WO2021049862A1 - Prostate cancer diagnostic marker containing indoleamine 2,3-dioxygenase - Google Patents

Prostate cancer diagnostic marker containing indoleamine 2,3-dioxygenase Download PDF

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WO2021049862A1
WO2021049862A1 PCT/KR2020/012143 KR2020012143W WO2021049862A1 WO 2021049862 A1 WO2021049862 A1 WO 2021049862A1 KR 2020012143 W KR2020012143 W KR 2020012143W WO 2021049862 A1 WO2021049862 A1 WO 2021049862A1
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prostate cancer
dioxygenase
indoleamine
metabolite
expression level
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PCT/KR2020/012143
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French (fr)
Korean (ko)
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박영자
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고려대학교 세종산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y113/00—Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13)
    • C12Y113/11—Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13) with incorporation of two atoms of oxygen (1.13.11)
    • C12Y113/11052—Indoleamine 2,3-dioxygenase (1.13.11.52), i.e. indoleamine 2,3-dioxygenase 1
    • 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
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • 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
    • 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
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/90241—Oxidoreductases (1.) acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)

Definitions

  • the present invention relates to a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including indoleamine 2,3-dioxygenase or a metabolite thereof.
  • Prostate cancer is a malignant tumor that occurs in the prostate. Cancer mortality ranks second in the West. Similarly, in Korea, prostate cancer has increased rapidly over the past decade as a leading cause of cancer mortality. Epidemiological investigations have been conducted on exogenous risk factors for prostate cancer, including diet, occupation, and sexually transmitted diseases for over several decades, but risk factors for prostate cancer have been identified only in terms of age, ethnicity and family history.
  • prostate cancers While most prostate cancers are asymptomatic and grow slowly at initial onset, certain prostate cancers cause pain and lead to death.
  • DRE rectal finger test
  • PSA test prostate surface antigen test
  • prostate cancer is a biopsy in which a small piece of prostate is removed from a suspected patient for microscopic examination of the presence of tumor cells. Obviously, such a procedure is somewhat invasive and less desirable for early screening and detection.
  • the inventors of the present invention were studying a new diagnostic method capable of diagnosing prostate cancer, and confirmed that indoleamine 2,3-dioxygenase or its metabolite was specifically overexpressed in prostate cancer, and indoleamine 2,3-
  • the present invention was completed by confirming that prostate cancer diagnosis capable of substituting or assisting the prostate surface antigen test (PSA test) can be performed by using a dioxygenase or a metabolite thereof.
  • PSA test prostate surface antigen test
  • an object of the present invention is a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis comprising indoleamine 2,3-dioxygenase or metabolite thereof, a composition for prostate cancer diagnosis or prostate cancer prediction using the same, a kit, To provide a method of providing information for diagnosing prostate cancer or predicting prostate cancer prognosis, and a method of screening a prostate cancer therapeutic agent.
  • the present invention provides a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including indoleamine 2,3-dioxygenase or a metabolite thereof.
  • the present invention provides a composition for diagnosing prostate cancer or predicting prognosis of prostate cancer, including an agent for measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite.
  • the present invention provides a kit for diagnosing prostate cancer or predicting prostate cancer prognosis comprising the composition.
  • the present invention provides a method of providing information for diagnosing prostate cancer or predicting prostate cancer prognosis, comprising measuring the expression level of an indoleamine 2,3-dioxygenase or metabolite thereof from a biological sample.
  • the present invention comprises the steps of: (a) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in a biological sample; (b) treating a candidate substance for prostate cancer treatment; (c) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in the biological sample treated with the candidate substance; And (d) comparing the expression level of the indoleamine 2,3-dioxygenase or metabolite thereof in the step (a) and the indoleamine 2,3-dioxygenase or metabolite thereof in the step (c). It provides a method for screening a prostate cancer therapeutic agent comprising the step of.
  • the indoleamine 2,3-dioxygenase or its metabolite is used as a diagnostic index for conventional prostate cancer through the characteristics of the indoleamine 2,3-dioxygenase or its metabolite that is overexpressed in prostate cancer.
  • PSA test prostate surface antigen test
  • prostate cancer can be diagnosed more accurately and quickly.
  • it can be usefully used in pharmaceutical and medical businesses related to prostate cancer.
  • FIG. 1 is a diagram showing the results of measuring the expression of IDO in prostate cancer cell line (PC-3) and human normal lung fibrous tissue cells (WI-38) as a control with an ELISA assay kit.
  • FIG. 2 is a diagram showing the results of measuring IDO expression in a new cohort serum sample with an ELISA assay kit.
  • FIG. 3 is a diagram showing the results of measuring the expression level of N-formyl kynurenine in prostate cancer cell line (PC-3) and control human normal lung fibrous tissue cells (WI-38) by ELISA assay kit.
  • FIG. 4 is a diagram showing the results of measuring the expression level of N-formyl kynurenine in a new cohort serum sample with an ELISA assay kit.
  • the present invention provides a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including indoleamine 2,3-dioxygenase or a metabolite thereof.
  • Indoleamine-2,3-dioxygenase according to the present invention is an intracellular heme-containing enzyme that catalyzes the initial rate limiting step of tryptophan degradation along the Kynurenine pathway. Depletion of tryptophan by IDO activity inhibits T-cell activation, while regulating T-cell proliferation and survival of tryptophan catabolism such as Kynurenine derivatives and O 2 free radicals. IDO is expressed in human tissues and cells and is known to be induced during inflammatory activity by IFN- ⁇ and other inflammatory cytokines.
  • the indoleamine 2,3-dioxygenase of the present invention can be used as a biomarker of prostate cancer, but if there is difficulty in detecting the enzyme itself due to the nature of the enzyme, the expression of indoleamine 2,3-dioxygenase is measured. In addition, it can be used as a biomarker of the present invention by measuring the amount of metabolite expression of the enzyme.
  • the metabolite of the indoleamine 2,3-dioxygenase according to the present invention may include all metabolites in the metabolic process of the enzyme, preferably N-formyl kynurenine. It can be, but is not limited thereto.
  • prostate cancer or “prostate tumor” as used herein may be used interchangeably, and the term “diagnosis” refers to the identification of a molecular or pathological state, disease or condition, such as identification of cancer, or Or it refers to the identification of cancer patients who may benefit from a specific treatment plan.
  • the diagnosis of prostate cancer of the present invention can be performed separately/simultaneously/sequentially with conventional prostate cancer diagnosis methods such as the prostate surface antigen test (PSA) test.
  • PSA prostate surface antigen test
  • the present invention may include a diagnosis for predicting the prognosis of prostate cancer, and the term “prognosis” means predicting a probability of benefit from a treatment such as cancer therapy.
  • the terms “predicting” or “predicting” are used herein to refer to the likelihood that a patient will respond favorably or unfavorably to a particular anti-prostate cancer therapy, specifically the patient being treated, e.g. It relates to whether and/or the probability of survival or improvement after treatment with a particular therapeutic agent and for a period of time without disease progression.
  • biomarker used in the present invention may also be used as a diagnostic marker or a diagnostic marker, and refers to a substance capable of distinguishing whether or not prostate cancer has occurred in a biological sample.
  • indoleamine 2,3-dioxygenase or its metabolite was increased in prostate cancer cell lines and serum, indoleamine 2,3-dioxygenase or its metabolism.
  • the body can be used as a biomarker for prostate cancer diagnosis or prognosis.
  • the present invention provides a composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including an agent for measuring the expression level of indoleamine 2,3-dioxygenase or metabolite thereof.
  • diagnosis of prostate cancer can be performed using a formulation measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite, and the formulation is the indoleamine 2,3-dioxygenase.
  • methods for measuring the expression level include Western blot, MALDI-TOF/MS, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, radioimmunodiffusion, and Ouch.
  • Ouchterlony immunodiffusion method Ouchterlony immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complete fixation assay, FACS (Flow Cytometry) or protein chip
  • methods for measuring the expression level include mass spectrometry, nuclear magnetic resonance spectroscopy, liquid chromatography, high performance liquid chromatography (HPLC), ultra high resolution liquid chromatography (UPLC), and ultraviolet spectrophotometer.
  • Infrared spectroscopy, fluorescence spectroscopy, or ELISA (enzyme-linked immunosorbent assay) may be included, but is not limited thereto.
  • the present invention provides a kit for diagnosing prostate cancer or predicting prostate cancer prognosis comprising the composition.
  • the "kit” according to the present invention refers to a tool capable of diagnosing/predicting prostate cancer by including an indoleamine 2,3-dioxygenase, a metabolite thereof, or an agent detecting the same.
  • the kit of the present invention can diagnose prostate cancer or predict prognosis by checking the expression level of indoleamine 2,3-dioxygenase or a metabolite thereof corresponding to a marker and detecting it.
  • the kit of the present invention may include other constituent compositions, solutions, and devices necessary for prostate cancer diagnosis.
  • the kit may include an ELISA kit, a micro array chip kit, or a protein chip kit.
  • Measurement of the expression level of the indoleamine 2,3-dioxygenase or metabolite thereof of the present invention is a process of confirming the presence and expression level of a marker in a biological sample for diagnosis or prognosis of cancer, the indoleamine 2, It can be confirmed using an antibody that specifically binds to 3-dioxygenase or its metabolite.
  • the biological sample may be selected from the group consisting of cancer tissue, cancer cells, blood, serum, plasma, lymph, cerebrospinal fluid, ascites, urine, and tissue biopsy, but is not limited thereto.
  • the kit for measuring the expression level of indoleamine 2,3-dioxygenase or metabolite thereof of the present invention is a substrate, a suitable buffer solution, a secondary antibody labeled with a color developing enzyme or a fluorescent substance for the immunological detection of the antibody. , And a color developing substrate, and the like.
  • the substrate may be a nitrocellulose membrane, a 96-well plate synthesized with polyvinyl resin, a 96-well plate synthesized with polystyrene resin, and a slide glass made of glass, and the coloring enzyme is peroxidase, alkaline force Fatase (alkaline phosphatase), etc. can be used, FITC, RITC, etc.
  • ABTS 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfur) Phonic acid)
  • OPD O-phenylenediamine
  • TMB tetramethyl benzidine
  • the present invention provides a method of providing information for diagnosing prostate cancer or predicting prostate cancer prognosis, comprising measuring the expression level of indoleamine 2,3-dioxygenase or metabolite thereof from a biological sample.
  • the information for diagnosing prostate cancer or predicting prostate cancer prognosis is measurement information on the expression of indoleamine 2,3-dioxygenase or its metabolite in a patient with prostate cancer, and for the purposes of the present invention, indoleamine 2,3-diacid When it is determined that the expression of digestive enzymes or metabolites thereof is increased, it is related to the prostate cancer risk group or the progression of prostate cancer.Based on the above information, the present invention provides specific information including the diagnosis and prognosis of prostate cancer of the subject. do.
  • the biological sample may be selected from the group consisting of cancer tissue, cancer cells, blood, serum, plasma, lymph fluid, cerebrospinal fluid, ascites, urine and tissue biopsy, preferably cancer tissue, cancer cells, blood or Serum but not limited thereto.
  • the method of checking the expression level of the indoleamine 2,3-dioxygenase or its metabolite is Western blot, MALDI-TOF/MS, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay.
  • the present invention comprises the steps of: (a) measuring the expression level of indoleamine 2,3-dioxygenase or a metabolite thereof in a biological sample; (b) treating a candidate substance for prostate cancer treatment; (c) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in the biological sample treated with the candidate substance; And (d) comparing the expression level of the indoleamine 2,3-dioxygenase or metabolite thereof in the step (a) and the indoleamine 2,3-dioxygenase or metabolite thereof in the step (c). It provides a method for screening a prostate cancer therapeutic agent comprising the step of.
  • the biological sample may be selected from the group consisting of cancer tissue, cancer cells, blood, serum, plasma, lymph fluid, cerebrospinal fluid, ascites, urine and tissue biopsy, preferably cancer tissue, cancer cells, blood or Serum but not limited thereto.
  • indoleamine 2,3-dioxygenase or its metabolite can be usefully used for screening cancer therapeutics by comparing the increase or decrease in the expression of indoleamine 2,3-dioxygenase or its metabolite in the presence and absence of a prostate cancer therapeutic agent candidate substance.
  • a substance that indirectly or directly reduces the expression level of indoleamine 2,3-dioxygenase or its metabolite can be selected as a therapeutic agent for prostate cancer disclosed in the present invention.
  • Example One Indoleamine 2,3-dioxygenase ( indoleamine 2,3- dioxygenase , IDO) or objection Metabolic Obtaining prostate cancer cell line and serum for expression confirmation
  • N-formyl kynurenine In order to confirm the expression of indoleamine 2,3-dioxygenase (hereinafter,'IDO') or its metabolite, N-formyl kynurenine, prostate cancer cell line (PC-3) and human normal lung Fibrous tissue cells (WI-38) were selected.
  • each cell line was cultured using a T-75 flask in a CO 2 incubator, respectively, using RPMI for PC-3, EMEM for WI-38, and a culture medium composed of 10% FBS and 1% Penicillin. It was used after incubation.
  • additional normal serum and prostate cancer risk group serum were provided and used from Chilgok Kyungpook National University Hospital.
  • Example 2.1 Identification of the possibility of IDO as a biomarker for cancer diagnosis and prognosis through identification of IDO expression in cell lines
  • the experimental group prostate cancer cell line (PC-3) and the control human normal lung fibrous tissue cells ( WI-38) was compared with the difference in the expression of IDO.
  • the expression of IDO in the experimental group and the control group was confirmed using an ELISA assay kit, and the results are shown in FIG. 1.
  • Example 2.2 Identification of the possibility of IDO as a biomarker for cancer diagnosis and prognosis through identification of IDO expression in new cohort serum
  • IDO expression in a new cohort serum sample provided from Kyungpook National University Hospital in Example 1 was analyzed. IDO expression in the new cohort serum sample was confirmed using an ELISA assay kit, and the results are shown in FIG. 2.
  • the IDO expression (11399.92 mU/mg) in the prostate cancer serum sample was statistically significantly increased compared to the IDO expression (9667.964 mU/mg) in the normal serum sample. Accordingly, it was confirmed that IDO, whose expression is specifically increased only in prostate cancer patients, can be used as a biomarker, and that prostate cancer can be easily diagnosed by measuring the expression of IDO in serum.
  • Example 3 Confirmation of the possibility of N-formyl kynurenine as a biomarker for cancer diagnosis and prognosis prediction by confirming the expression level of N-formyl kynurenine, which is a metabolite of IDO
  • IDO is a heme-containing enzyme included in the kynurenine pathway involved in the metabolic process of tryptophan. More specifically, in the first step of the kynurenine pathway, L-tryptophan is oxidized to N-formyl kynurenine through IDO. do.
  • N-formyl kynurenine as a marker capable of predicting prostate cancer diagnosis and prognosis of prostate cancer patients, the experimental group determined in Example 1, the prostate cancer cell line (PC-3), Differences in the expression levels of N-formyl kynurenine in the control human normal lung fibrous tissue cells (WI-38), normal serum (control sera), and prostate cancer risk group serum (PCa sera) were compared.
  • the N-formyl kynurenine expression was confirmed using an ELISA assay kit, and the results are shown in FIG. 3.
  • the amount of N-formyl kynurenine expression (700.4464 pmole) in the prostate cancer cell line (PC-3) was statistically significantly increased compared to the amount (443.5406 pmole) detected in the control (WI-38). It was confirmed that the amount of N-formyl kynurenine (3312.203 pmole) in the serum of the prostate cancer risk group was increased compared to that of the N-formyl kynurenine (2954.856 pmole) in the normal serum.
  • N-formyl kynurenine whose expression is specifically increased only in prostate cancer patients, can be used as a biomarker, and also, prostate cancer can be easily diagnosed by measuring the amount of N-formyl kynurenine expression in cells and serum. Was confirmed.
  • N-formyl kynurenine in order to confirm the availability of N-formyl kynurenine as a marker capable of predicting prostate cancer diagnosis and prognosis of prostate cancer patients, N-formyl kynurenine in a new cohort serum sample provided from Kyungpook National University Hospital in Example 1 above. The amount of expression was analyzed. The expression of N-formyl kynurenine in the new cohort serum sample was confirmed using an ELISA assay kit, and the results are shown in FIG. 4.
  • N-formyl kynurenine (754.1928 pmole) in the prostate cancer serum sample was increased than that of the N-formyl kynurenine expression amount (644.604 pmole) in the normal serum sample. Therefore, it was confirmed that N-formyl kynurenine, which is specifically increased in expression only in prostate cancer patients, can be used as a biomarker, and that prostate cancer can be easily diagnosed by measuring the amount of N-formyl kynurenine expression in serum. I did.
  • indoleamine 2,3-dioxygenase or metabolite thereof of the present invention it is possible to quickly and accurately diagnose prostate cancer or predict prognosis through the expression analysis of the enzyme and metabolite. It was confirmed that it can be used as a biomarker for predicting prognosis.

Abstract

The present invention pertains to a prostate cancer diagnostic marker composition containing an indoleamine 2,3-dioxygenase or a metabolite thereof. Because an indoleamine 2,3-dioxygenase or a metabolite thereof according to the present invention has the property of being overexpressed in prostate cancer, the indoleamine 2,3-dioxygenase or metabolite thereof can be used to replace or supplement the prostate surface antigen test (PSA test) conventionally used as a diagnostic indicator of prostate cancer, thus enabling a more accurate and faster diagnosis of prostate cancer. In addition, the prostate cancer diagnostic marker composition can be used advantageously in pharmaceutical and medical projects related to prostate cancer.

Description

인돌아민 2,3-이산소화 효소를 포함하는 전립선암 진단용 마커Prostate cancer diagnostic marker containing indoleamine 2,3-dioxygenase
본 발명은 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 바이오 마커 조성물에 관한 것이다. The present invention relates to a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including indoleamine 2,3-dioxygenase or a metabolite thereof.
전립선암(prostate cancer)은 전립선에서 발생하는 악성 종양으로 서양에서 암으로 인한 사망률이 2위를 차지하며, 비슷하게 한국에서도 암 사망률의 주요 원인으로 지난 10년간 전립선암 발생이 빠르게 증가했다. 수십년 넘게 식이, 직업, 성병인자들을 포함하는 전립선암에 대한 외인성 위험 인자에 대한 역학 조사가 이뤄졌지만, 전립선암의 위험인자는 나이, 민족, 가족력에 대해서만 밝혀졌다. Prostate cancer is a malignant tumor that occurs in the prostate. Cancer mortality ranks second in the West. Similarly, in Korea, prostate cancer has increased rapidly over the past decade as a leading cause of cancer mortality. Epidemiological investigations have been conducted on exogenous risk factors for prostate cancer, including diet, occupation, and sexually transmitted diseases for over several decades, but risk factors for prostate cancer have been identified only in terms of age, ethnicity and family history.
대부분의 전립선암은 초기 발병 시에 무증상이고 느리게 성장하는 반면에, 특정 전립선암은 통증을 유발하고 치사에 이르게 된다. 현재, 두 가지 주요 유형의 비-침습성 스크리닝 시험이 남성에서의 전립선암 검출에 이용가능하다. 하나는 직장 수지 검사(DRE)로, 장갑 낀 손가락을 직장에 집어넣어 전립선을 촉진함으로써 의사로 하여금 전립선 이상을 검출하게 해주며, 다른 하나는 전립선 표면 항원 시험(PSA 시험)으로, 혈액 샘플 중 PSA 항원의 수준을 측정하는 것이다. While most prostate cancers are asymptomatic and grow slowly at initial onset, certain prostate cancers cause pain and lead to death. Currently, two main types of non-invasive screening tests are available for detection of prostate cancer in men. One is the rectal finger test (DRE), which allows doctors to detect prostate abnormalities by placing a gloved finger in the rectum to stimulate the prostate, and the other is the prostate surface antigen test (PSA test), which is a PSA in a blood sample. It is to measure the level of the antigen.
비록 FDA에서는 남성에서의 전립선암 검출에 도움을 주기 위하여 DRE와 함께 PSA 시험을 이용하는 것을 승인하였지만, PSA 시험에 의한 전립선암의 진단의 정확도는 아직 논란이 되고 있다. 최근에, PSA 스크리닝이 전립선암 사망률을 전혀 또는 거의 줄이지 못하면서 불필요한 통증과 부작용을 초래하는 치료 또는 시험으로 이끈다는 소견을 근거로, PSA 스크리닝에 대해 반대 입장의 권고를 한 문헌 등이 발표된 바 있다. 실제로 PSA 수치가 기준치보다 낮음에도 전립선암으로 밝혀지는 위음성, 또는 기준치보다 높음에도 진단되는 위양성인 경우가 보고되어 추가적인 진단의 필요성은 지속적으로 지적되고 있다. Although the FDA has approved the use of the PSA test with DRE to help detect prostate cancer in men, the accuracy of the diagnosis of prostate cancer by the PSA test is still controversial. Recently, on the basis of the findings that PSA screening leads to treatments or trials that cause unnecessary pain and side effects while not reducing prostate cancer mortality at all or little, literature and the like have been published that made opposing recommendations to PSA screening . In fact, even though the PSA level is lower than the reference value, a false-negative, which is identified as prostate cancer, or a false-positive, which is diagnosed even though it is higher than the reference value, has been reported, and the need for additional diagnosis is constantly being pointed out.
한편 전립선암의 대부분의 확진은 종양 세포의 존재에 대한 현미경 검사를 위하여 의심이 가는 환자로부터의 작은 전립선 조각을 적출하는 생검이다. 명백하게 그러한 절차는 다소 침습적이며 조기 스크리닝 및 검출에는 보다 덜 바람직하다. Meanwhile, most confirmation of prostate cancer is a biopsy in which a small piece of prostate is removed from a suspected patient for microscopic examination of the presence of tumor cells. Obviously, such a procedure is somewhat invasive and less desirable for early screening and detection.
따라서, 종래 PSA 시험법을 보완하며 보다 정확하게 전립선 암을 진단하기 위한 새로운 검출 지표 및 마커에 대한 필요성이 있다. Therefore, there is a need for new detection indicators and markers to more accurately diagnose prostate cancer and complement the conventional PSA test method.
이에 본 발명자들은 전립선암을 진단할 수 있는 새로운 진단 방법에 대해 연구하던 중, 인돌아민 2,3-이산소화 효소 또는 이의 대사체가 전립선암에서 특이적으로 과발현 되는 것을 확인하고 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 이용하면 전립선 표면 항원 시험 (PSA 시험)을 대체하거나 이를 보조할 수 있는 전립선암 진단이 가능함을 확인하여 본 발명을 완성하였다. Accordingly, the inventors of the present invention were studying a new diagnostic method capable of diagnosing prostate cancer, and confirmed that indoleamine 2,3-dioxygenase or its metabolite was specifically overexpressed in prostate cancer, and indoleamine 2,3- The present invention was completed by confirming that prostate cancer diagnosis capable of substituting or assisting the prostate surface antigen test (PSA test) can be performed by using a dioxygenase or a metabolite thereof.
따라서 본 발명의 목적은 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 바이오마커 조성물, 이를 이용한 전립선암 진단 또는 전립선암 예후 예측용 조성물, 키트, 전립선암 진단 또는 전립선암 예후 예측을 위한 정보 제공 방법 및 전립선암 치료제의 스크리닝 방법을 제공하는 것이다. Accordingly, an object of the present invention is a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis comprising indoleamine 2,3-dioxygenase or metabolite thereof, a composition for prostate cancer diagnosis or prostate cancer prediction using the same, a kit, To provide a method of providing information for diagnosing prostate cancer or predicting prostate cancer prognosis, and a method of screening a prostate cancer therapeutic agent.
상기 목적을 달성하기 위하여, 본 발명은 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 바이오마커 조성물을 제공한다. In order to achieve the above object, the present invention provides a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including indoleamine 2,3-dioxygenase or a metabolite thereof.
또한 본 발명은 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 제제를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 조성물을 제공한다. In addition, the present invention provides a composition for diagnosing prostate cancer or predicting prognosis of prostate cancer, including an agent for measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite.
또한 본 발명은 상기 조성물을 포함하는 전립선암 진단 또는 전립선암 예후 예측용 키트를 제공한다. In addition, the present invention provides a kit for diagnosing prostate cancer or predicting prostate cancer prognosis comprising the composition.
또한 본 발명은 생물학적 시료로부터 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계를 포함하는 전립선암 진단 또는 전립선암 예후 예측을 위한 정보 제공 방법을 제공한다. In addition, the present invention provides a method of providing information for diagnosing prostate cancer or predicting prostate cancer prognosis, comprising measuring the expression level of an indoleamine 2,3-dioxygenase or metabolite thereof from a biological sample.
또한 본 발명은 (a) 생물학적 시료에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계; (b) 전립선암 치료제 후보물질을 처리하는 단계; (c) 상기 후보물질이 처리된 생물학적 시료에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계; 및 (d) 상기 (a) 단계의 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현과 상기 (c) 단계의 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 비교하는 단계를 포함하는 전립선암 치료제의 스크리닝 방법을 제공한다. In addition, the present invention comprises the steps of: (a) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in a biological sample; (b) treating a candidate substance for prostate cancer treatment; (c) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in the biological sample treated with the candidate substance; And (d) comparing the expression level of the indoleamine 2,3-dioxygenase or metabolite thereof in the step (a) and the indoleamine 2,3-dioxygenase or metabolite thereof in the step (c). It provides a method for screening a prostate cancer therapeutic agent comprising the step of.
본 발명에 따른 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 이용하면 전립선암에서 과발현되는 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 특성을 통해 종래 전립선암의 진단 지표로 사용되고 있는 전립선 표면 항원 시험 (PSA 시험)을 대체하거나 보조하여, 전립선암을 보다 정확하고 빠르게 진단할 수 있다. 또한, 전립선암과 관련된 제약 및 의료 사업에서도 유용하게 사용될 수 있다. Using the indoleamine 2,3-dioxygenase or its metabolite according to the present invention, it is used as a diagnostic index for conventional prostate cancer through the characteristics of the indoleamine 2,3-dioxygenase or its metabolite that is overexpressed in prostate cancer. By replacing or assisting with the prostate surface antigen test (PSA test), prostate cancer can be diagnosed more accurately and quickly. In addition, it can be usefully used in pharmaceutical and medical businesses related to prostate cancer.
도 1은 전립선암 세포주(PC-3)와 대조군인 인간 정상 폐섬유 조직 세포(WI-38)에서의 IDO의 발현을 ELISA assay kit로 측정한 결과를 나타낸 도이다. 1 is a diagram showing the results of measuring the expression of IDO in prostate cancer cell line (PC-3) and human normal lung fibrous tissue cells (WI-38) as a control with an ELISA assay kit.
도 2는 신규 코호트 혈청 샘플에서의 IDO 발현을 ELISA assay kit로 측정한 결과를 나타낸 도이다. 2 is a diagram showing the results of measuring IDO expression in a new cohort serum sample with an ELISA assay kit.
도 3은 전립선암 세포주(PC-3)와 대조군인 인간 정상 폐섬유 조직 세포(WI-38)에서의 N-포밀 키누레닌의 발현양을 ELISA assay kit로 측정한 결과를 나타낸 도이다.3 is a diagram showing the results of measuring the expression level of N-formyl kynurenine in prostate cancer cell line (PC-3) and control human normal lung fibrous tissue cells (WI-38) by ELISA assay kit.
도 4는 신규 코호트 혈청 샘플에서의 N-포밀 키누레닌의 발현양을 ELISA assay kit로 측정한 결과를 나타낸 도이다. 4 is a diagram showing the results of measuring the expression level of N-formyl kynurenine in a new cohort serum sample with an ELISA assay kit.
이하, 본 발명에 대하여 보다 상세히 설명한다. Hereinafter, the present invention will be described in more detail.
본 발명은 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 바이오마커 조성물을 제공한다. The present invention provides a biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including indoleamine 2,3-dioxygenase or a metabolite thereof.
본 발명에 따른 인돌아민 2,3-이산소화 효소 (Indoleamine-2,3-dioxygenase, IDO)는 Kynurenine 경로를 따라 트립토판 분해의 초기 속도 제한 단계를 촉매하는 세포 내 헴 함유 효소이다. IDO 활성에 의한 트립토판의 고갈은 T-세포의 활성화를 억제하는 반면에 Kynurenine 유도체 및 O 2 자유 라디칼과 같은 트립토판 이화의 T-세포 증식 및 생존을 조절한다. IDO는 인간 조직 및 세포에서 발현되고 IFN-γ및 다른 염증성 사이토카인에 의한 염증 활동이 진행되는 동안 유도되는 것으로 알려져 있다. Indoleamine-2,3-dioxygenase (IDO) according to the present invention is an intracellular heme-containing enzyme that catalyzes the initial rate limiting step of tryptophan degradation along the Kynurenine pathway. Depletion of tryptophan by IDO activity inhibits T-cell activation, while regulating T-cell proliferation and survival of tryptophan catabolism such as Kynurenine derivatives and O 2 free radicals. IDO is expressed in human tissues and cells and is known to be induced during inflammatory activity by IFN-γ and other inflammatory cytokines.
본 발명의 상기 인돌아민 2,3-이산소화 효소는 전립선암의 바이오마커로서 사용될 수 있으나, 효소의 특성 상 효소 자체의 검출의 곤란성이 존재한다면, 인돌아민 2,3-이산소화 효소의 발현 측정과 더불어 상기 효소의 대사체 발현양을 측정하여 본원 발명의 바이오마커로서 이용할 수 있다. The indoleamine 2,3-dioxygenase of the present invention can be used as a biomarker of prostate cancer, but if there is difficulty in detecting the enzyme itself due to the nature of the enzyme, the expression of indoleamine 2,3-dioxygenase is measured. In addition, it can be used as a biomarker of the present invention by measuring the amount of metabolite expression of the enzyme.
따라서, 본 발명에 따른 인돌아민 2,3-이산소화 효소의 대사체는 상기 효소의 대사 과정에서의 대사체를 모두 포함할 수 있으며, 바람직하게는 N-포밀 키누레닌(N-formyl kynurenine)일 수 있으나 이에 제한되지 않는다. Therefore, the metabolite of the indoleamine 2,3-dioxygenase according to the present invention may include all metabolites in the metabolic process of the enzyme, preferably N-formyl kynurenine. It can be, but is not limited thereto.
본 발명에서 사용되는 용어 "전립선암" 또는 "전립선 종양"은 상호 교환적으로 사용될 수 있으며, 용어 "진단" 은 분자적 또는 병리학적 상태, 질환 또는 병태의 확인, 예컨대 암의 확인을 언급하거나, 또는 특정 치료 계획으로부터 이익을 얻을 수 있는 암 환자의 확인을 의미한다. The terms "prostate cancer" or "prostate tumor" as used herein may be used interchangeably, and the term "diagnosis" refers to the identification of a molecular or pathological state, disease or condition, such as identification of cancer, or Or it refers to the identification of cancer patients who may benefit from a specific treatment plan.
본 발명의 전립선암 진단은 전립선 표면 항원 시험 (PSA) 시험과 같은 종래 전립선암 진단 방법과 개별적으로/동시에/순차적으로 수행될 수 있다. The diagnosis of prostate cancer of the present invention can be performed separately/simultaneously/sequentially with conventional prostate cancer diagnosis methods such as the prostate surface antigen test (PSA) test.
한편 본 발명은 전립선암의 예후 예측에 대한 진단을 포함할 수 있으며, 용어 "예후"는 암 요법과 같은 치료로부터의 이익 가능성의 예측을 의미한다. 용어 "예측" 또는 "예측하는"은 본원에서 환자가 특정 항-전립선암 요법에 호의적으로 또는 비-호의적으로 (unfavorably) 반응하게 될 가능성을 언급하는 데 사용되며 구체적으로 환자가 치료, 예를 들어 특정 치료제로 치료 뒤에, 및 질환 진행 없이 소정 기간 동안 생존하거나 또는 호전할 것인지 여부 및/또는 그렇게 생존하거나 또는 호전할 확률에 관계한다. Meanwhile, the present invention may include a diagnosis for predicting the prognosis of prostate cancer, and the term “prognosis” means predicting a probability of benefit from a treatment such as cancer therapy. The terms “predicting” or “predicting” are used herein to refer to the likelihood that a patient will respond favorably or unfavorably to a particular anti-prostate cancer therapy, specifically the patient being treated, e.g. It relates to whether and/or the probability of survival or improvement after treatment with a particular therapeutic agent and for a period of time without disease progression.
본 발명에서 사용되는 용어 "바이오마커"는 진단용 마커 또는 진단 마커로도 쓰일 수 있으며, 생물학적 시료에서 전립선암 발생 여부를 구분하여 진단할 수 있는 물질을 말한다. 본 발명은 구체적인 일실시예로, 전립선암 세포주 및 혈청에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현이 증가하는 것을 확인하였는바, 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 전립선암 진단 또는 예후 예측용 바이오마커로 활용할 수 있다.The term "biomarker" used in the present invention may also be used as a diagnostic marker or a diagnostic marker, and refers to a substance capable of distinguishing whether or not prostate cancer has occurred in a biological sample. In a specific embodiment of the present invention, it was confirmed that the expression of indoleamine 2,3-dioxygenase or its metabolite was increased in prostate cancer cell lines and serum, indoleamine 2,3-dioxygenase or its metabolism. The body can be used as a biomarker for prostate cancer diagnosis or prognosis.
또한, 본 발명은 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 제제를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 조성물을 제공한다. In addition, the present invention provides a composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including an agent for measuring the expression level of indoleamine 2,3-dioxygenase or metabolite thereof.
본 발명에서는 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 제제를 이용하여 전립선암에 대한 진단을 수행할 수 있으며, 상기 제제는 상기 인돌아민 2,3-이산소화 효소 또는 이의 대사체에 특이적으로 결합하는 올리고펩타이드, 모노클로날 항체, 폴리클로날 항체, 키메릭(chimeric) 항체, 리간드, PNA(Peptide nucleic acid) 또는 앱타머(aptamer) 일 수 있으나 이에 제한되지 않는다. 또한, 상기 발현 수준을 측정할 수 있는 방법은 웨스턴 블롯, MALDI-TOF/MS, 효소면역분석법(enzyme-linked immunosorbent assay, ELISA), 방사선면역분석법(radioimmunoassay), 방사면역확산법(radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역확산법, 로케트(Ouchterlony) 면역 전기 영동, 조직 면역 염색, 면역 침전 분석(immunoprecipitation assay), 보체 고정 분석법(complete fixation assay), FACS(Flow Cytometry) 또는 단백질 칩(protein chip)을 포함할 수 있으며 상기 대사체가 화합물인 경우 발현 수준을 측정할 수 있는 방법은 질량분석기, 핵자기공명분광기, 액상 크로마토그래피, 고성능 액상 크로마토그래피(HPLC), 초고해상 액상 크로마토그래피(UPLC), 자외선분광기, 적외선분광기, 형광분광기 또는 ELISA(enzyme-linked immunosorbent assay)를 포함할 수 있으나 이에 제한되지 않는다.In the present invention, diagnosis of prostate cancer can be performed using a formulation measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite, and the formulation is the indoleamine 2,3-dioxygenase. Or oligopeptides, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, ligands, peptide nucleic acids (PNA), or aptamers that specifically bind to their metabolites, but are not limited thereto. Does not. In addition, methods for measuring the expression level include Western blot, MALDI-TOF/MS, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, radioimmunodiffusion, and Ouch. Ouchterlony immunodiffusion method, Ouchterlony immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complete fixation assay, FACS (Flow Cytometry) or protein chip In case the metabolite is a compound, methods for measuring the expression level include mass spectrometry, nuclear magnetic resonance spectroscopy, liquid chromatography, high performance liquid chromatography (HPLC), ultra high resolution liquid chromatography (UPLC), and ultraviolet spectrophotometer. , Infrared spectroscopy, fluorescence spectroscopy, or ELISA (enzyme-linked immunosorbent assay) may be included, but is not limited thereto.
또한, 본 발명은 상기 조성물을 포함하는 전립선암 진단 또는 전립선암 예후 예측용 키트를 제공한다. In addition, the present invention provides a kit for diagnosing prostate cancer or predicting prostate cancer prognosis comprising the composition.
본 발명에 따른 “키트”란 인돌아민 2,3-이산소화 효소, 이의 대사체 또는 이를 검출하는 제제를 포함함으로써, 전립선암을 진단/예측할 수 있도록 하는 도구를 의미한다. 본 발명의 키트는 마커에 해당하는 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 확인하여 이를 검출함으로써 전립선암의 진단 또는 예후 예측을 할 수 있다. 본 발명의 키트에는 상기 조성물 외에도 전립선암 진단에 필요한 다른 구성성분 조성물, 용액, 장치가 포함될 수 있다. The "kit" according to the present invention refers to a tool capable of diagnosing/predicting prostate cancer by including an indoleamine 2,3-dioxygenase, a metabolite thereof, or an agent detecting the same. The kit of the present invention can diagnose prostate cancer or predict prognosis by checking the expression level of indoleamine 2,3-dioxygenase or a metabolite thereof corresponding to a marker and detecting it. In addition to the above composition, the kit of the present invention may include other constituent compositions, solutions, and devices necessary for prostate cancer diagnosis.
또한, 상기 키트는 ELISA 키트, 마이크로어레이 칩(micro array chip) 키트 또는 단백질 칩 키트를 포함할 수 있다. In addition, the kit may include an ELISA kit, a micro array chip kit, or a protein chip kit.
본 발명의 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준 측정은 암의 진단 또는 예후 예측을 위하여 생물학적 시료에서 마커의 존재 여부와 발현 정도를 확인하는 과정으로, 상기 인돌아민 2,3-이산소화 효소 또는 이의 대사체에 특이적으로 결합하는 항체를 이용해 확인할 수 있다. Measurement of the expression level of the indoleamine 2,3-dioxygenase or metabolite thereof of the present invention is a process of confirming the presence and expression level of a marker in a biological sample for diagnosis or prognosis of cancer, the indoleamine 2, It can be confirmed using an antibody that specifically binds to 3-dioxygenase or its metabolite.
본 발명에 있어서, 상기 생물학적 시료는 암 조직, 암 세포, 혈액, 혈청, 혈장, 림프액, 뇌척수액, 복수, 요 및 조직생검으로 이루어진 군에서 선택될 수 있으나, 이에 제한되지 않는다. In the present invention, the biological sample may be selected from the group consisting of cancer tissue, cancer cells, blood, serum, plasma, lymph, cerebrospinal fluid, ascites, urine, and tissue biopsy, but is not limited thereto.
또한, 본 발명의 인돌아민 2,3-이산소화 효소 또는 이의 대사체 발현 수준을 측정하기 위한 키트는 항체의 면역학적 검출을 위하여 기질, 적당한 완충용액, 발색 효소 또는 형광물질로 표지된 2차 항체, 및 발색 기질 등을 포함할 수 있다. 상기에서 기질은 니트로셀룰로오스 막, 폴리비닐 수지로 합성된 96 웰 플레이트, 폴리스티렌 수지로 합성된 96 웰 플레이트 및 유리로 된 슬라이드 글라스 등이 이용될 수 있고, 발색효소는 퍼옥시다아제(peroxidase), 알칼라인 포스파타아제(alkaline phosphatase) 등이 사용될 수 있고, 형광물질은 FITC, RITC 등이 사용될 수 있고, 발색기질액은 ABTS(2,2'-아지노-비스-(3-에틸벤조티아졸린-6-설폰산)) 또는 OPD(O-페닐렌디아민), TMB(테트라메틸 벤지딘)가 사용될 수 있다. 바람직하게는 개체의 시료로부터 본 발명의 인돌아민 2,3-이산소화 효소 또는 이의 대사체 발현 수준을 확인함으로써 해당 개체의 전립선암 발병 여부뿐만 아니라, 향후 해당 개체의 생존 예후가 좋을지 여부에 대해서까지 예측할 수 있다.In addition, the kit for measuring the expression level of indoleamine 2,3-dioxygenase or metabolite thereof of the present invention is a substrate, a suitable buffer solution, a secondary antibody labeled with a color developing enzyme or a fluorescent substance for the immunological detection of the antibody. , And a color developing substrate, and the like. In the above, the substrate may be a nitrocellulose membrane, a 96-well plate synthesized with polyvinyl resin, a 96-well plate synthesized with polystyrene resin, and a slide glass made of glass, and the coloring enzyme is peroxidase, alkaline force Fatase (alkaline phosphatase), etc. can be used, FITC, RITC, etc. can be used as fluorescent materials, and ABTS (2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfur) Phonic acid)) or OPD (O-phenylenediamine), TMB (tetramethyl benzidine) can be used. Preferably, by checking the expression level of the indoleamine 2,3-dioxygenase of the present invention or its metabolite from the sample of the individual, not only whether the individual develops prostate cancer, but also whether the individual has a good survival prognosis in the future. It is predictable.
또한, 본 발명은 생물학적 시료로부터 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계를 포함하는 전립선암 진단 또는 전립선암 예후 예측을 위한 정보 제공 방법을 제공한다. In addition, the present invention provides a method of providing information for diagnosing prostate cancer or predicting prostate cancer prognosis, comprising measuring the expression level of indoleamine 2,3-dioxygenase or metabolite thereof from a biological sample.
상기 전립선암 진단 또는 전립선암 예후 예측을 위한 정보는 전립선암 환자의 인돌아민 2,3-이산소화 효소 또는 이의 대사체 발현에 대한 측정 정보이고, 본 발명의 목적상, 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현이 증가된 것으로 측정되는 경우 전립선암 위험군 혹은 전립선암 진행과 관련되며, 상기와 같은 정보를 기반으로 본 발명은 대상의 전립선암 진단 및 예후 예측을 포함한 구체적인 정보를 제공한다. The information for diagnosing prostate cancer or predicting prostate cancer prognosis is measurement information on the expression of indoleamine 2,3-dioxygenase or its metabolite in a patient with prostate cancer, and for the purposes of the present invention, indoleamine 2,3-diacid When it is determined that the expression of digestive enzymes or metabolites thereof is increased, it is related to the prostate cancer risk group or the progression of prostate cancer.Based on the above information, the present invention provides specific information including the diagnosis and prognosis of prostate cancer of the subject. do.
본 발명에 있어서 상기 생물학적 시료는 암 조직, 암 세포, 혈액, 혈청, 혈장, 림프액, 뇌척수액, 복수, 요 및 조직생검으로 이루어진 군에서 선택될 수 있으며, 바람직하게는 암 조직, 암 세포, 혈액 또는 혈청이나 이에 제한되지 않는다. In the present invention, the biological sample may be selected from the group consisting of cancer tissue, cancer cells, blood, serum, plasma, lymph fluid, cerebrospinal fluid, ascites, urine and tissue biopsy, preferably cancer tissue, cancer cells, blood or Serum but not limited thereto.
상기 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 확인하는 방법은 웨스턴 블롯, MALDI-TOF/MS, 효소면역분석법(enzyme-linked immunosorbent assay, ELISA), 방사선면역분석법(radioimmunoassay), 방사면역확산법(radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역확산법, 로케트(Ouchterlony) 면역 전기 영동, 조직 면역 염색, 면역 침전 분석(immunoprecipitation assay), 보체 고정 분석법(complete fixation assay), FACS(Flow Cytometry) 또는 단백질 칩(protein chip)을 포함할 수 있으며 상기 대사체가 화합물인 경우 발현 수준을 측정할 수 있는 방법은 질량분석기, 핵자기공명분광기, 액상 크로마토그래피, 고성능 액상 크로마토그래피(HPLC), 초고해상 액상 크로마토그래피(UPLC), 자외선분광기, 적외선분광기, 형광분광기 또는 ELISA(enzyme-linked immunosorbent assay)를 포함할 수 있으나 이에 제한되지 않는다.The method of checking the expression level of the indoleamine 2,3-dioxygenase or its metabolite is Western blot, MALDI-TOF/MS, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay. , Radioimmunodiffusion, Ouchterlony immunodiffusion, Ouchterlony immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complete fixation assay, FACS (Flow Cytometry) or protein chip, and when the metabolite is a compound, the method for measuring the expression level is mass spectrometry, nuclear magnetic resonance spectroscopy, liquid chromatography, high performance liquid chromatography (HPLC), ultra high Water liquid chromatography (UPLC), ultraviolet spectrophotometer, infrared spectrometer, fluorescence spectrometer, or ELISA (enzyme-linked immunosorbent assay) may be included, but is not limited thereto.
또한, 본 발명은 (a) 생물학적 시료에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계; (b) 전립선암 치료제 후보물질을 처리하는 단계; (c) 상기 후보물질이 처리된 생물학적 시료에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계; 및 (d) 상기 (a) 단계의 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현과 상기 (c) 단계의 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 비교하는 단계를 포함하는 전립선암 치료제의 스크리닝 방법을 제공한다. In addition, the present invention comprises the steps of: (a) measuring the expression level of indoleamine 2,3-dioxygenase or a metabolite thereof in a biological sample; (b) treating a candidate substance for prostate cancer treatment; (c) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in the biological sample treated with the candidate substance; And (d) comparing the expression level of the indoleamine 2,3-dioxygenase or metabolite thereof in the step (a) and the indoleamine 2,3-dioxygenase or metabolite thereof in the step (c). It provides a method for screening a prostate cancer therapeutic agent comprising the step of.
본 발명에 있어서 상기 생물학적 시료는 암 조직, 암 세포, 혈액, 혈청, 혈장, 림프액, 뇌척수액, 복수, 요 및 조직생검으로 이루어진 군에서 선택될 수 있으며, 바람직하게는 암 조직, 암 세포, 혈액 또는 혈청이나 이에 제한되지 않는다. In the present invention, the biological sample may be selected from the group consisting of cancer tissue, cancer cells, blood, serum, plasma, lymph fluid, cerebrospinal fluid, ascites, urine and tissue biopsy, preferably cancer tissue, cancer cells, blood or Serum but not limited thereto.
구체적으로, 전립선암 치료제 후보 물질의 존재 및 부존재하에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 증가 또는 감소를 비교하는 방법으로 암 치료제를 스크리닝하는데 유용하게 사용할 수 있다. 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 간접적으로 또는 직접적으로 감소시키는 물질은 본 발명에서 개시하고 있는 전립선암의 치료제로서 선택할 수 있다.Specifically, it can be usefully used for screening cancer therapeutics by comparing the increase or decrease in the expression of indoleamine 2,3-dioxygenase or its metabolite in the presence and absence of a prostate cancer therapeutic agent candidate substance. A substance that indirectly or directly reduces the expression level of indoleamine 2,3-dioxygenase or its metabolite can be selected as a therapeutic agent for prostate cancer disclosed in the present invention.
본 명세서에서 달리 정의되지 않은 용어들은 본 발명이 속하는 기술분야에서 통상적으로 사용되는 의미를 갖는 것이다.Terms that are not otherwise defined in the present specification have the meanings commonly used in the technical field to which the present invention pertains.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail by examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following.
실시예Example 1. One. 인돌아민Indoleamine 2,3-이산소화효소( 2,3-dioxygenase ( indoleamineindoleamine 2,3- 2,3- dioxygenasedioxygenase , IDO) 또는 이의 , IDO) or objection 대사체의Metabolic 발현 확인을 위한 전립선암 세포주 및 혈청의 수득 Obtaining prostate cancer cell line and serum for expression confirmation
인돌아민 2,3-이산소화효소(이하, 'IDO') 또는 이의 대사체인 N-포밀 키누레닌(N-formyl kynurenine)의 발현을 확인하기 위하여, 전립선암 세포주(PC-3) 및 인간 정상 폐섬유 조직 세포(WI-38)를 선정하였다. 본 실험에서는 각각의 세포주들을 CO 2 incubator에서 T-75 flask를 사용하여 배양하였고, 각각 PC-3은 RPMI, WI-38은 EMEM를 사용하고 10% FBS, 1% Penicillin으로 조성된 배양액을 사용하여 배양시킨 후 사용하였다. 더불어 N-포밀 키누레닌의 발현 확인을 위해서는 추가적으로 정상 혈청 및 전립선암 위험군 혈청을 칠곡경북대학교병원으로부터 제공받아 사용하였다. In order to confirm the expression of indoleamine 2,3-dioxygenase (hereinafter,'IDO') or its metabolite, N-formyl kynurenine, prostate cancer cell line (PC-3) and human normal lung Fibrous tissue cells (WI-38) were selected. In this experiment, each cell line was cultured using a T-75 flask in a CO 2 incubator, respectively, using RPMI for PC-3, EMEM for WI-38, and a culture medium composed of 10% FBS and 1% Penicillin. It was used after incubation. In addition, to confirm the expression of N-formyl kynurenine, additional normal serum and prostate cancer risk group serum were provided and used from Chilgok Kyungpook National University Hospital.
또한, 신규 코호트 혈청 샘플(정상 50개, 전립선암 50개)을 경북대학교병원으로부터 제공받아 본 실험을 위해 사용하였다. In addition, new cohort serum samples (normal 50, prostate cancer 50) were provided from Kyungpook National University Hospital and used for this experiment.
실시예 2. IDO 발현 확인을 통한 IDO의 암 진단 및 예후 예측의 바이오마커로서의 가능성 확인 Example 2. Confirmation of the possibility of IDO as a biomarker of cancer diagnosis and prognosis through identification of IDO expression
실시예 2.1. 세포주에서의 IDO 발현 확인을 통한 IDO의 암 진단 및 예후 예측의 바이오마커로서의 가능성 확인 Example 2.1. Identification of the possibility of IDO as a biomarker for cancer diagnosis and prognosis through identification of IDO expression in cell lines
IDO가 전립선암 진단 및 전립선암 환자의 예후를 예측할 수 있는 마커로서의 이용가능성을 확인하기 위하여, 상기 실시예 1에서 결정한 실험군인 전립선암 세포주(PC-3)와 대조군인 인간 정상 폐섬유 조직 세포(WI-38)에서의 IDO의 발현의 차이를 비교하였다. 상기 실험군과 대조군의 IDO 발현은 ELISA assay kit를 사용하여 확인하였고, 그 결과를 도 1에 나타내었다. In order to confirm the availability of IDO as a marker capable of diagnosing prostate cancer and predicting the prognosis of patients with prostate cancer, the experimental group prostate cancer cell line (PC-3) and the control human normal lung fibrous tissue cells ( WI-38) was compared with the difference in the expression of IDO. The expression of IDO in the experimental group and the control group was confirmed using an ELISA assay kit, and the results are shown in FIG. 1.
도 1에 나타난 바와 같이, 전립선암 세포주(PC-3)에서의 IDO 발현(1729.497 mU/mg)이 대조군에서 검출된 발현(483.1597 mU/mg)에 비해 약 3.58배 증가한 것을 확인하였다. 따라서, 전립선암 환자에게만 특이적으로 발현이 증가하는 IDO가 바이오마커로서 활용될 수 있으며, 또한 세포 내 IDO 발현을 측정하면 전립선암을 손쉽게 진단할 수 있음을 확인하였다. As shown in FIG. 1, it was confirmed that the expression of IDO (1729.497 mU/mg) in the prostate cancer cell line (PC-3) increased by about 3.58 times compared to the expression (483.1597 mU/mg) detected in the control group. Accordingly, it was confirmed that IDO, whose expression is specifically increased only in prostate cancer patients, can be used as a biomarker, and that prostate cancer can be easily diagnosed by measuring intracellular IDO expression.
실시예 2.2. 신규 코호트 혈청에서의 IDO 발현 확인을 통한 IDO의 암 진단 및 예후 예측의 바이오마커로서의 가능성 확인 Example 2.2. Identification of the possibility of IDO as a biomarker for cancer diagnosis and prognosis through identification of IDO expression in new cohort serum
IDO가 전립선암 진단 및 전립선암 환자의 예후를 예측할 수 있는 마커로서의 이용가능성을 확인하기 위하여, 상기 실시예 1에서 경북대학교병원으로부터 제공받은 신규 코호트 혈청 샘플에서의 IDO 발현을 분석하였다. 상기 신규 코호트 혈청 샘플에서의 IDO 발현을 ELISA assay kit를 사용하여 확인하였고, 그 결과를 도 2에 나타내었다. In order to confirm the availability of IDO as a marker for diagnosing prostate cancer and predicting the prognosis of patients with prostate cancer, the expression of IDO in a new cohort serum sample provided from Kyungpook National University Hospital in Example 1 was analyzed. IDO expression in the new cohort serum sample was confirmed using an ELISA assay kit, and the results are shown in FIG. 2.
도 2에 나타난 바와 같이, 전립선암 혈청 샘플에서의 IDO 발현(11399.92 mU/mg)이 정상 혈청 샘플에서의 IDO 발현(9667.964 mU/mg)보다 통계적으로 유의미하게 증가한 것을 확인하였다. 따라서, 전립선암 환자에게만 특이적으로 발현이 증가하는 IDO가 바이오마커로서 활용될 수 있으며, 또한 혈청 내 IDO 발현을 측정하면 전립선암을 손쉽게 진단할 수 있음을 확인하였다.As shown in FIG. 2, it was confirmed that the IDO expression (11399.92 mU/mg) in the prostate cancer serum sample was statistically significantly increased compared to the IDO expression (9667.964 mU/mg) in the normal serum sample. Accordingly, it was confirmed that IDO, whose expression is specifically increased only in prostate cancer patients, can be used as a biomarker, and that prostate cancer can be easily diagnosed by measuring the expression of IDO in serum.
실시예 3. IDO의 대사체인 N-포밀 키누레닌(N-formyl kynurenine) 발현양 확인을 통한 N-포밀 키누레닌(N-formyl kynurenine)의 암 진단 및 예후 예측의 바이오마커로서의 가능성 확인 Example 3. Confirmation of the possibility of N-formyl kynurenine as a biomarker for cancer diagnosis and prognosis prediction by confirming the expression level of N-formyl kynurenine, which is a metabolite of IDO
실시예 3.1. 세포주 및 혈청에서의 N-포밀 키누레닌의 발현양 확인 Example 3.1. Confirmation of the expression level of N-formyl kynurenine in cell lines and serum
IDO는 트립토판의 대사 과정에 관여하는 키누레닌 경로(kynurenine pathway)에 포함되는 헴-포함 효소로서, 보다 구체적으로 상기 키누레닌 경로의 첫 단계에서는 IDO를 통해 L-트립토판이 N-포밀 키누레닌으로 산화된다. IDO is a heme-containing enzyme included in the kynurenine pathway involved in the metabolic process of tryptophan. More specifically, in the first step of the kynurenine pathway, L-tryptophan is oxidized to N-formyl kynurenine through IDO. do.
따라서, IDO 대사체인 N-포밀 키누레닌의 전립선암 진단 및 전립선암 환자의 예후를 예측할 수 있는 마커로서의 이용가능성을 확인하기 위하여, 상기 실시예 1에서 결정한 실험군인 전립선암 세포주(PC-3), 대조군인 인간 정상 폐섬유 조직 세포(WI-38), 정상 혈청(control sera) 및 전립선암 위험군 혈청(PCa sera)에서의 N-포밀 키누레닌의 발현양의 차이를 비교하였다. 상기 N-포밀 키누레닌 발현은 ELISA assay kit를 사용하여 확인하였고, 그 결과를 도 3에 나타내었다. Therefore, in order to confirm the availability of the IDO metabolite, N-formyl kynurenine, as a marker capable of predicting prostate cancer diagnosis and prognosis of prostate cancer patients, the experimental group determined in Example 1, the prostate cancer cell line (PC-3), Differences in the expression levels of N-formyl kynurenine in the control human normal lung fibrous tissue cells (WI-38), normal serum (control sera), and prostate cancer risk group serum (PCa sera) were compared. The N-formyl kynurenine expression was confirmed using an ELISA assay kit, and the results are shown in FIG. 3.
도 3에 나타난 바와 같이, 전립선암 세포주(PC-3)에서의 N-포밀 키누레닌 발현양(700.4464 pmole)이 대조군(WI-38)에서 검출된 양(443.5406 pmole)에 비해 통계적으로 유의미하게 증가한 것을 확인하였으며 정상 혈청에서의 N-포밀 키누레닌 발현양(2954.856 pmole)에 비해 전립선암 위험군 혈청에서의 N-포밀 키누레닌 발현양(3312.203 pmole)이 증가한 것을 확인하였다. 따라서, 전립선암 환자에게만 특이적으로 발현이 증가하는 N-포밀 키누레닌이 바이오마커로서 활용될 수 있으며, 또한 세포 및 혈청 내 N-포밀 키누레닌 발현양을 측정하면 전립선암을 손쉽게 진단할 수 있음을 확인하였다.As shown in Figure 3, the amount of N-formyl kynurenine expression (700.4464 pmole) in the prostate cancer cell line (PC-3) was statistically significantly increased compared to the amount (443.5406 pmole) detected in the control (WI-38). It was confirmed that the amount of N-formyl kynurenine (3312.203 pmole) in the serum of the prostate cancer risk group was increased compared to that of the N-formyl kynurenine (2954.856 pmole) in the normal serum. Therefore, N-formyl kynurenine, whose expression is specifically increased only in prostate cancer patients, can be used as a biomarker, and also, prostate cancer can be easily diagnosed by measuring the amount of N-formyl kynurenine expression in cells and serum. Was confirmed.
실시예 3.2. 신규 코호트 혈청에서의 N-포밀 키누레닌 발현양 확인 Example 3.2. Confirmation of N-formyl kynurenine expression level in new cohort serum
N-포밀 키누레닌의 전립선암 진단 및 전립선암 환자의 예후를 예측할 수 있는 마커로서의 이용가능성을 확인하기 위하여, 상기 실시예 1에서 경북대학교병원으로부터 제공받은 신규 코호트 혈청 샘플에서의 N-포밀 키누레닌 발현양을 분석하였다. 상기 신규 코호트 혈청 샘플에서의 N-포밀 키누레닌 발현을 ELISA assay kit를 사용하여 확인하였고, 그 결과를 도 4에 나타내었다. In order to confirm the availability of N-formyl kynurenine as a marker capable of predicting prostate cancer diagnosis and prognosis of prostate cancer patients, N-formyl kynurenine in a new cohort serum sample provided from Kyungpook National University Hospital in Example 1 above. The amount of expression was analyzed. The expression of N-formyl kynurenine in the new cohort serum sample was confirmed using an ELISA assay kit, and the results are shown in FIG. 4.
도 4에 나타난 바와 같이, 전립선암 혈청 샘플에서의 N-포밀 키누레닌 발현양(754.1928 pmole)이 정상 혈청 샘플에서의 N-포밀 키누레닌 발현양(644.604 pmole)보다 증가한 것을 확인하였다. 따라서, 전립선암 환자에게만 특이적으로 발현이 증가하는 N-포밀 키누레닌이 바이오마커로서 활용될 수 있으며, 또한 혈청 내 N-포밀 키누레닌 발현양을 측정하면 전립선암을 손쉽게 진단할 수 있음을 확인하였다.As shown in FIG. 4, it was confirmed that the expression amount of N-formyl kynurenine (754.1928 pmole) in the prostate cancer serum sample was increased than that of the N-formyl kynurenine expression amount (644.604 pmole) in the normal serum sample. Therefore, it was confirmed that N-formyl kynurenine, which is specifically increased in expression only in prostate cancer patients, can be used as a biomarker, and that prostate cancer can be easily diagnosed by measuring the amount of N-formyl kynurenine expression in serum. I did.
상기 실시예를 통해 본 발명의 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 이용할 경우 상기 효소 및 대사체의 발현 분석을 통해 전립선암의 빠르고 정확한 진단 또는 예후 예측이 가능하여 전립선암 진단 또는 예후 예측을 위한 바이오마커로 활용할 수 있음을 확인하였다. In the case of using the indoleamine 2,3-dioxygenase or metabolite thereof of the present invention through the above examples, it is possible to quickly and accurately diagnose prostate cancer or predict prognosis through the expression analysis of the enzyme and metabolite. It was confirmed that it can be used as a biomarker for predicting prognosis.

Claims (9)

  1. 인돌아민 2,3-이산소화 효소 또는 이의 대사체를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 바이오마커 조성물. A biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis, including indoleamine 2,3-dioxygenase or a metabolite thereof.
  2. 제 1항에 있어서, 상기 대사체는 N-포밀 키누레닌(N-formyl kynurenine)인 것을 특징으로 하는 전립선암 진단 또는 전립선암 예후 예측용 바이오마커 조성물. The biomarker composition for diagnosing prostate cancer or predicting prostate cancer prognosis according to claim 1, wherein the metabolite is N-formyl kynurenine.
  3. 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 제제를 포함하는 전립선암 진단 또는 전립선암 예후 예측용 조성물. A composition for diagnosing prostate cancer or predicting prostate cancer prognosis, comprising an agent for measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite.
  4. 제 3항에 있어서, 상기 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준의 측정은 웨스턴 블롯, MALDI-TOF/MS, 효소면역분석법(enzyme-linked immunosorbent assay, ELISA), 방사선면역분석법(radioimmunoassay), 방사면역확산법(radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역확산법, 로케트(Ouchterlony) 면역 전기 영동, 조직 면역 염색, 면역 침전 분석(immunoprecipitation assay), 보체 고정 분석법(complete fixation assay), FACS(Flow Cytometry), 단백질 칩(protein chip), 질량분석기, 핵자기공명분광기, 액상 크로마토그래피, 고성능 액상 크로마토그래피(HPLC), 초고해상 액상 크로마토그래피(UPLC), 자외선분광기, 적외선분광기 및 형광분광기로 이루어진 군에서 선택된 1종 이상의 방법에 의해 측정되는 것을 특징으로 하는 전립선암 진단 또는 전립선암 예후 예측용 조성물. The method of claim 3, wherein the measurement of the expression level of the indoleamine 2,3-dioxygenase or its metabolite is Western blot, MALDI-TOF/MS, enzyme-linked immunosorbent assay (ELISA), radioimmunity. Radioimmunoassay, radioimmunodiffusion, Ouchterlony immunodiffusion, Ouchterlony immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complete fixation assay , FACS (Flow Cytometry), protein chip, mass spectrometer, nuclear magnetic resonance spectroscopy, liquid chromatography, high performance liquid chromatography (HPLC), ultra high resolution liquid chromatography (UPLC), ultraviolet spectrometer, infrared spectrometer and fluorescence A composition for diagnosing prostate cancer or predicting prostate cancer prognosis, characterized in that measured by at least one method selected from the group consisting of a spectroscope.
  5. 제 3항 또는 제 4항의 조성물을 포함하는 전립선암 진단 또는 전립선암 예후 예측용 키트. A kit for diagnosing prostate cancer or predicting prostate cancer prognosis comprising the composition of claim 3 or 4.
  6. 제 5항에 있어서, 상기 키트는 ELISA 키트, 마이크로어레이 칩 키트 및 단백질 칩 키트로 이루어진 군에서 선택된 1종 이상인 것을 특징으로 하는 전립선암 진단 또는 전립선암 예후 예측용 키트. The kit for diagnosing prostate cancer or predicting prostate cancer prognosis according to claim 5, wherein the kit is at least one selected from the group consisting of an ELISA kit, a microarray chip kit, and a protein chip kit.
  7. 시료로부터 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계를 포함하는 전립선암 진단 또는 전립선암 예후 예측을 위한 정보 제공 방법. A method of providing information for diagnosing prostate cancer or predicting prostate cancer prognosis, comprising measuring the expression level of indoleamine 2,3-dioxygenase or a metabolite thereof from a sample.
  8. 제 7항에 있어서, 상기 시료는 암 조직, 암 세포, 혈액, 혈청, 혈장, 림프액, 뇌척수액, 복수, 요 및 조직생검으로 이루어진 군에서 선택되는 것을 특징으로 하는 전립선암 진단 또는 전립선암 예후 예측을 위한 정보 제공 방법. The method of claim 7, wherein the sample is selected from the group consisting of cancer tissue, cancer cells, blood, serum, plasma, lymph, cerebrospinal fluid, ascites, urine, and tissue biopsy. How to provide information.
  9. (a) 생물학적 시료에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계;(a) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in the biological sample;
    (b) 전립선암 치료제 후보물질을 처리하는 단계;(b) treating a candidate substance for prostate cancer treatment;
    (c) 상기 후보물질이 처리된 생물학적 시료에서 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 측정하는 단계; 및(c) measuring the expression level of indoleamine 2,3-dioxygenase or its metabolite in the biological sample treated with the candidate substance; And
    (d) 상기 (a) 단계의 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현과 상기 (c) 단계의 인돌아민 2,3-이산소화 효소 또는 이의 대사체의 발현 수준을 비교하는 단계;를 포함하는 전립선암 치료제의 스크리닝 방법.(d) comparing the expression level of the indoleamine 2,3-dioxygenase or metabolite thereof in the step (a) and the indoleamine 2,3-dioxygenase or metabolite thereof in the step (c) Step; Screening method for a prostate cancer therapeutic agent comprising.
PCT/KR2020/012143 2019-09-10 2020-09-09 Prostate cancer diagnostic marker containing indoleamine 2,3-dioxygenase WO2021049862A1 (en)

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