR), nuclease protection assay (RNase, S1 nuclease assay), in situ hybridization, nucleic acid microarray, northern blot, DNA chip, multiplex PCR, and ddPCR, but is not limited thereto.
  • polymerase chain reaction real-time RT-PCR, reverse transcription polymerase chain reaction, competitive polymerase chain reaction (Competitive RT-PCR), nuclease protection assay (RNase, S1 nuclease assay), in situ hybridization, nucleic acid microarray, northern blot, DNA chip, multiplex PCR, and ddPCR, but is not limited thereto.
  • the above formulation is a formulation that can be measured at the protein level, and may be at least one selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by one or more genes selected from the group consisting of antibodies, antibody fragments, aptamers, avidity multimers, and peptidomimetics that specifically bind to a surface marker of isolated CTCs, but is not limited thereto.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • the antibody fragment may be any one selected from the group consisting of Fab, Fd, Fab', dAb, F(ab'), F(ab')2, scFv (single chain fragment variable), Fv, single-chain antibody, Fv dimer, complementarity determining region fragment, humanized antibody, chimeric antibody and diabody, but is not limited thereto.
  • the above measurement may be performed by one or more methods selected from the group consisting of, but not limited to, western blot, ELISA (enzyme linked immunosorbent assay), radioimmunoassay (RIA), radioimmunodiffusion, immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, FACS, mass spectrometry, and protein microarray.
  • ELISA enzyme linked immunosorbent assay
  • RIA radioimmunoassay
  • immunoelectrophoresis immunoelectrophoresis
  • tissue immunostaining immunostaining
  • immunoprecipitation assay immunoprecipitation assay
  • complement fixation assay FACS
  • mass spectrometry protein microarray.
  • the above “surface marker” is a protein specifically expressed on the surface of CTC, and any CTC-specific marker known in the art can be used without limitation.
  • the surface markers include, but are not limited to, epithelial markers, mesenchymal markers, beta-catenin, cadherin-11, GSK-3 beta, MMP2, SUMO2, Twist-1, ZEB1, CD321, CD45, or CD66b.
  • epithelial cell adhesion molecule EpCAM
  • primer means a short nucleic acid sequence having a short free 3-terminal hydroxyl group, which can form base pairs with a complementary template and functions as a starting point for copying the template strand.
  • the primer can initiate DNA synthesis in the presence of a reagent for polymerization reaction (i.e., DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates in an appropriate buffer and temperature.
  • a reagent for polymerization reaction i.e., DNA polymerase or reverse transcriptase
  • probe used in the present invention refers to a nucleic acid fragment such as RNA or DNA, which is short, a few bases, or a long, several hundred bases, and can specifically bind to mRNA, and is labeled so that the presence or absence of a specific mRNA can be confirmed.
  • the probe can be produced in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, an RNA probe, etc.
  • hybridization is performed using a probe complementary to the PSMA, PSA, or AR-V7 gene, and the level of gene expression can be diagnosed through hybridization.
  • the selection of an appropriate probe and hybridization conditions can be modified based on what is known in the art, and therefore, the present invention does not specifically limit them.
  • the primers or probes of the present invention can be chemically synthesized using the phosphoramidite solid support method, or other well known methods.
  • Such nucleic acid sequences can also be modified using many means known in the art. Non-limiting examples of such modifications include methylation, capping, substitution with one or more homologues of a natural nucleotide, and modifications between nucleotides, such as modifications with uncharged linkers (e.g., methyl phosphonate, phosphotriester, phosphoroamidate, carbamate, etc.) or charged linkers (e.g., phosphorothioate, phosphorodithioate, etc.).
  • uncharged linkers e.g., methyl phosphonate, phosphotriester, phosphoroamidate, carbamate, etc.
  • charged linkers e.g., phosphorothioate, phosphorodithioate, etc.
  • suitable conditions for hybridizing a probe with a cDNA molecule can be determined as a series of steps by an optimization procedure. Such procedures are performed as a series of steps by those skilled in the art to establish a protocol for use in a laboratory. For example, conditions such as temperature, concentration of components, hybridization and washing time, buffer components, and their pH and ionic strength depend on various factors such as the length of the probe, the GC amount, and the target nucleotide sequence.
  • high stringency conditions mean hybridization at 65°C in 0.5 M NaHPO4, 7% SDS (sodium dodecyl sulfate), 1 mM EDTA, and washing at 68°C in 0.1x SSC (standard saline citrate)/0.1% SDS.
  • high stringency conditions mean washing at 48°C in 6x SSC/0.05% sodium pyrophosphate.
  • These stringent conditions mean, for example, washing at 42°C in 0.2x SSC/0.1% SDS.
  • antibody used in the present invention is a term known in the art and refers to a specific protein molecule directed against an antigenic site.
  • the antibody refers to an antibody that specifically binds to a protein expressed in the PSMA, PSA, EpCAM, AR-V7 gene, which is a biomarker of the present invention, or a CTC surface marker, and the method for producing the antibody can be produced using a well-known method. This also includes a partial peptide that can be produced from the protein.
  • the form of the antibody of the present invention is not particularly limited, and a polyclonal antibody, a monoclonal antibody, or a part thereof that has antigen binding property is also included in the antibody of the present invention, and all immunoglobulin antibodies are included. Furthermore, the antibody of the present invention also includes special antibodies such as humanized antibodies.
  • the present invention provides a kit for predicting treatment response or prognosis of prostate cancer, comprising an agent for measuring at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTC).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTC isolated circulating tumor cells
  • the kit may further include tools and/or reagents for collecting a biological sample from a subject or patient, as well as tools and/or reagents for preparing genomic DNA, cDNA, RNA or protein from the sample.
  • it may include PCR primers for amplifying a relevant region of genomic DNA.
  • the kit may include probes for genetic factors useful for pharmacogenomic profiling.
  • labeled oligonucleotides can be used for easy identification during analysis.
  • the kit may further contain DNA polymerase and a labeling substance such as dNTP (dGTP, dCTP, dATP and dTTP), a fluorescent substance, etc.
  • kit for predicting treatment responsiveness or prognosis of prostate cancer used in the present invention means a kit including the composition for predicting treatment responsiveness or prognosis of prostate cancer of the present invention. Therefore, it may be a kit for predicting anticancer drug or ADT treatment responsiveness or prognosis of prostate cancer.
  • kit for predicting anticancer drug or ADT treatment responsiveness or prognosis of prostate cancer may be used interchangeably or interchangeably with “composition for predicting anticancer drug or ADT treatment responsiveness or prognosis of prostate cancer.”
  • the present invention provides a kit for screening for a prostate cancer treatment agent, comprising an agent for measuring at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), a protein encoded by the at least one gene, or isolated circulating tumor cells (CTCs).
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • CTCs isolated circulating tumor cells
  • the prostate cancer may be metastatic castrate-resistant prostate cancer (mCRPC) that is resistant to anticancer drugs or androgen deprivation therapy (ADT).
  • mCRPC metastatic castrate-resistant prostate cancer
  • ADT androgen deprivation therapy
  • the above kit can be used to screen for, but is not limited to, a composition for enhancing the therapeutic effect of an anticancer drug, preferably docetaxel, in mCRPC with anticancer drug resistance, an inhibitor for suppressing the progression or metastasis of cancer, etc.
  • kit can screen for, but is not limited to, a composition for enhancing the therapeutic effect of ADT, preferably a second-line hormonal agent, and an inhibitor for suppressing the progression or metastasis of cancer in mCRPC with ADT resistance.
  • the present invention provides a method for providing information necessary for predicting the treatment response or prognosis of prostate cancer, including the steps of: a) identifying an expression level of at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), an expression level of a protein encoded by the gene, or a concentration of isolated circulating tumor cells (CTCs) in a sample isolated from a test subject; and b) comparing the results with the corresponding results of the corresponding genes in a normal control sample.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • a method for providing information necessary for predicting treatment responsiveness or prognosis of prostate cancer of the present invention may further include a step of determining resistance to an anticancer agent or ADT based on the expression level of PSMA, PSA, EpCAM and/or AR-V7 genes, which are biomarkers of the present invention, or the concentration of CTCs, wherein the prostate cancer is preferably metastatic castrate-resistant prostate cancer (mCRPC) that is resistant to an anticancer agent or ADT.
  • the normal control group may be a group of mCRPC patients who do not show resistance to anticancer agent or ADT treatment.
  • the patient in the method for providing information of the present invention, in mCRPC patients receiving anticancer treatment, if the patient shows high expression of PSMA, PSA and EpCAM genes compared to a group of mCRPC patients who do not show resistance to the anticancer drug, the patient can be determined to have resistance to the anticancer drug.
  • the patient in the method for providing information of the present invention, in mCRPC patients receiving ADT treatment, if the expression level of PSMA, PSA, EpCAM and/or AR-V7 genes is high, or the number of CTCs is high, compared to a group of mCRPC patients who did not show resistance to ADT, the patient can be determined to have resistance to ADT.
  • the sample may be at least one selected from the group consisting of blood, tissue, cells, plasma, stool, urine, and semen, but is not limited thereto.
  • it may be blood or circulating tumor cells (CTCs), but is not limited thereto.
  • the present invention provides a method for screening a prostate cancer treatment agent, comprising the step of treating a sample with a candidate substance and selecting a candidate substance that inhibits the expression or activity of at least one gene selected from the group consisting of prostate-specific membrane antigen (PSMA), prostate specific antigen (PSA), epithelial cell adhesion molecule (EpCAM), and androgen receptor variant 7 (AR-V7), or inhibits at least one gene selected from the group consisting of growth, proliferation, and metastasis of CTCs.
  • PSMA prostate-specific membrane antigen
  • PSA prostate specific antigen
  • EpCAM epithelial cell adhesion molecule
  • AR-V7 androgen receptor variant 7
  • the prostate cancer is metastatic castrate-resistant prostate cancer (mCRPC) that is resistant to anticancer drugs or ADT.
  • mCRPC metastatic castrate-resistant prostate cancer
  • the above anticancer agent may be a taxane series anticancer agent, preferably at least one selected from the group consisting of docetaxel, paclitaxel, and cabazitaxel, and more preferably docetaxel, but is not limited thereto.
  • the present invention can screen for a candidate substance that can enhance the therapeutic effect of an anticancer agent, preferably docetaxel, in mCRPC with anticancer agent resistance, or a candidate substance that inhibits the progression or metastasis of cancer, but is not limited thereto.
  • a candidate substance to be analyzed can be brought into contact with a cancer cell containing the gene or protein.
  • the candidate substance means an unknown substance used in screening to examine whether it affects the expression level of the gene, the amount of the protein, or the activity of the protein.
  • the ADT may be a secondary hormone agent.
  • the secondary hormone agent may be any known secondary hormone agent without limitation, and preferably, it may be at least one selected from the group consisting of enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, ARN-509, ODM-201, and galeterone, and more preferably, it may be enzalutamide or abiratarone, but is not limited thereto.
  • the present invention can screen, but is not limited to, a candidate substance that can enhance the therapeutic effect of docetaxel or a secondary hormonal agent, preferably in mCRPC with anticancer drug or ADT resistance, or a candidate substance that inhibits the progression or metastasis of cancer.
  • a candidate substance to be analyzed can be brought into contact with a cancer cell including the gene, the protein encoded by the gene, or CTCs above a cutoff value.
  • the candidate substance means an unknown substance used in screening to examine whether it affects the expression amount of the gene, the amount of the protein, the activity of the protein, or the activity of the CTC.
  • the above candidate substances may include, but are not limited to, chemicals, antisense oligonucleotides, antisense-RNA, siRNA, shRNA, miRNA, antibodies specific for the protein, or natural product extracts.
  • sample is used in the broadest sense. On the one hand, it includes a specimen or culture (e.g., a microbial culture). On the other hand, it includes both biological and environmental samples. In addition, the sample may include a sample of synthetic origin.
  • the above biological samples include whole blood, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirates, breath, urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid, leukocytes, peripheral blood mononuclear cells, buffy coat, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, trachea.
  • the sample may be at least one selected from the group consisting of organ secretions, cells, cell extracts, and cerebrospinal fluid, but is not limited thereto.
  • the sample may be blood isolated from an animal or circulating tumor cells (CTCs) isolated therefrom.
  • CTCs circulating tumor cells
  • the baseline PSA level of patients treated with docetaxel was compared with the PSA nadir value, and a decrease of 50% or more in the baseline PSA level was considered to have a good prognosis, and a decrease of 50% or less was considered to have a poor prognosis. All samples were approved by the institutional review boards of Haeundae-Paik Hospital (HPIRB 2018-01-005-004) and Seoul National University Bundang Hospital (B-1902-522-304), and the characteristics and clinical information are shown in Table 1 below.
  • the administered second-line hormonal agents were Abiraterone and Enzalutamide.
  • 60 patients (62 patients) who received second-line hormonal agents were analyzed for whom clinical prognosis could be observed.
  • the peripheral blood of each experimental group classified above was subjected to a density gradient to remove red blood cells, treated with Ficoll solution (1.119 g/mL), and centrifuged at 700 g for 30 minutes. After centrifugation, the white blood cells and circulating tumor cells (CTCs) (i.e., blood cancer cells) layers were separated, washed with 10 mL of PBS buffer, and centrifuged at 200 g for 10 minutes. After washing once more with 200 ⁇ L of PBS buffer, centrifuged at 200 g for 5 minutes to obtain the white blood cell and CTC layers.
  • CTCs circulating tumor cells
  • EpCAM cocktail solution (antibodies other than anti-EpCAM antibody antigen and Dextran) capable of attaching to EpCAM, a CTC-specific antigen, was treated, and incubated under ice conditions for 1 hour to bind the anti-EpCAM of the cocktail to the EpCAM antigen of blood cancer cells
  • 20 ⁇ L of nanometer-sized immunomagnetic beads magnetic nanobeads with a diameter of several tens of nm coated with anti-dextran antibodies
  • capable of specifically binding to EpCAM were treated, and incubated under ice conditions for 1 hour and 30 minutes to cause the dextran and anti-dextran of the cocktail to bind, ultimately inducing binding in the form of 'cancer cell-anti-EpCAM antibody-dextran-magnetic nanobeads'.
  • lateral magnetic phoretic separation was performed using a microparticle separation device utilizing magnetic phoresis described in Korean Patent No. 10-1622342.
  • 0.2% BSA PBS buffer and the blood sample prepared above were each flowed at a rate of 2 mL/h through the above device, and the separated sample was collected in a 1.5 mL e-tube.
  • genes PSMA, PSA, AR (Androgeen Receptor), AR-V7 (Androgen receptor variant 7), EpCAM, and KRT19 (Cytokeratin 19) in the CTC samples separated as described above was analyzed by the ddPCR (Droplet digital PCR) method. Specifically, first, the CTC sample was centrifuged at 200 g for 5 minutes, then 300 ⁇ L of cell disruption solution was treated, and total RNA was isolated with Dynabeads mRNA Direct Kit (Invitrogen). Then, for cDNA synthesis, a final 20 ⁇ L of cDNA was synthesized using Bionner's AccuPower CycleScript RT PreMix (dT20).
  • a pre-amplification process was applied to increase the efficiency of the final gene detection using ddPCR.
  • the primer information used for the above pre-amplification is described in Table 2 below.
  • 5 ⁇ L of diluted cDNA template was mixed with the forward and reverse primers according to the protocol in the multiplex PCR supermix (AccuPower Multiplex PCR PreMix, Bioneer) to make a final 50 ⁇ L pre-amplification sample.
  • the PCR conditions used were as follows: ramp rate 4 °C/s, initial denaturation step at 95 °C for 10 min, followed by 18 cycles including denaturation at 95 °C for 30 s, annealing at 56 °C for 1 min, and extension at 72 °C for 30 s.
  • the final extension step was performed at 72 °C for 10 min.
  • 20 ⁇ L of the PCR mixture containing the above pre-amplified sample was injected into the sample inlet of the droplet-generating cartridge (DG8 Cartridges for QX100/QX200 droplet generator, Bio-RAD), and 70 ⁇ L of droplet generation oil (Droplet generation oil for EvaGreen, Bio-RAD) was injected into the oil inlet.
  • the droplet generating cartridge was attached to the droplet generator (QX200 Droplet generator, Bio-Rad) to form droplets, and droplets were formed for 2 minutes.
  • the formed droplets were transferred to a 96 PCR well plate and sealed with a sealer.
  • PCR was performed using a PCR cycler (GeneAmp PcR System 9700, Applied Biosystems) under the following conditions: 95°C for 5 minutes (Enzyme activation), 40 cycles of 95°C for 30 seconds (denaturation) + 56°C for 1 minute (Annealing and extension), and 4°C for 5 minutes + 90°C for 5 minutes (signal stabilization), and analyzed with a droplet reader (QX200 Droplet reader, Bio-RAD). Information on the primers used for ddPCR is also described in Table 2 below.
  • the recruited patient group was divided into a group with a good prognosis and a group with a poor prognosis by performing the Best PSA response analysis, a known prostate cancer diagnosis method.
  • the Best PSA response analysis method compares the patient's baseline PSA level and the lowest PSA level (PSA Nadir) value (Baseline PSA - PSA Nadir / Baseline PSA), expresses it as a percentage, and then quantifies it by taking the x -1 value. In other words, if the Baseline PSA value shows a 50% or greater increase rate compared to the PSA Nadir value, the patient is classified as a group with a poor prognosis and a group with a poor drug response.
  • the values of the graph go to the right (above the -50% threshold), it was found that there were many groups with high expression levels of PSMA, PSA, and EpCAM genes.
  • Patients with a response value of -50% or higher were determined to have a poor prognosis after taking secondary hormones. Through this, 35 patients were classified into the experimental group with a positive PSA reaction (the experimental group with a good prognosis) and 25 patients were classified into the experimental group with a negative PSA reaction (the experimental group with a poor prognosis).
  • the expression level of each gene was displayed according to the increase in the number of CTCs, and the expression level was displayed by converting to a log scale without a reference value of the gene.
  • the number of CTCs was separated and immunofluorescent staining was performed according to a method known in the art, and the cell nucleus was stained with blue (DAPI), cytokeratin (Pan-cytokeratin) green, and CD45 red.
  • DAPI blue
  • cytokeratin Pan-cytokeratin
  • CD45 red CD45 red.
  • a heatmap is a representation of a data matrix converted into z-scores, with the lowest value expressed in red and the highest value expressed in bright green.
  • Fig. 7 the number of isolated blood CTCs and genetic analysis through a heatmap were counted and shown in Fig. 7.
  • the group was divided into a group with good PSA response and a group with poor PSA response, and each group was sorted in the direction of increasing number of CTCs.
  • the gene expression level of each sample was also displayed in a heatmap in the sorted order, and the heatmap is expressed by converting the data matrix into a z-score, and a lower expression level is displayed in red and a higher expression level is displayed in green.
  • the number of CTCs was measured to be much higher than in the group with good prognosis, and even among samples with similar numbers, the expression levels of PSMA, PSA, and AR-V7 genes were measured higher in the group with poor prognosis.
  • PSMA PSA-Progression-Free Survival
  • PSA PSA
  • PSA PSA
  • EpCAM EpCAM
  • Radiological-PFS PSMA (p-value: ⁇ 0.001)
  • PSA PSA
  • EpCAM EpCAM
  • Clinical-PFS PSMA (p-value: ⁇ 0.001), PSA (p-value: ⁇ 0.001), and EpCAM (p-value: ⁇ 0.001) were confirmed.
  • PSMA p-value: 0.009
  • PSA p-value: 0.003
  • EpCAM p-value: 0.002
  • the P value was 0.05 or higher, so AR, AR-V7, KRT19, or CTC# were judged to be not useful markers for diagnosing resistance to docetaxel.
  • PSMA PSA-Progression-Free Survival
  • PSA PSA
  • PSA PSA
  • AR-V7 p-value: 0.046
  • CTCs# CTCs#
  • the above three PSMA, PSA, and AR-V7 genes and the number of CTCs were determined to be useful markers for diagnosing resistance to secondary hormone agents in mCRPC.
  • AR p-value: 0.824
  • EpCAM p-value: 0.708
  • KRT19 p-value: 0.089
  • AR p-value: 0.482
  • EpCA p-value: 0.094
  • KRT19 p-value: 0.089
  • Clinical-PFS AR (p-value: 0.660), EpCAM (p-value: 0.033), and KRT19 (p-value: 0.114) were identified.
  • the AR, EpCAM, or KRT19 genes showed high p-values (higher than 0.05) unlike the biomarker according to the present invention, and thus, it was confirmed that they did not show statistical significance.
  • the HR value of EpCAM-mRNA was the highest at 3.59, and the HR value of PSMA-mRNA was the second highest at 3.20.
  • PSA-mRNA showed the third highest value at 2.64.
  • the HR value of EpCAM-mRNA was the highest at 3.80, and the HR value of PSMA-mRNA was the second highest at 3.67.
  • PSA-mRNA showed the third highest value at 2.67.
  • the HR value of EpCAM-mRNA was significantly significant at 8.33, and the HR value of PSMA-mRNA was the second highest at 7.01. PSA-mRNA showed the third highest value at 6.71.
  • the HR value of PSA-mRNA was 3.95
  • the HR value of PSMA-mRNA was 3.25
  • the HR value of EpCAM was 3.90.
  • PSMA, PSA and EpCAM according to the present invention showed high expression in mCRPC patients with poor prognosis even after docetaxel treatment, and had an effect on the high mortality rate of mCRPC patients treated with docetaxel.
  • the HR value of CTC# was the highest at 2.67, and the HR value of PSA-mRNA was the second highest at 2.52.
  • PSMA-mRNA showed a HR value of 2.28
  • AR-V7 mRNA showed a HR value of 1.82.
  • the HR value of PSMA-mRNA was the highest at 4.75, and the HR value of CTC# was the second highest at 3.24.
  • the HR value of PSA-mRNA was 2.51, and the HR value of AR-V7 mRNA was 2.07.
  • the HR value of PSMA-mRNA was 6.30, which was significantly significant, and the HR value of PSA-mRNA was 5.59, which was the second highest.
  • the HR value of CTC# was 3.73, and the HR value of EpCAM mRNA was 2.36.
  • the HR value of PSMA-mRNA was 7.00
  • the HR value of PSA-mRNA was 6.55
  • the HR value of CTC# was 3.57
  • the HR value of AR-V7 mRNA was 2.52
  • the HR value of EpCAM mRNA was 2.99.
  • EpCAM mRNA also showed a significant HR value, but no significant HR value was confirmed in PSA-PFS and Radiological-PFS, so it was determined that it is not a consistent biomarker gene.
  • PSMA, PSA and AR-V7 genes and CTC counts according to the present invention were highly expressed in mCRPC patients with poor prognosis even after secondary hormonal treatment, and had an effect on the high mortality rate of mCRPC patients who received secondary hormonal treatment.
  • the genes of PSMA, PSA and EpCAM were shown to have higher expression than in the experimental group not resistant to docetaxel, and it was thought that this would also have an effect on the mortality rate.
  • the genes of PSMA, PSA and EpCAM according to the present invention can be usefully utilized as a technology that can accurately determine whether mCRPC has anticancer drug resistance. Therefore, in the treatment of mCRPC, the expression of the above genes can be analyzed first and then the treatment direction can be determined accordingly, which can greatly contribute to improving the survival rate of mCRPC patients.
  • the genes of PSMA, PSA and AR-V7 and the number of CTCs according to the present invention can be usefully utilized as a technology that can accurately determine whether mCRPC has resistance to secondary hormone agents. Therefore, in the treatment of mCRPC, the expression of the above genes can be analyzed first and then the treatment direction can be determined accordingly, which can greatly contribute to improving the survival rate of mCRPC patients.

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Abstract

La présente invention concerne un biomarqueur pouvant prédire un mCRPC résistant à l'agent anticancéreux docétaxel ou à l'ADT. Selon la présente invention, les gènes PMSA, PSA et EpCAM présentent des niveaux d'expression spécifiques dans les mCRPC présentant un mauvais pronostic en raison d'une résistance au docétaxel, et peuvent donc être utilisés efficacement comme biomarqueur pour prédire le pronostic du cancer de la prostate présentant une résistance aux agents anticancéreux ou la réactivité thérapeutique du cancer de la prostate à un agent anticancéreux. En outre, les gènes PMSA, PSA et AR-V7 présentent des niveaux d'expression spécifiques dans les CPRCm de mauvais pronostic en raison de la résistance aux agents hormonaux secondaires et du nombre élevé de CTC, et peuvent donc être utilisés efficacement comme biomarqueurs pour prédire la réactivité thérapeutique ou le pronostic du cancer de la prostate présentant une résistance à l'ADT. Ainsi, la présente invention permet d'abord d'analyser l'expression des gènes, puis de déterminer la direction à prendre en matière de traitement de la mCRPC en conséquence, et peut donc contribuer de manière significative à l'amélioration du taux de survie des patients atteints de mCRPC.
PCT/KR2024/008332 2023-08-02 2024-06-17 Composition de biomarqueur pour prédire la réactivité thérapeutique ou le pronostic du cancer de la prostate Pending WO2025028789A1 (fr)

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KR1020230101139A KR20250021155A (ko) 2023-08-02 2023-08-02 전립선암의 항암제 치료 반응성 또는 예후 예측용 바이오마커 조성물

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