US20140038838A1 - Use of markers in the diagnosis and treatment of prostate cancer - Google Patents

Use of markers in the diagnosis and treatment of prostate cancer Download PDF

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US20140038838A1
US20140038838A1 US13/929,723 US201313929723A US2014038838A1 US 20140038838 A1 US20140038838 A1 US 20140038838A1 US 201313929723 A US201313929723 A US 201313929723A US 2014038838 A1 US2014038838 A1 US 2014038838A1
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keratin
prostate cancer
level
filamin
subject
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Niven Rajin Narain
Rangaprasad Sarangarajan
Vivek K. Vishnudas
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Berg Pharma LLC
BERG LLC
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Individual
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Priority to US15/059,238 priority patent/US9797905B2/en
Priority to US15/706,105 priority patent/US20180031563A1/en
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    • 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
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4742—Keratin; Cytokeratin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the invention relates to treatment, prevention, reduction, diagnosis, monitoring, and prognosis of abnormal prostate states, including benign prostate hyperplasia and oncological disorders, especially prostate cancer, in humans using filamin B, lymphocyte antigen 9 (LY9), keratins and tubulin, specifically using keratins 4, 7, 8, 15, 18, and 19, and tubulin-beta 3, particularly keratins 7, 15, or 19.
  • the filamin B, lymphocyte antigen 9 (LY9), keratins and tubulin can further be used in conjunction with prostate specific antigen (PSA) for the treatment, prevention, reduction, diagnosis, monitoring, and prognosis of abnormal prostate states, including benign prostate hyperplasia and oncological disorders, especially prostate cancer.
  • PSA prostate specific antigen
  • the invention also relates to panels and kits for use in practicing the methods of the invention.
  • Oncological disorders such as cancer
  • cancer are presently one of the leading causes of death in developed countries and is a serious threat to modern society.
  • Cancer can develop in any tissue of any organ at any age. Worldwide, more than 10 million people are diagnosed with cancer every year and it is estimated that this number will grow to 15 million new cases every year by 2020. It is believed that cancer causes six million deaths every year or 12% of the deaths worldwide.
  • Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing. However, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly to the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Other symptoms can potentially develop during later stages of the disease.
  • Prostate cancer tends to develop in men over the age of fifty and, although it is one of the most prevalent types of cancer in men, many never have symptoms or undergo therapy for prostate cancer, and eventually die of other causes. Further, treatment of prostate cancer may do more harm to the subject than the prostate cancer itself.
  • Prostate specific antigen (PSA) screening has lead to a significant rise in the number of men diagnosed with prostate cancer with an associated increase in potentially unnecessary biopsies preformed. Despite its limitations, including a positive predictive value of only 25-40%, PSA remains the only generally accepted biomarker for prostate cancer.
  • Prostate cancer is, in most cases, slow-growing and symptom-free. Moreover, since men with the condition are typically older, they often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unrelated cancers, or old age. On the other hand, the more aggressive prostate cancers account for more cancer-related deaths among men in the United States than any other cancer except lung cancer.
  • prostate cancer cases are slow growing, whereas the other third are more aggressive and fast developing. It is important to be able to distinguish between aggressive and non-aggressive forms of the disease, and further, to distinguish prostate cancer from benign prostate hyperplasia (BPH). Commonly used screening tests, e.g., for prostate specific antigen (PSA) cannot distinguish between prostate cancer and BPH.
  • PSA prostate specific antigen
  • the present invention is based, at least in part, on Applicants' discovery that keratins 4, 7, 8, 15, 18, and 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) are differentially regulated in prostate cancer cells.
  • the invention provides methods for diagnosing, monitoring (e.g., of disease progression or treatment), prognosing, treating, alleviating symptoms of, inhibiting progression of, or preventing, an oncological disease state, e.g., prostate cancer, in a mammal.
  • the invention further provides panels and kits for practicing the methods of the invention.
  • the invention provides methods for diagnosing an abnormal prostate state in a subject comprising:
  • the one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19. In certain embodiments, an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to a normal control sample is indicative of an abnormal prostate state in the subject.
  • no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to a normal control sample is indicative of a normal prostate state in the subject.
  • levels of one, two, or all three of filamin B, LY9, and keratin 19 can be detected. For the marker levels detected, none of the markers have increased levels.
  • the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample and preferably further comprising comparing the level of PSA in the biological sample to the level of PSA in a normal control sample.
  • PSA prostate specific antigen
  • an increase in the level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample has greater predictive value of the subject having an abnormal prostate state than the predictive value of a single marker alone.
  • no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample has a greater predictive value of the subject having a normal prostate state than any single marker alone.
  • one or more of filamin B, LY9 and keratin 19 is understood as any of filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
  • the abnormal prostate state is prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer. In certain embodiments of the invention, the prostate cancer is androgen-independent prostate cancer. In certain embodiments of the invention, the prostate cancer is aggressive prostate cancer. In certain embodiments of the invention, the prostate cancer is non-aggressive prostate cancer.
  • the abnormal prostate state is benign prostate hyperplasia.
  • the invention provides a method for identifying a subject as being at increased risk for developing prostate cancer, the method comprising:
  • prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a biological sample from the subject; and
  • the one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19.
  • an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample is indicative of an increased risk for developing prostate cancer in the subject.
  • no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample is indicative of no increased risk for developing prostate cancer in the subject.
  • the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample and preferably further comprises comparing the level of PSA in the biological sample to the level of PSA in a normal control sample.
  • PSA prostate specific antigen
  • an increase in the level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample has greater predictive value of an increased risk for developing prostate cancer in the subject than an increase in any of the individual markers alone.
  • no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, has greater predictive value of no increased risk for developing prostate cancer in the subject than any single marker alone.
  • one or more prostate cancer markers selected from the group consisting of filamin B, LY9 and keratin 19 is: filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments, one or more prostate cancer related markers is selected from the group consisting of keratin 7, keratin 8, and keratin 15. In certain embodiments, one or more prostate cancer related markers is selected from the group consisting of keratin 7 and keratin 15. In certain embodiments, one or more prostate cancer markers is selected from the group consisting of keratin 7, 15, and 19.
  • the diagnostic and prognostic methods of the invention further comprise detecting the level of prostate specific antigen (PSA) in the biological sample, and preferably further comprise comparing the level of PSA in the biological sample to a level of PSA in a control sample.
  • PSA prostate specific antigen
  • control sample for PSA is the same control sample as for the other prostate cancer related markers of the invention. In certain embodiments, the control sample for PSA is different from the control sample for the other prostate cancer related markers of the invention
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an abnormal prostate state in the subject.
  • a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an abnormal prostate state in the subject.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of a normal prostate state in the subject.
  • a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of a normal prostate state in the subject.
  • prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an increased risk of developing prostate cancer in the subject.
  • a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an increased risk of developing prostate cancer in the subject.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of no increased risk of developing prostate cancer in the subject.
  • a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of no increased risk of developing prostate cancer in the subject.
  • the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample, and preferably further comprises comparing the level of PSA in the biological sample to the level of PSA in a normal control sample.
  • PSA prostate specific antigen
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increase in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an abnormal prostate state in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an decrease in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an abnormal prostate state in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, is indicative of a normal prostate state in the subject.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of a normal prostate state in the subject.
  • the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample, and preferably further comprises comparing the level of PSA in the biological sample to the level of PSA in a normal control sample.
  • PSA prostate specific antigen
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increase in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an increased risk for the subject of developing prostate cancer wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an decrease in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an increased risk for the subject of developing prostate cancer wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, is indicative of an decreased risk or normal risk of developing prostate cancer in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of a decreased risk or normal risk of developing prostate cancer in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • the method may further comprise comparing the level of the one or more prostate cancer related markers in the biological sample with the level of the one or more prostate cancer related markers in a control sample selected from the group consisting of: a sample obtained from the same subject at an earlier time point than the biological sample, a sample from a subject with benign prostatic hyperplasia (BPH), a sample from a subject with non-metastatic prostate cancer, a sample from a subject with metastatic prostate cancer, a sample from a subject with androgen sensitive prostate cancer, a sample from a subject with androgen insensitive prostate cancer, a sample from a subject with aggressive prostate cancer, and a sample from a subject with non-aggressive prostate cancer.
  • BPH benign prostatic hyperplasia
  • comparison with one or more additional control sample can facilitate differentiating between two prostate cancer states selected from the group consisting of: normal prostate and prostate cancer, benign prostate hyperplasia and prostate cancer, benign prostate hyperplasia and normal prostate, androgen dependent and androgen independent prostate cancer, aggressive prostate cancer and non-aggressive prostate cancer, and metastatic prostate cancer and non-metastatic prostate cancer; or differentiating between any two or more of normal prostate, prostate cancer, benign prostate hyperplasia, androgen dependent prostate cancer, androgen independent prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, and non-metastatic prostate cancer.
  • the method when a tumor is present, the method further comprises detecting the size of the prostate tumor in the subject.
  • the method further comprises obtaining a sample from a subject.
  • the method further comprises selecting a subject who has or is suspected of having prostate cancer.
  • the method further comprises selecting a treatment regimen for the subject based on the level of the one or more prostate cancer markers. In certain embodiments of the invention, the method further comprises treating the subject with a a treatment regimen based on the level of the one or more prostate cancer markers. In certain embodiments, a treatment regimen comprises one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, growth factor therapy, cytokine therapy, and chemotherapy.
  • the invention provides methods for monitoring prostate cancer in a subject, the method comprising
  • prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a first biological sample obtained at a first time from a subject having prostate cancer;
  • the subject is actively treated for prostate cancer prior to obtaining the second sample. That is, the subject is undergoing active treatment for prostate cancer.
  • the subject is not actively treated for prostate cancer prior to obtaining the second sample. That is, the subject is being monitored using watchful waiting.
  • one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19.
  • an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample as compared to the first biological sample is indicative of progression of the prostate cancer in the subject.
  • no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample as compared to the first biological sample is indicative of non-progression of the prostate cancer in the subject.
  • the methods further comprise determining the level of prostate specific antigen (PSA) in the first biological sample and the second biological sample and preferably, further comprising comparing the level of PSA in the second biological sample to the level of PSA in the first biological sample.
  • PSA prostate specific antigen
  • an increased level of the one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample relative to the level of the one or more prostate cancer related markers in the first biological sample in combination with an increase in the level of PSA in the second biological sample relative to the level of PSA in the first biological sample has greater predictive value of progression of the prostate cancer in the subject than any single marker alone.
  • no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample relative to the level of the one or more prostate cancer related markers in the first biological sample in combination with a decreased or same level of PSA in the second biological sample relative to the level of PSA in the first biological sample has greater predictive value of non-progression of the prostate cancer in the subject than any single marker alone.
  • the one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 is: filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
  • the one or more prostate cancer markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments of the monitoring methods of the invention, the one or more prostate cancer related markers is selected from the group consisting of keratin 7, keratin 8, and keratin 15. In certain embodiments of the monitoring methods of the invention, the one or more prostate cancer related markers is selected from the group consisting of keratin 7, keratin 15, and keratin 19. In certain embodiments of the monitoring methods of the invention, the one or more prostate cancer related markers is selected from the group consisting of keratin 7 and keratin 15.
  • the methods further comprise determining the level of prostate specific antigen (PSA) in the first biological sample and the second biological sample, and preferably further comprise comparing the level of PSA in the second biological sample to the level of PSA in the first biological sample.
  • PSA prostate specific antigen
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of prostate tumor progression in the subject.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • a decreased or normal level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of prostate tumor progression in the subject.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of no prostate tumor progression in the subject.
  • a decreased or normal level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of no prostate tumor progression in the subject.
  • the method further comprises detecting the level of prostate specific antigen (PSA) in the second sample, and preferably further comprises comparing the level of PSA in the second sample to the level of PSA in a first sample.
  • PSA prostate specific antigen
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increase in the level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with an increase in the level of PSA in the second sample as compared to the level of PSA in the first sample is indicative of prostate tumor progression in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an decrease in the level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with an increase in the level of PSA in the second sample as compared to the level of PSA in the first sample is indicative of prostate tumor progression in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • a decreased or normal level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with a decreased or normal level of PSA in the second sample as compared to the level of PSA in the first sample, is indicative of no prostate tumor progression in the subject.
  • one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3
  • an increased or normal level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with a decreased or normal level of PSA in the second sample as compared to the level of PSA in the first sample is indicative of no prostate tumor progression in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
  • the methods further comprise comparing the level of the one or more prostate cancer related markers in the first biological sample or the second biological sample with the level of the one or more prostate cancer related markers in a control sample selected from the group consisting of: a normal control sample, a sample from a subject with benign prostatic hyperplasia (BPH), a sample from a subject with non-metastatic prostate cancer, a sample from a subject with metastatic prostate cancer, a sample from a subject with androgen sensitive prostate cancer, a sample from a subject with androgen insensitive prostate cancer, a sample from a subject with aggressive prostate cancer, and a sample from a subject with non-aggressive prostate cancer.
  • BPH benign prostatic hyperplasia
  • the methods further comprise detecting the size of the prostate tumor in the subject.
  • the methods further comprise obtaining a first sample and a second sample from the subject.
  • the methods further comprise selecting and/or administering a different treatment regimen for the subject based on progression of the prostate cancer in the subject.
  • the methods further comprise comprises maintaining a treatment regimen for the subject based on non-progression of the prostate cancer in the subject.
  • the treatment regimens comprise one or more treatments selected from the group consisting of: surgery, radiation, hormone therapy, antibody therapy, growth factor therapy, cytokine therapy, and chemotherapy.
  • the methods further comprise withholding an active treatment of the prostate cancer in the subject based on non-progression of the prostate cancer in the subject.
  • the active treatment is one or more treatments selected from the group consisting of: surgery, radiation, hormone therapy, antibody therapy, growth factor therapy, cytokine therapy, and chemotherapy.
  • the invention provides methods for detecting a set of prostate cancer related markers, the method comprising:
  • prostate cancer related markers comprises filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
  • the set of prostate cancer related markers comprises filamin B, LY9, and keratin 19.
  • the two or more prostate cancer related markers are: filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
  • the set of prostate cancer related markers comprises keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3.
  • the set of prostate cancer related markers comprises keratin 7, keratin 8, and keratin 15.
  • the set of prostate cancer related markers comprises keratin 7, keratin 15, and keratin 19.
  • the set of prostate cancer related markers comprises keratin 7 and keratin 15.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises isolating a component of the biological sample.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises labeling a component of the biological sample.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises processing the biological sample.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises contacting a prostate cancer related marker to be detected with a prostate cancer related marker binding agent.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises forming a complex between a prostate cancer related marker to be detected and a prostate cancer related marker binding agent.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises contacting each of the one or more prostate cancer related markers with a prostate cancer related marker binding agent.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises forming a complex between each of the one or more prostate cancer related markers and a prostate cancer related marker binding agent.
  • the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises attaching a prostate cancer related marker to be detected to a solid surface.
  • the invention provides a panel of reagents for use in a detection method, the panel comprising at least two detection reagents, wherein each detection reagent is specific for the detection of at least one prostate cancer related marker of a set of prostate cancer related markers, wherein the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3 and PSA.
  • the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19.
  • the two or more prostate cancer related markers is: filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
  • the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments, the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of keratin 7, keratin 8, and keratin 15. In certain embodiments, the set of prostate cancer specific markers comprises keratin 7 and keratin 15.
  • the set of prostate cancer specific markers further comprises PSA.
  • the panel of reagents comprises a detection reagent specific for the detection of PSA.
  • the invention provides for the use of any of the foregoing panels of the invention in any of the methods provided by the invention.
  • the invention provides a kit for the diagnosis, monitoring, or characterization of an abnormal prostate state, comprising: at least one reagent specific for the detection of a level of at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9.
  • the kit further comprises instructions for the diagnosis, monitoring, or characterization of an abnormal prostate state based on the level of the at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 detected.
  • the kit further comprises instructions to detect the level of PSA in a sample in which the at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 is detected.
  • the at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 is detected.
  • the kit further comprises at least one reagent specific for the detection of a level of PSA.
  • the invention provides a kit comprising at least one reagent specific for the detection of a level of at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, and LY9 and at least one reagent specific for the detection of a level of PSA.
  • the invention provides methods for diagnosing prostate cancer comprising determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in a biological sample obtained from a subject; and comparing the level of expression of the one or more markers in the biological sample obtained from the subject with the level of expression of the corresponding one or more markers in a control sample, wherein a modulation in the level of expression of the one or more markers in the biological sample is an indication that the subject is afflicted with prostate cancer.
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9
  • an increase in the level of expression of filamin B (FLNB), lymphocyte antigen 9 (LY9), or keratin 19 in the biological sample as compared to a normal control sample is an indication that the subject is afflicted with prostate cancer.
  • the invention further provides methods prognosing whether a subject is predisposed to developing prostate cancer, the method comprising determining the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) present in a biological sample obtained from the subject; and comparing the level of expression of the one or more markers present in the biological sample obtained from the subject with the level of expression of the corresponding markers in a control sample, wherein a modulation in the level of expression of the one or more markers in the biological sample obtained from the subject with the level of expression of the corresponding marker in a control sample is an indication that the subject is predisposed to developing prostate cancer.
  • the invention further provides methods for monitoring the treatment of prostate cancer in a subject, the methods comprising determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) present in a first sample obtained from the subject prior to administering at least a portion of a treatment regimen to the subject; determining a level of expression of a corresponding one or more markers in a second sample obtained from the subject following administration of at least a portion of the treatment regimen to the subject; and comparing the level of expression of the one or more markers in the first sample with the expression level of the corresponding one or more markers in the second sample, wherein a modulation in the level of expression of the one or more in the second sample as compared to the one or more markers in the first sample is an indication of a
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) further include detection of prostate specific antigen (PSA) for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • PSA prostate specific antigen
  • the invention also provides methods for diagnosing prostate cancer comprising determining a level of expression of keratin 7 or keratin 15 in a biological sample obtained from a subject; and comparing the level of expression of keratin 7 or keratin 15 in the biological sample obtained from the subject with the level of expression of keratin 7 or keratin 15 in a control sample, wherein an modulation in the level of expression of keratin 7 or keratin 15 in the biological sample as compared to the control sample is an indication that the subject is afflicted with prostate cancer.
  • the invention provides methods of prognosing whether a subject is predisposed to developing prostate cancer, the method comprising determining the level of expression of keratin 7 or keratin 15 present in a biological sample obtained from the subject; and comparing the level of expression of keratin 7 or keratin 15 present in the biological sample obtained from the subject with the level of expression of keratin 7 or keratin 15 in a control sample, wherein a modulation in the level of expression of keratin 7 or keratin 15 in the biological sample obtained from the subject with the level of expression of keratin 7 or keratin 15 in a control sample is an indication that the subject is predisposed to developing prostate cancer.
  • the invention provides methods for monitoring the treatment of prostate cancer in a subject, the methods comprising determining a level of expression of keratin 7 or keratin 15 present in a first sample obtained from the subject prior to administering at least a portion of a treatment regimen to the subject; determining a level of expression of keratin 7 or keratin 15 in a second sample obtained from the subject following administration of at least a portion of the treatment regimen to the subject; and comparing the level of expression of keratin 7 or keratin 15 in the first sample with the expression level of keratin 7 or keratin 15 in the second sample, wherein a modulation in the level of expression of keratin 7 or keratin 15 in the second sample as compared to keratin 7 or keratin 15 in the first sample is an indication that the therapy is modulating prostate cancer in the subject.
  • the invention also provides methods for diagnosing prostate cancer comprising determining a level of expression of keratin 19 in a biological sample obtained from a subject; and comparing the level of expression of keratin 19 in the biological sample obtained from the subject with the level of expression of keratin 19 in a control sample, wherein an increase in the level of expression of keratin 19 in the biological sample as compared to a normal control sample is an indication that the subject is afflicted with prostate cancer.
  • the invention provides methods prognosing whether a subject is predisposed to developing prostate cancer, the method comprising determining the level of expression of keratin 19 present in a biological sample obtained from the subject; and comparing the level of expression of keratin 19 present in the biological sample obtained from the subject with the level of expression of keratin 19 in a control sample, wherein a modulation in the level of expression of keratin 19 in the biological sample obtained from the subject with the level of expression of keratin 19 in a normal control sample is an indication that the subject is predisposed to developing prostate cancer.
  • the invention provides methods for monitoring the treatment of prostate cancer in a subject, the methods comprising determining a level of expression of keratin 19 present in a first sample obtained from the subject prior to administering at least a portion of a treatment regimen to the subject; determining a level of expression of keratin 19 in a second sample obtained from the subject following administration of at least a portion of the treatment regimen to the subject; and comparing the level of expression of keratin 19 in the first sample with the expression level of keratin 19 in the second sample, wherein a decrease in the level of expression of keratin 19 in the second sample as compared to keratin 19 in the first sample is an indication that the subject is responding to treatment for prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of filamin B for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of LY9 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of PSA for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of filamin B for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of keratin 4 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of keratin 8 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of keratin 18 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of tubulin-beta 3 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
  • keratin 7, 15, or 19 is keratin 7. In certain embodiments, keratin 7, 15, or 19 is keratin 15. In certain embodiments, keratin 7, 15, or 19 is keratin 19. In certain embodiments, keratin 7, 15, or 19 is keratin 7 and 15. In certain embodiments, keratin 7, 15, or 19 is keratin 7 and 19. In certain embodiments, keratin 7, 15, or 19 is keratin 15 and 19. In certain embodiments, keratin 7, 15, or 19 is keratin 7, 15, and 19.
  • filamin B, LY9, or keratin 19 is filamin B. In certain embodiments, filamin B, LY9, or keratin 19 is LY9. In certain embodiments, filamin B, LY9, or keratin 19 is keratin 19. In certain embodiments, filamin B, LY9, or keratin 19 is filamin B and LY9. In certain embodiments, filamin B, LY9, or keratin 19 is filamin B and keratin 19. In certain embodiments, filamin B, LY9, or keratin 19 is LY9, and keratin 19. In certain embodiments, filamin B, LY9, or keratin 19 is filamin B, LY9, and keratin 19.
  • control sample is a sample from a normal subject or normal tissue. In certain embodiments, the control sample is a sample from the same subject from an earlier time point than the biological sample. In certain embodiments, the control sample is a sample from a subject with benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • diagnosing includes differentiating between normal prostate and prostate cancer. In certain embodiments, diagnosing includes differentiating between benign prostate hyperplasia and prostate cancer.
  • the invention provides methods of characterizing prostate cancer status in a subject, the method comprising determining the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) present in a biological sample obtained from the subject; and comparing the level of expression of the one or more markers present in the biological sample obtained from the subject with the level of expression of the one or more markers in a control sample, wherein the level of expression of the one or more markers in the biological sample obtained from the subject compared to the level of expression of the corresponding marker in a control sample is an indication of the prostate cancer status in the subject.
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin
  • the invention provides methods of characterizing prostate cancer status in a subject, the method comprising determining the level of expression of keratin 7, 15, or 19 present in a biological sample obtained from the subject; and comparing the level of expression of keratin 7, 15, or 19 present in the biological sample obtained from the subject with the level of expression of keratin 7, 15, or 19 in a control sample, wherein the level of expression of keratin 7, 15, or 19 in the biological sample obtained from the subject compared to the level of expression of keratin 7, 15, or 19 in a control sample is an indication of the prostate cancer status in the subject.
  • the methods further comprises detection of the level of expression of prostate specific antigen (PSA) in the biological sample in which the expression level of filamin B or LY9 is detected in the methods of characterization of prostate cancer.
  • the method further includes comparing the level of expression of PSA in the biological sample with the level of PSA in a control sample.
  • PSA prostate specific antigen
  • the results from the detection of the expression level of PSA is used in conjunction with the results from detection of the level of one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the methods of characterization of prostate cancer.
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the methods of characterization of prostate cancer.
  • control sample is a sample from a normal subject or normal tissue. In certain embodiments, the control sample is a sample from the same subject from an earlier time point than the biological sample. In certain embodiments, the control sample is a sample from a subject with benign prostatic hyperplasia (BPH). In certain embodiments, the control sample is a sample from a subject with androgen dependent prostate cancer. In certain embodiments, the control sample is a sample from a subject with androgen independent prostate cancer. In certain embodiments, the control sample is a sample from a subject with an aggressive prostate cancer. In certain embodiments, the control sample is a sample from a subject with a non-aggressive prostate cancer.
  • BPH benign prostatic hyperplasia
  • characterizing includes differentiating between normal prostate and prostate cancer. In certain embodiments, characterizing includes differentiating between benign prostate hyperplasia and prostate cancer. In certain embodiments, characterizing includes differentiating between androgen sensitive and androgen insensitive prostate cancer. In certain embodiments, characterizing includes differentiating between aggressive prostate cancer and non-aggressive prostate cancer. In certain embodiments, characterizing includes differentiating between any two or more of normal prostate, prostate cancer, benign prostate hyperplasia, androgen sensitive prostate cancer, androgen insensitive prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer and non-metastatic prostate cancer.
  • characterizing includes detecting a change in status from androgen independent prostate cancer to androgen dependent prostate cancer. In certain embodiments, characterizing includes detecting a change in status from androgen independent prostate cancer to androgen dependent prostate cancer in response prior to a change in response to treatment. In certain embodiments, characterizing includes detecting a change in the size or relative aggressiveness of the prostate cancer. In certain embodiments, characterizing includes detecting a change from non-metastatic to metastatic prostate cancer.
  • an increase in the expression level of keratin 19 is an indication of increased pathology of prostate cancer or increased likelihood of developing prostate cancer.
  • a decrease in the expression level of keratin 19 is an indication of decreased pathology of prostate cancer or decreased likelihood of developing prostate cancer.
  • no significant change in the expression level of keratin 19 is an indication of no significant change in prostate cancer status.
  • an increase in the expression level of filamin B or LY9 is an indication of increased pathology of prostate cancer or increased likelihood of developing prostate cancer.
  • an decrease in the expression level of filamin B or LY9 is an indication of decreased pathology of prostate cancer or decreased likelihood of developing prostate cancer.
  • no significant change in the expression level of filamin B or LY9 is an indication of no significant change in prostate cancer status.
  • methods of the invention further comprise obtaining a biological sample from a subject.
  • methods of the invention further comprise selecting a subject for having or being suspected of having prostate cancer.
  • methods of the invention further comprise selection of a regimen for treatment of the subject including one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, and chemotherapy.
  • the method further comprises selection of the one ore more specific treatment regimens for the subject based on the results of the methods.
  • the method further comprises changing the treatment regimen of the subject based on the results of the methods.
  • the method further comprises a change in hormone based therapy based on monitoring of the subject based on the results of the methods.
  • the method further comprises not treating the subject with one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, or chemotherapy for an interval prior to performing a subsequent diagnostic, prognostic, or monitoring method provided herein.
  • the invention provides methods of treating a subject with prostate cancer by determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), present in a first sample obtained from the subject having prostate cancer; determining a level of expression of the one or more markers in a second sample obtained from the subject after administration of at least a portion of a treatment for prostate cancer; comparing the level of expression of the one or more markers in the first sample with the expression level of the one or more markers in the second sample, wherein a modulated level of expression of the one or more markers in the second sample as compared to the one or more markers in the first sample is an indication that the subject is an indication of modulation of prostate cancer in the subject; and selecting a treatment for the subject based on the expression level of
  • a decrease in the level of filamin B, LY9, or keratin 19 is an indication that the subject is responding to treatment.
  • An increase in the level of filamin B, LY9, or keratin 19 is an indication that the subject is not responding to treatment.
  • modulation is understood as a change in an expression level of a marker, particularly a statistically significant change in an expression level of a marker as compared to an appropriate control.
  • the meaning of an increase or a decrease in an expression level of the marker as compared to a control depends, at least, on the specific identity of the marker and the control used. Such considerations are well understood by those of skill in the art.
  • the meaning of the modulation in the expression level(s) of markers can be determined based on the teachings provided herein.
  • the treatment method further comprises determining a level of expression of PSA in the first sample and determining a level of expression of PSA in the second sample.
  • the treatment of the subject is maintained upon detection of a decrease in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, indicating that the subject was responsive to the treatment.
  • the treatment of the subject is discontinued upon detection of a decrease in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, indicating that disease is no longer present or minimized such that treatment is no longer required.
  • a new treatment of the subject is initiated upon detection of a decrease in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, e.g., resection after shrinkage of the tumor.
  • the treatment of the subject is discontinued upon detection of an increase in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, indication of a lack of response or discontinuation of response to the treatment.
  • a new treatment of the subject is initiated upon detection of an increase in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, e.g., due to lack of response or discontinuation of response to treatment.
  • One of skill in the art can select appropriate methods of treatment of a subject based, at least in part, on his response, or non-response, to treatments being used as determined by the expression level of the markers.
  • the invention provides method of selecting a subject with prostate cancer for administration of active treatment, rather than watchful waiting, by determining a level of expression of filamin B, LY9, or keratin 19, present in a first sample obtained from the subject having prostate cancer wherein the subject has not been actively treated for prostate cancer; determining a level of expression of filamin B, LY9, or keratin 19 in a second sample obtained from the subject; comparing the level of expression of filamin B, LY9, or keratin 19 in the first sample obtained at an earlier time point with the expression level of filamin B, LY9, or keratin 19 in the second sample; wherein a decreased level of expression of filamin B, LY9, or keratin 19 in the second sample as compared to filamin B, LY9, or keratin 19 in the first sample is an indication that the subject should not be administered active treatment for prostate cancer; and selecting against active treatment of a subject for prostate cancer.
  • the invention also provides methods of selecting a subject with prostate cancer for administration of active treatment by determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), present in a first sample obtained from the subject having prostate cancer wherein the subject has not been actively treated for prostate cancer; determining a level of expression of the corresponding one or more markers in a second sample obtained from the subject; comparing the level of expression of the one or more markers in the first sample obtained at an earlier time point with the expression level of the one or more markers in the second sample; wherein an modulated level of expression of the one or more markers in the second sample as compared to the one or more markers in the first sample is considered in determining if a subject should be actively treated for prostate cancer.
  • one or more markers
  • actively treating the subject for prostate cancer comprises treating the subject with one or more therapies such as hormone therapy, chemotherapy, radiation therapy, and surgery.
  • therapies such as hormone therapy, chemotherapy, radiation therapy, and surgery.
  • methods of subject selection further comprise determining a level of expression of PSA in the first sample and determining a level of expression of PSA in the second sample.
  • a decreased level of expression of PSA in the second sample as compared to the level of expression of PSA in the first sample is an indication that the subject should not be administered active treatment for prostate cancer.
  • an increased level of expression of PSA in the second sample as compared to the level of expression of PSA in the first sample is an indication that the subject should be administered active treatment for prostate cancer.
  • filamin B or LY9 is understood as filamin B and LY9. In certain embodiments of any of the methods provided herein, filamin B or LY9 is understood as filamin B. In certain embodiments of any of the methods provided herein, filamin B or LY9 is understood as LY9.
  • keratin 7, 15, or 19 is understood as keratin 7. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 15. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 19. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 7 and 15. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 15 and 19. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 7 and 19. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 7, 15, and 19.
  • one or more markers selected from any group provided herein does not include keratin 4. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 7. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 8. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 15. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 18. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 19. In certain embodiments, one or more markers selected from any group provided herein does not include tubulin-beta 3.
  • one or more markers selected from any group provided herein does not include filamin B. In certain embodiments, one or more markers selected from any group provided herein does not include LY9. In certain embodiments, one or more markers selected from any group provided herein does not include PSA.
  • the methods further comprising obtaining a biological sample from the subject.
  • the invention provides methods of identifying a compound for treating prostate cancer comprising obtaining a test cell; contacting the test cell with a test compound; determining the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in the test cell; comparing the level of expression of the one or more markers in the test cell with a control cell not contacted by the test compound; and selecting a test compound that modulates the level of expression of the one or more markers in the test cell, thereby identifying a compound for treating a disorder in a subject.
  • the methods further include identifying a compound that modulates the level of expression of PSA.
  • the invention provides methods of identifying a compound for treating prostate cancer comprising obtaining a test cell; contacting the test cell with a test compound; determining the level of expression of keratin 7, 15, or 19 in the test cell; comparing the level of expression of keratin 7, 15, or 19 in the test cell with a control cell not contacted by the test compound; and selecting a test compound that modulates the level of expression of keratin 7, 15, or 19 in the test cell, thereby identifying a compound for treating a disorder in a subject.
  • the invention provides methods of identifying a compound for treating prostate cancer comprising obtaining a test cell; contacting the test cell with a test compound; determining the level of expression of filamin B or LY9 in the test cell; comparing the level of expression of filamin B or LY9 in the test cell with a control cell not contacted by the test compound; and selecting a test compound that modulates the level of expression of filamin B or LY9 in the test cell, thereby identifying a compound for treating a disorder in a subject.
  • the methods of identifying a compound for treating prostate cancer further include identifying a compound that modulates the level of expression of PSA.
  • test cell is contacted with the agent in vitro.
  • the test cell is contacted with the agent in vivo. In certain embodiments, the test cell is present in a xenogenic model of cancer. In certain embodiments, the test cell is present in an animal model of prostate cancer. In certain embodiments, the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) is detected in the test cell by detection of the expression level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in a biological sample in the organism
  • kits for the diagnosis, monitoring, or characterization of prostate cancer comprising at least one reagent specific for the detection of the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in a sample.
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in a sample.
  • the kit further comprises instructions for the diagnosis, monitoring, or characterization of prostate cancer based on the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
  • the kit includes instructions to detect the level of expression of PSA in the same sample in which the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) is detected.
  • the kit includes at least one reagent specific for the detection of the level of expression of PSA.
  • kits include at least one antibody or nucleic acid for binding to f one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) for use in the methods provided herein.
  • the kit includes at least one antibody or nucleic acid for binding to keratin 7 and one antibody or nucleic acid for binding to keratin 15.
  • the kits further include at least one antibody or nucleic acid for binding to PSA for use in the methods provided herein.
  • the kits may further provide instructions for practicing the methods provided herein.
  • any one of the embodiments described herein are contemplated to be able to combine with any other one or more embodiments, even though the embodiments are described under different aspects of the invention.
  • FIG. 1 Schematic representing the underlying principles of the Interrogative Platform Technology provided in WO2012119129.
  • FIGS. 2A-C Causal associations of Keratins, including (A-B) KRT8, KRT18 and (C) KRT19 in human prostate cancer cells as inferred by the Interrogative Platform Technology.
  • FIGS. 3A-D Mechanistic insight into regulation of keratins by mitochondrial function inferred by the Interrogative Platform Technology.
  • A-B KRT8-KRT15 association is abolished upon ubidecaronone treatment. Note change of direction of arrow between and positions of KRT7 and KRT15 before treatment (A) and after treatment (B).
  • C Tubulin-beta 3 interacts with a number of proteins.
  • D Expression levels of keratin 19 in biological samples from subjects with prostate cancer or control samples.
  • FIG. 4 Inference of filamin B (FLNB) as a hub of activity in prostate cancer and as a biomarker using the Interrogative Platform Technology provided in WO2012119129.
  • FLNB filamin B
  • FIG. 5 Portion of an inference map showing filamin B is connected directly to LY9, which is, in turn, connected to at least one other marker.
  • FIGS. 6A-B Validation of filamin B levels in human serum samples. Levels of (A) filamin B and (B) PSA were elevated in prostate cancer samples when compared to normal serum. Data represents percent average change, with normal donors set to 100% on a log scale.
  • FIG. 7 Validation of LY9 levels in human serum samples. Levels of LY9 were elevated in prostate cancer samples when compared to normal serum. Data represents percent average change, with normal donors set to 100% on a log scale.
  • FIGS. 8A-C Validation of (A) filamin B, (B) LY9, and (C) PSA levels in human serum samples. Data are shown as ng/ml of the marker in serum.
  • FIGS. 9A-B ROC curve analysis of sensitivity and false positive rate (FPR) of PSA, FLNB and the combination of PSA and FLNB (A) and area under the curve values (AUC) calculated (B) based on the analysis.
  • FPR sensitivity and false positive rate
  • AUC area under the curve values
  • FIGS. 10A-B ROC curve analysis of PSA, FLNB, LY9 and combinations of PSA, FLNB, and LY9 using linear (A) and non-linear (B) scoring functions.
  • the combination of PSA, LY9, and FLNB was more sensitive than any marker alone.
  • a “patient” or “subject” to be treated by the method of the invention can mean either a human or non-human animal, preferably a mammal.
  • subject is meant any animal, including horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
  • a human subject may be referred to as a patient. It should be noted that clinical observations described herein were made with human subjects and, in at least some embodiments, the subjects are human.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease, e.g., the amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment, e.g., is sufficient to ameliorate at least one sign or symptom of the disease, e.g., to prevent progression of the disease or condition, e.g., prevent tumor growth, decrease tumor size, induce tumor cell apoptosis, reduce tumor angiogenesis, prevent metastasis. When administered for preventing a disease, the amount is sufficient to avoid or delay onset of the disease.
  • the “therapeutically effective amount” will vary depending on the compound, its therapeutic index, solubility, the disease and its severity and the age, weight, etc., of the patient to be treated, and the like.
  • certain compounds discovered by the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.
  • Administration of a therapeutically effective amount of a compound may require the administration of more than one dose of the compound.
  • Prevention refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). Prevention does not require that the disease or condition never occurs in the subject. Prevention includes delaying the onset or severity of the disease or condition.
  • prophylactic or therapeutic treatment refers to administration to the subject of one or more agents or interventions to provide the desired clinical effect. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing at least one sign or symptom of the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or maintain at least one sign or symptom of the existing unwanted condition or side effects therefrom).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • treatment refers to performing an intervention to treat prostate cancer in a subject, e.g., reduce at least one of the growth rate, reduction of tumor burden, reduce or maintain the tumor size, or the malignancy (e.g., likelihood of metastasis) of the tumor; or to increase apoptosis in the tumor by one or more of administration of a therapeutic agent, e.g., chemotherapy or hormone therapy; administration of radiation therapy (e.g., pellet implantation, brachytherapy), or surgical resection of the tumor, or any combination thereof appropriate for treatment of the subject based on grade and stage of the tumor and other routine considerations.
  • a therapeutic agent e.g., chemotherapy or hormone therapy
  • radiation therapy e.g., pellet implantation, brachytherapy
  • Active treatment is distinguished from “watchful waiting” (i.e., not active treatment) in which the subject and tumor are monitored, but no interventions are performed to affect the tumor.
  • Watchful waiting can include administration of agents that alter effects caused by the tumor (e.g., incontinence, erectile dysfunction) that are not administered to alter the growth or pathology of the tumor itself.
  • therapeutic effect refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or in the enhancement of desirable physical or mental development and conditions in an animal or human.
  • a therapeutic effect can be understood as a decrease in tumor growth, decrease in tumor growth rate, stabilization or decrease in tumor burden, stabilization or reduction in tumor size, stabilization or decrease in tumor malignancy, increase in tumor apoptosis, and/or a decrease in tumor angiogenesis.
  • disorders disorders
  • diseases disorders
  • abnormal state refers to any deviation from the normal structure or function of any part, organ, or system of the body (or any combination thereof).
  • a specific disease is manifested by characteristic symptoms and signs, including biological, chemical, and physical changes, and is often associated with a variety of other factors including, but not limited to, demographic, environmental, employment, genetic, and medically historical factors. Certain characteristic signs, symptoms, and related factors can be quantitated through a variety of methods to yield important diagnostic information.
  • the disorder, disease, or abnormal state is an abnormal prostate state, including benign prostate hyperplasia and cancer, particularly prostate cancer.
  • abnormal prostate state of prostate cancer can be further subdivided into stages and grades of prostate cancer as provided, for example in Prostate.
  • Edge S B Byrd D R, Compton C C, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, N.Y.: Springer, 2010, pp 457-68 (incorporated herein by reference).
  • abnormal prostate states can be classified as one or more of benign prostate hyperplasia (BPH), androgen sensitive prostate cancer, androgen insensitive or resistant prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, and non-metastatic prostate cancer.
  • BPH benign prostate hyperplasia
  • BPH benign prostate hyperplasia
  • androgen sensitive prostate cancer androgen insensitive or resistant prostate cancer
  • aggressive prostate cancer aggressive prostate cancer
  • non-aggressive prostate cancer metastatic prostate cancer
  • metastatic prostate cancer metastatic prostate cancer
  • non-metastatic prostate cancer non-metastatic prostate cancer
  • a subject at “increased risk for developing prostate cancer” may or may not develop prostate cancer. Identification of a subject at increased risk for developing prostate cancer should be monitored for additional signs or symptoms of prostate cancer.
  • the methods provided herein for identifying a subject with increased risk for developing prostate cancer can be used in combination with assessment of other known risk factors or signs of prostate cancer including, but not limited to decreased urinary stream, urgency, hesitancy, nocturia, incomplete bladder emptying, and age.
  • expression is used herein to mean the process by which a polypeptide is produced from DNA. The process involves the transcription of the gene into mRNA and the translation of this mRNA into a polypeptide. Depending on the context in which used, “expression” may refer to the production of RNA, or protein, or both.
  • level of expression of a gene refers to the level of mRNA, as well as pre-mRNA nascent transcript(s), transcript processing intermediates, mature mRNA(s) and degradation products, or the level of protein, encoded by the gene in the cell.
  • reagents for specific identification of a marker bind to only one isoform of the marker. In certain embodiments, reagents for specific identification of a marker bind to more than one isoform of the marker. In certain embodiments, reagents for specific identification of a marker bind to all known isoforms of the marker.
  • modulation refers to upregulation (i.e., activation or stimulation), down-regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.
  • a “modulator” is a compound or molecule that modulates, and may be, e.g., an agonist, antagonist, activator, stimulator, suppressor, or inhibitor.
  • control sample refers to any clinically relevant comparative sample, including, for example, a sample from a healthy subject not afflicted with an oncological disorder, e.g., prostate cancer, or a sample from a subject from an earlier time point, e.g., prior to treatment, an earlier tumor assessment time point, at an earlier stage of treatment.
  • a control sample can be a purified sample, protein, and/or nucleic acid provided with a kit. Such control samples can be diluted, for example, in a dilution series to allow for quantitative measurement of levels of analytes, e.g., markers, in test samples.
  • a control sample may include a sample derived from one or more subjects.
  • a control sample may also be a sample made at an earlier time point from the subject to be assessed.
  • the control sample could be a sample taken from the subject to be assessed before the onset of an oncological disorder, e.g., prostate cancer, at an earlier stage of disease, or before the administration of treatment or of a portion of treatment.
  • the control sample may also be a sample from an animal model, or from a tissue or cell lines derived from the animal model of oncological disorder, e.g., prostate cancer.
  • the level of activity or expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), lymphocyte antigen 9 (LY9), and PSA in a control sample consists of a group of measurements may be determined, e.g., based on any appropriate statistical measure, such as, for example, measures of central tendency including average, median, or modal values. Different from a control is preferably statistically significantly different from a control.
  • control level refers to an accepted or pre-determined level of a marker in a subject sample.
  • a control level can be a range of values. Marker levels can be compared to a single control value, to a range of control values, to the upper level of normal, or to the lower level of normal as appropriate for the assay.
  • control is a standardized control, such as, for example, a control which is predetermined using an average of the levels of expression of one or more markers from a population of subjects having no cancer, especially subjects having no prostate cancer.
  • a control level of a marker in a non-cancerous sample(s) derived from the subject having cancer For example, when a biopsy or other medical procedure reveals the presence of cancer in one portion of the tissue, the control level of a marker may be determined using the non-affected portion of the tissue, and this control level may be compared with the level of the marker in an affected portion of the tissue.
  • the control can be from a subject, or a population of subject, having an abnormal prostate state.
  • the control can be from a subject suffering from benign prostate hyperplasia (BPH), androgen sensitive prostate cancer, androgen insensitive or resistant prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, or non-metastatic prostate cancer. It is understood that not all markers will have different levels for each of the abnormal prostate states listed. It is understood that a combination of maker levels may be most useful to distinguish between abnormal prostate states, possibly in combination with other diagnostic methods. Further, marker levels in biological samples can be compared to more than one control sample (e.g., normal, abnormal, from the same subject, from a population control). Marker levels can be used in combination with other signs or symptoms of an abnormal prostate state to provide a diagnosis for the subject.
  • BPH benign prostate hyperplasia
  • Marker levels in biological samples can be compared to more than one control sample (e.g., normal, abnormal, from the same subject, from a population control). Marker levels
  • a control can also be a sample from a subject at an earlier time point, e.g., a baseline level prior to suspected presence of disease, before the diagnosis of a disease, at an earlier assessment time point during watchful waiting, before the treatment with a specific agent (e.g., chemotherapy, hormone therapy) or intervention (e.g., radiation, surgery).
  • a change in the level of the marker in a subject can be more significant than the absolute level of a marker, e.g., as compared to control.
  • a sample obtained at an “earlier time point” is a sample that was obtained at a sufficient time in the past such that clinically relevant information could be obtained in the sample from the earlier time point as compared to the later time point.
  • an earlier time point is at least four weeks earlier. In certain embodiments, an earlier time point is at least six weeks earlier. In certain embodiments, an earlier time point is at least two months earlier. In certain embodiments, an earlier time point is at least three months earlier. In certain embodiments, an earlier time point is at least six months earlier. In certain embodiments, an earlier time point is at least nine months earlier. In certain embodiments, an earlier time point is at least one year earlier.
  • Multiple subject samples e.g., 3, 4, 5, 6, 7, or more
  • Appropriate intervals for testing for a particular subject can be determined by one of skill in the art based on ordinary considerations.
  • “changed as compared to a control” sample or subject is understood as having a level of the analyte or diagnostic or therapeutic indicator (e.g., marker) to be detected at a level that is statistically different than a sample from a normal, untreated, or abnormal state control sample.
  • Changed as compared to control can also include a difference in the rate of change of the level of one or more markers obtained in a series of at least two subject samples obtained over time. Determination of statistical significance is within the ability of those skilled in the art, e.g., the number of standard deviations from the mean that constitute a positive or negative result.
  • the term “obtaining” is understood herein as manufacturing, purchasing, or otherwise coming into possession of.
  • detecting As used herein, “detecting”, “detection”, “determining”, and the like are understood that an assay performed for identification of a specific marker in a sample, e.g., one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), lymphocyte antigen 9 (LY9), and PSA.
  • the amount of marker expression or activity detected in the sample can be none or below the level of detection of the assay or method.
  • greater predictive value is understood as an assay that has significantly greater sensitivity and/or specificity, preferably greater sensitivity and specificity, than the test to which it is compared.
  • an element means one element or more than one element.
  • filamin B or LY9 is understood to include filamin B alone, LY9 alone, and the combination of filamin B and LY9.
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
  • variable in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups.
  • the recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • Keratin 4 also known as as as K4; CK4; CK-4; CYK4, is a member of the keratin gene family.
  • the type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in differentiated layers of the mucosal and esophageal epithelia with family member KRT13. Mutations in these genes have been associated with White Sponge Nevus, characterized by oral, esophageal, and anal leukoplakia. The type II cytokeratins are clustered in a region of chromosome 12q12-q13.
  • keratin 4 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI Gene ID for human keratin 4 is 3851 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3851 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens keratin 4, GenBank Accession No. NM — 002272 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 1 and 2. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
  • the invention includes the use of any fragments of keratin 4 sequences as long as the fragment can allow for the specific identification of keratin 4. Moreover, it is understood that there are naturally occurring variants of keratin 4 which may or may not be associated with a specific disease state, the use of which are also included in this application.
  • the type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues.
  • This type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels.
  • the genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described.
  • keratin 7 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI Gene ID for human keratin 7 is 3855 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3855 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens keratin 7, GenBank Accession No. NM — 005556 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 3 and 4. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
  • the invention includes the use of any fragments of keratin 7 sequences as long as the fragment can allow for the specific identification of keratin 7. Moreover, it is understood that there are naturally occurring variants of keratin 7 which may or may not be associated with a specific disease state, the use of which are also included in this application.
  • Keratin 8 also known as K8; KO; CK8; CK-8; CYK8; K2C8; CARD2 is a member of the type II keratin family clustered on the long arm of chromosome 12.
  • Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells.
  • the product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells.
  • This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene.
  • keratin 8 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI Gene ID for human keratin 8 is 3856 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3856 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens keratin 8, variant 1, GenBank Accession No. NM — 001256282 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 5 and 6; and homo sapiens keratin 8, variant 3, GenBank Acession No.
  • GenBank numbers are incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.
  • the invention includes the use of either on of or both of the variants of keratin 8 provided in the sequence listing and any fragments of keratin 8 sequences as long as the fragment can allow for the specific identification of keratin 8. Moreover, it is understood that there are naturally occurring variants of keratin 8 which may or may not be associated with a specific disease state, the use of which are also included in this application.
  • Keratin 15 also known as as as K15; CK15; K1CO, is a member of the keratin gene family.
  • the keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins.
  • Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region on chromosome 17q21.2.
  • keratin 15 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI Gene ID for human keratin 15 is 3866 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3866 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens keratin 15, GenBank Accession No. NM — 002275 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 9 and 10. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
  • the invention includes the use of any fragments of keratin 15 sequences as long as the fragment can allow for the specific identification of keratin 15. Moreover, it is understood that there are naturally occurring variants of keratin 15 which may or may not be associated with a specific disease state, the use of which are also included in this application.
  • keratin 15 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI Gene ID for human keratin 18 is 3875 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3875 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens keratin 18, variant 1, GenBank Accession No. NM — 000224 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 11 and 12
  • homo sapiens keratin 18, variant 2, GenBank Accession No. 199187 amino acid and nucleotide sequences, respectively are provided in SEQ ID NOs: 13 and 14.
  • GenBank numbers are incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.
  • the invention includes the use of either on of or both of the variants of keratin 18 provided in the sequence listing and any fragments of keratin 18 sequences as long as the fragment can allow for the specific identification of keratin 18. Moreover, it is understood that there are naturally occurring variants of keratin 18 which may or may not be associated with a specific disease state, the use of which are also included in this application.
  • Keratin 19 also known as K19; CK19; K1CS, is a member of the keratin gene family.
  • the keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins.
  • the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. Unlike its related family members, this smallest known acidic cytokeratin is not paired with a basic cytokeratin in epithelial cells. It is specifically expressed in the periderm, the transiently superficial layer that envelopes the developing epidermis.
  • the type I cytokeratins are clustered in a region of chromosome 17q12-q21.
  • keratin 19 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI Gene ID for human keratin 19 is 3880 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3880 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens keratin 19, GenBank Accession No. NM — 002276 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 15 and 16. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
  • the invention includes the use of any fragments of keratin 19 sequences as long as the fragment can allow for the specific identification of keratin 19. Moreover, it is understood that there are naturally occurring variants of keratin 19 which may or may not be associated with a specific disease state, the use of which are also included in this application.
  • Tubulin-beta also known as CDCBM; TUBB4; beta-4; CFEOM3A
  • Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6.
  • Tubulin-beta 3 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI Gene ID for human Tubulin-beta 3 is 10381 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/10381 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens Tubulin-beta 3, variant 2, GenBank Accession No. NM — 001197181 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 17 and 18.
  • GenBank numbers are incorporated herein by reference in the versions available on the filing date of the application to which this application claims priority.
  • the invention includes the use of any fragments of Tubulin-beta 3 sequences as long as the fragment can allow for the specific identification of Tubulin-beta 3. Moreover, it is understood that there are naturally occurring variants of Tubulin-beta 3 which may or may not be associated with a specific disease state, the use of which are also included in this application.
  • Filamin B is also known as filamin-3, beta-filamin, ABP-280 homolog, filamin homolog 1, thyroid autoantigen, actin binding protein 278, actin-binding-like protein, Larsen syndrome 1 (autosomal dominant), AOI; FH1; SCT; TAP; LRS1; TABP; FLN-B; FLN1L; ABP-278; and ABP-280.
  • the gene encodes a member of the filamin family.
  • the encoded protein interacts with glycoprotein Ib alpha as part of the process to repair vascular injuries.
  • the platelet glycoprotein Ib complex includes glycoprotein Ib alpha, and it binds the actin cytoskeleton.
  • Mutations in this gene have been found in several conditions: atelosteogenesis type 1 and type 3; boomerang dysplasia; autosomal dominant Larsen syndrome; and spondylocarpotarsal synostosis syndrome. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.
  • filamin B refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI gene ID for filamin B is 2317 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/2317 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens filamin B, beta (FLNB), RefSeqGene on chromosome 3, locus NG — 012801 is shown in SEQ ID NO: 21.
  • Homo sapiens filamin B, beta (FLNB), transcript variant 1, GenBank Accession No. NM — 001164317.1 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 22 and 23.
  • Homo sapiens filamin B, beta (FLNB), transcript variant 3, GenBank Accession No. NM — 001164318.1 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 24 and 25.
  • NM — 001164319.1 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 26 and 27.
  • Homo sapiens filamin B, beta (FLNB), transcript variant 2, GenBank Accession No. NM — 001457.3 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 28 and 29. (Each GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
  • the invention includes the use of any combination of one or more of the filamin B sequences provided in the sequence listing or any fragments thereof as long as the fragment can allow for the specific identification of filamin B.
  • Methods of the invention and reagents can be used to detect single isoforms of filamin B, combinations of filamin ⁇ isoforms, or all of the filamin B isoforms simultaneously.
  • filamin B can be considered to refer to one or more isoforms of filamin B, including total filamin B.
  • there are naturally occurring variants of filamin B which may or may not be associated with a specific disease state, the use of which are also included in the instant application.
  • Lymphocyte antigen 9 is also known as RP11-312J18.1, CD229, SLAMF3, hly9, mLY9, T-lymphocyte surface antigen Ly-9; and cell surface molecule Ly-9.
  • LY9 belongs to the SLAM family of immunomodulatory receptors (see SLAMF1; MIM 603492) and interacts with the adaptor molecule SAP (SH2D1A; MIM 300490) (Graham et al., 2006).
  • LY9 refers to both the gene and the protein unless clearly indicated otherwise by context.
  • NCBI gene ID for LY9 is 4063 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/4063 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens lymphocyte antigen 9 (LY9), transcript variant 2, GenBank Accession No. NM — 001033667 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 30 and 31.
  • Homo sapiens lymphocyte antigen 9 (LY9), transcript variant 3, GenBank Accession No. NM — 001261456 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 32 and 33.
  • LY9 Homo sapiens lymphocyte antigen 9
  • transcript variant 1 GenBank Accession No. NM — 002348 is shown amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 36 and 37. (Each GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
  • the invention includes the use of any combination of one or more of the LY9 sequences provided in the sequence listing or any fragments thereof as long as the fragment can allow for the specific identification of LY9.
  • Methods of the invention and reagents can be used to detect single isoforms of LY9, combinations of LY9 isoforms, or all of the LY9 isoforms simultaneously.
  • LY9 can be considered to refer to one or more isoforms of LY9, including total LY9.
  • there are naturally occurring variants of LY9 which may or may not be associated with a specific disease state, the use of which are also included in the instant application.
  • Prostate-specific antigen is also known as kallikrein-3, seminin, P-30 antigen, semenogelase, gamma-seminoprotein, APS, hK3, and KLK2A1.
  • Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its protein product is a protease present in seminal plasma.
  • PSA serum level of this protein
  • PSA refers to both the gene and the protein, in both processed and unprocessed forms, unless clearly indicated otherwise by context.
  • NCBI gene ID for PSA is 354 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/354 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • Homo sapiens PSA is located on chromosome 19 at 19q13.41Sequence: NC — 000019.9 (51358171.51364020).
  • NC — 000019.9 51358171.51364020.
  • Four splice variants of human PSA are known: Prostate-specific antigen isoform 3 preproprotein, NM — 001030047.1; Prostate-specific antigen isoform 4 preproprotein, NM — 001030048.1; Prostate-specific antigen isoform 6 preproprotein, NM — 001030050.1; and Prostate-specific antigen isoform 1 preproprotein, NM — 001648.2.
  • GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
  • the invention includes the use of any combination of one or more of the PSA sequences provided in the sequence listing or any fragments thereof as long as the fragment can allow for the specific identification of PSA.
  • Methods of the invention and reagents can be used to detect single isoforms of PSA, combinations of PSA isoforms, or all of the PSA isoforms simultaneously.
  • PSA can be considered to refer to one or more isoforms of PSA, including total PSA.
  • there are naturally occurring variants of PSA which may or may not be associated with a specific disease state, the use of which are also included in the instant application.
  • the present invention provides methods for use of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) to treat disease states in a subject, e.g., a mammal, e.g., a human.
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) to treat disease states in a subject, e.g., a mammal, e.g., a human.
  • the present invention also provides methods for treatment of a subject with prostate cancer with a therapeutic, e.g., a nucleic acid based therapeutic, that modulates the expression or activity of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
  • a therapeutic e.g., a nucleic acid based therapeutic
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
  • the invention also provides methods for selection and/or administration of known treatment agents, especially hormone based therapies vs. non-hormone based therapies, and aggressive or active treatment vs. “watchful waiting”, depending on the detection of a change in the level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), as compared to a control.
  • the selection of treatment regimens can further include the detection of PSA to assist in selection of the therapeutic methods. Selection of treatment methods can also include other diagnostic considerations and patient characteristics including results from imaging studies, tumor size or growth rates, risk of poor outcomes, disruption of daily activities, and age.
  • the term “aggressive oncological disorder”, such as aggressive prostate cancer, refers to an oncological disorder involving a fast-growing tumor.
  • An aggressive oncological disorder typically does not respond, responds poorly, or loses response to therapeutic treatment.
  • an prostate cancer may be considered to become an aggressive prostate cancer upon loss of response to hormone therapy, necessitating treatment with chemotherapy, surgery, and/or radiation.
  • an aggressive prostate cancer for example, is one that will likely or has metastasized.
  • an aggressive prostate cancer is one that will result in significant changes in quality of life as the tumor grows. Active treatment is therapeutically indicated for an aggressive oncological disorder, e.g., aggressive prostate cancer.
  • non-aggressive oncological disorder such as a non-aggressive prostate cancer
  • a non-aggressive oncological disorder typically responds favorably or moderately to therapeutic treatment or grows so slowly that immediate treatment is not warranted.
  • a non-aggressive prostate tumor is one that a person skilled in the art, e.g., an oncologist, may decide to not actively treat with routine interventions for the treatment of cancer, e.g., chemotherapy, radiation, surgery, as the active treatment may do more harm than the disease, particularly in an older subject.
  • a non-aggressive prostate tumor is one that a person skilled in the art may decide to monitor with “watchful waiting” rather than subjecting the person to any active therapeutic interventions to alter the presence or growth of the tumor (e.g., radiation, surgery, chemotherapy, hormone therapy).
  • active therapeutic interventions e.g., radiation, surgery, chemotherapy, hormone therapy.
  • the invention provides methods for diagnosing an abnormal prostate state, e.g., BPH or an oncological disease state, e.g., prostate cancer, in a subject.
  • the invention further provides methods for prognosing or monitoring progression or monitoring response of an abnormal prostate state, e.g., BPH or prostate cancer, to a therapeutic treatment during active treatment or watchful waiting.
  • the invention provides, in one embodiment, methods for diagnosing an oncological disorder, e.g., prostate cancer.
  • the methods of the present invention can be practiced in conjunction with any other method used by the skilled practitioner to prognose the occurrence or recurrence of an oncologic disorder and/or the survival of a subject being treated for an oncologic disorder.
  • the diagnostic and prognostic methods provided herein can be used to determine if additional and/or more invasive tests or monitoring should be performed on a subject. It is understood that a disease as complex as an oncological disorder is rarely diagnosed using a single test. Therefore, it is understood that the diagnostic, prognostic, and monitoring methods provided herein are typically used in conjunction with other methods known in the art.
  • the methods of the invention may be performed in conjunction with a morphological or cytological analysis of the sample obtained from the subject, imaging analysis, and/or physical exam.
  • Cytological methods would include immunohistochemical or immunofluorescence detection (and quantitation if appropriate) of any other molecular marker either by itself, in conjunction with other markers.
  • Other methods would include detection of other markers by in situ PCR, or by extracting tissue and quantitating other markers by real time PCR. PCR is defined as polymerase chain reaction.
  • Methods for assessing tumor progression during watchful waiting or the efficacy of a treatment regimen e.g., chemotherapy, radiation therapy, surgery, hormone therapy, or any other therapeutic approach useful for treating an oncologic disorder in a subject are also provided.
  • the amount of marker in a pair of samples (a first sample obtained from the subject at an earlier time point or prior to the treatment regimen and a second sample obtained from the subject at a later time point, e.g., at a later time point when the subject has undergone at least a portion of the treatment regimen) is assessed.
  • the methods of the invention include obtaining and analyzing more than two samples (e.g., 3, 4, 5, 6, 7, 8, 9, or more samples) at regular or irregular intervals for assessment of marker levels. Pairwise comparisons can be made between consecutive or non-consecutive subject samples. Trends of marker levels and rates of change of marker levels can be analyzed for any two or more consecutive or non-consecutive subject samples.
  • the invention also provides a method for determining whether an oncologic disorder, e.g., prostate cancer, is aggressive.
  • the method comprises determining the amount of a marker present in a sample and comparing the amount to a control amount of the marker present in one or more control samples, as defined in Definitions, thereby determining whether an oncologic disorder is aggressive.
  • Marker levels can be compared to marker levels in samples obtained at different times from the same subject or marker levels from normal or abnormal prostate state subjects. A rapid increase in the level of marker may be indicative of a more aggressive cancer than a slow increase or no increase or change in the marker level.
  • the methods of the invention may also be used to select a compound that is capable of modulating, i.e., decreasing, the aggressiveness of an oncologic disorder, e.g., prostate cancer.
  • a cancer cell is contacted with a test compound, and the ability of the test compound to modulate the expression and/or activity of a marker in the invention in the cancer cell is determined, thereby selecting a compound that is capable of modulating aggressiveness of an oncologic disorder.
  • a variety of molecules may be screened in order to identify molecules which modulate, e.g., increase or decrease the expression and/or activity of a marker of the invention, i.e., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), optionally in combination with PSA.
  • a marker of the invention i.e., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9)
  • a marker of the invention i.e., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9)
  • FLNB fil
  • the invention relates to markers (hereinafter “biomarkers”, “markers” or “markers of the invention”).
  • the preferred markers of the invention are one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
  • Methods of the invention also include use of the marker PSA in conjunction with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
  • one or more markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
  • the invention provides nucleic acids and proteins (e.g., isolated nucleic acids and isolated proteins or fragments thereof) that are encoded by, or correspond to, the markers (hereinafter “marker nucleic acids” and “marker proteins,” respectively). These markers are particularly useful in screening for the presence of an altered prostate state, e.g., BPH or prostate cancer, in assessing aggressiveness and metastatic potential of an oncologic disorder, assessing the androgen dependent status of an oncological disorder, assessing whether a subject is afflicted with an oncological disorder, identifying a composition for treating an oncological disorder, assessing the efficacy of a compound for treating an oncological disorder, monitoring the progression of an oncological disorder, prognosing the aggressiveness of an oncological disorder, prognosing the survival of a subject with an oncological disorder, prognosing the recurrence of an oncological disorder, and prognosing whether a subject is predisposed to developing an oncological disorder.
  • markers hereinafter “mark
  • biomarkers can be used in connection with the methods of the present invention.
  • the term “one or more biomarkers” is intended to mean that one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), are assayed, optionally in combination with PSA, and, in various embodiments, more than one other biomarker may be assayed, such as two, three, four, five, six, seven, eight, nine, or more biomarkers in the list may be assayed.
  • One or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and keratin 19 can be assayed in combination with one or more of filamin B, LY9, and PSA.
  • Filamin B can be used in conjunction with one or more other biomarkers, e.g., LY9 or PSA, known to be associated with prostate cancer.
  • LY9 can be used in conjunction with one or more other biomarkers, e.g., filamin B or PSA, known to be associated with prostate cancer.
  • any combination of the filamin B and LY9 biomarkers, optionally with PSA can be used, e.g., filamin B; LY9; filamin B and PSA; filamin B and LY9; LY9 and PSA; filamin B, LY9, and PSA; all of which can optionally be combined with other markers, e.g., one or more of keratins 4, 7, 8, 15, 18, 19, or tubulin-beta 3.
  • Methods, kits, and panels provided herein include any combination of 1, 2, 3, 4, 5, 6, 7, 8, or 9 markers of the set filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3.
  • Such combinations include any of the following marker sets:
  • Marker sets with two members filamin B, LY9; filamin B, keratin 4; filamin B, keratin 7; filamin B, keratin 8; filamin B, keratin 15; filamin B, keratin 18; filamin B, keratin 19; filamin B, tubulin-beta 3; LY9, keratin 4; LY9, keratin 7; LY9, keratin 8; LY9, keratin 15; LY9, keratin 18; LY9, keratin 19; LY9, tubulin-beta 3; keratin 4, keratin 7; keratin 4, keratin 8; keratin 4, keratin 15; keratin 4, keratin 18; keratin 4, keratin 19; keratin 4, tubulin-beta 3; keratin 7, keratin 4, keratin 8;
  • Marker sets with four members filamin B, LY9, keratin 4, keratin 7; filamin B, LY9, keratin 4, keratin 8; filamin B, LY9, keratin 4, keratin 15; filamin B, LY9, keratin 4, keratin 18; filamin B, LY9, keratin 4, keratin 19; filamin B, LY9, keratin 4, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8; filamin B, keratin 4, keratin 7, keratin 15; filamin B, keratin 4, keratin 7, keratin 18; filamin B, keratin 4, keratin 7, tubulin-beta 3; filamin B, keratin 4, keratin 4, keratin 7, tubulin-beta 3; filamin B, keratin
  • Marker sets with five members keratin 8, keratin 15, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 15, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 18 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; keratin 4, keratin 15, keratin 18, keratin 19 tubulin-beta 3; keratin 4, keratin 8, keratin 18, keratin
  • Marker sets with six members keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3; keratin 4, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; keratin 4, kerat
  • Marker sets with seven members keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8,
  • Marker sets with eight members LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 15, keratin 18, kerat
  • Any marker set can be used in combination with PSA.
  • the invention provides for the use of various combinations and sub-combinations of markers. It is understood that any single marker or combination of the markers provided herein can be used in the invention unless clearly indicated otherwise. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
  • filamin B, LY9 and keratin 19 is understood as any of: filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
  • any single marker or combination of the markers of the invention can be used in conjunction with PSA.
  • combination of the filamin B and LY9 with PSA is understood as any of filamin B; LY9; filamin B and PSA; filamin B and LY9; LY9 and PSA; filamin B, LY9, and PSA.
  • one or more prostate cancer markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 is understood as any of keratin 4; keratin 7; keratin 8; keratin 15; keratin 18; tubulin beta-3; keratin 4 and keratin 7; keratin 4 and keratin 8; keratin 4 and keratin 15; keratin 4 and keratin 18; keratin 4 and tubulin beta-3; keratin 7 and keratin 8; keratin 7 and keratin 15; keratin 7 and keratin 18; keratin and tubulin beta-3; keratin 8 and keratin 15; keratin 8 and keratin 18; keratin 8 and tubulin beta-3; keratin 15 and keratin 18; keratin 15 and tubulin beta-3; ker
  • one or more prostate cancer markers selected from the group consisting of keratin 7, 15, and 19 is understood as any of keratin 7; keratin 15; keratin 19; keratin 7 and 15; keratin 7 and 19; keratin 15 and 19; and keratin 7, 15, and 19. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
  • one or more prostate cancer markers selected from the group consisting of keratin 7, 8, and 15 is understood as any of keratin 7; keratin 8; keratin 15; keratin 7 and 8; keratin 7 and 15; keratin 8 and 15; and keratin 7, 8, and 15. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
  • one or more prostate cancer markers selected from the group consisting of keratin 7 and 15 is understood as any of keratin 7; keratin 15; or keratin 7 and 15. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
  • one or more prostate cancer markers selected from the group consisting filamin B, LY9, or keratin 19 is understood as any of filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9, and keratin 19; and filamin B, LY9, and keratin 19.
  • any single marker or combination of the markers of the invention can be used in conjunction with PSA.
  • methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level sets of markers including of keratin 7, 15, or 19 and filamin B; keratin 7, 15, 19 or LY9; keratin 7, 15, 19, or PSA; keratin 4, 7, 15, or 19; keratin 7, 8, 15, or 19; keratin 7, 15, 18, or 19; and keratin 7, 15, 19, or tubulin-beta 3.
  • a “marker” is a gene whose altered level of expression in a tissue or cell from its expression level in normal or healthy tissue or cell is associated with a disease state, such as an abnormal prostate state.
  • the marker is detected in a blood sample, e.g., serum or plasma.
  • the marker is detected in serum.
  • the marker is detected in plasma.
  • the serum or plasma can be further processed to remove abundant blood proteins (e.g., albumin) or proteins that are not marker proteins prior to analysis.
  • a “marker nucleic acid” is a nucleic acid (e.g., mRNA, cDNA) encoded by or corresponding to a marker of the invention.
  • marker nucleic acids include DNA (e.g., cDNA) comprising the entire or a partial sequence of any of the nucleic acid sequences provided herein or the complement of such a sequence.
  • the marker nucleic acids also include RNA comprising the entire or a partial sequence of any of the nucleic acid sequences provided herein or the complement of such a sequence, wherein all thymidine residues are replaced with uridine residues.
  • a “marker protein” is a protein encoded by or corresponding to a marker of the invention.
  • a marker protein comprises the entire or a partial sequence of any of the amino acid sequences provided herein.
  • the terms “protein” and “polypeptide” are used interchangeably.
  • a “biological sample” or a “subject sample” is a body fluid or tissue in which a prostate cancer related marker may be present.
  • the sample is blood or a blood product (e.g., serum or plasma).
  • the sample is a tissue sample, e.g., a tissue sample from at or near the site of the prostate hyperplasia or tumor, or the suspected prostate hyperplasia or tumor.
  • a tissue sample can be obtained, for example, during biopsy or surgical resection of the prostate.
  • a tissue sample can include one or more of normal tissue, hyperplasia, and cancerous tissue. Methods of distinguishing between such tissue types are known, e.g., histological analysis, immunohistochemical analysis.
  • the control sample can be a normal portion of sample tissue removed from a subject.
  • an “oncological disorder-associated” body fluid is a fluid which, when in the body of a subject, contacts, or passes through oncological cells or into which cells or proteins shed from oncological cells are capable of passing.
  • exemplary oncological disorder-associated body fluids include blood fluids (e.g. whole blood, blood serum, blood having platelets removed therefrom), and are described in more detail below.
  • Many oncological disorder-associated body fluids can have oncological cells therein, particularly when the cells are metastasizing.
  • Cell-containing fluids which can contain oncological cells include, but are not limited to, whole blood, blood having platelets removed therefrom, lymph, prostatic fluid, urine, and semen.
  • the “normal” level of expression of a marker is the level of expression of the marker in cells of a human subject or patient or a population of subjects not afflicted with an oncological disorder or an abnormal prostate state, e.g., BPH or prostate cancer.
  • an “over-expression”, “higher level of expression”, “higher level”, and the like of a marker refers to an expression level in a test sample that is greater than the standard error of the assay employed to assess expression, and is preferably at least 25% more, at least 50% more, at least 75% more, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten times the expression level of the marker in a control sample (e.g., sample from a healthy subject not having the marker associated disease, i.e., an abnormal prostate state) and preferably, the average expression level of the marker or markers in several control samples.
  • a control sample e.g., sample from a healthy subject not having the marker associated disease, i.e., an abnormal prostate state
  • a “lower level of expression” or “lower level” of a marker refers to an expression level in a test sample that is less than 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of the expression level of the marker in a control sample (e.g., sample from a healthy subjects not having the marker associated disease, i.e., an abnormal prostate state) and preferably, the average expression level of the marker in several control samples.
  • a control sample e.g., sample from a healthy subjects not having the marker associated disease, i.e., an abnormal prostate state
  • a “transcribed polynucleotide” or “nucleotide transcript” is a polynucleotide (e.g. an mRNA, hnRNA, a cDNA, or an analog of such RNA or cDNA) which is complementary to or having a high percentage of identity (e.g., at least 80% identity) with all or a portion of a mature mRNA made by transcription of a marker of the invention and normal post-transcriptional processing (e.g. splicing), if any, of the RNA transcript, and reverse transcription of the RNA transcript.
  • a polynucleotide e.g. an mRNA, hnRNA, a cDNA, or an analog of such RNA or cDNA
  • a high percentage of identity e.g., at least 80% identity
  • normal post-transcriptional processing e.g. splicing
  • “Complementary” refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that an adenine residue of a first nucleic acid region is capable of forming specific hydrogen bonds (“base pairing”) with a residue of a second nucleic acid region which is antiparallel to the first region if the residue is thymine or uracil. Similarly, it is known that a cytosine residue of a first nucleic acid strand is capable of base pairing with a residue of a second nucleic acid strand which is antiparallel to the first strand if the residue is guanine.
  • a first region of a nucleic acid is complementary to a second region of the same or a different nucleic acid if, when the two regions are arranged in an antiparallel fashion, at least one nucleotide residue of the first region is capable of base pairing with a residue of the second region.
  • the first region comprises a first portion and the second region comprises a second portion, whereby, when the first and second portions are arranged in an antiparallel fashion, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion. More preferably, all nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion.
  • nucleotide sequence similarity refers to nucleotide sequence similarity between two regions of the same nucleic acid strand or between regions of two different nucleic acid strands. When a nucleotide residue position in both regions is occupied by the same nucleotide residue, then the regions are identical at that position. A first region is identical to a second region if at least one nucleotide residue position of each region is occupied by the same residue. Identity between two regions is expressed in terms of the proportion of nucleotide residue positions of the two regions that are occupied by the same nucleotide residue.
  • a region having the nucleotide sequence 5′-ATTGCC-3′ and a region having the nucleotide sequence 5′-TATGGC-3′ share 50% identity.
  • the first region comprises a first portion and the second region comprises a second portion, whereby, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residue positions of each of the portions are occupied by the same nucleotide residue. More preferably, all nucleotide residue positions of each of the portions are occupied by the same nucleotide residue.
  • Proteins of the invention encompass marker proteins and their fragments; variant marker proteins and their fragments; peptides and polypeptides comprising an at least a 15 amino acid segment of a marker or variant marker protein; and fusion proteins comprising a marker or variant marker protein, or an at least a 15 amino acid segment of a marker or variant marker protein.
  • a protein of the invention is a peptide sequence or epitope large enough to permit the specific binding of an antibody to the marker.
  • the invention further provides antibodies, antibody derivatives and antibody fragments which specifically bind with the marker proteins and fragments of the marker proteins of the present invention.
  • antibody and “antibodies” broadly encompass naturally-occurring forms of antibodies (e.g., IgG, IgA, IgM, IgE) and recombinant antibodies such as single-chain antibodies, chimeric and humanized antibodies and multi-specific antibodies, as well as fragments and derivatives of all of the foregoing, which fragments and derivatives have at least an antigenic binding site.
  • Antibody derivatives may comprise a protein or chemical moiety conjugated to an antibody.
  • the positive or negative fold change refers to that of any gene described herein.
  • positive fold change refers to “up-regulation” or “increase (of expression)” of a gene that is listed herein.
  • negative fold change refers to “down-regulation” or “decrease (of expression)” of a gene that is listed herein.
  • nucleic acid molecules including nucleic acids which encode a marker protein or a portion thereof.
  • isolated nucleic acids of the invention also include nucleic acid molecules sufficient for use as hybridization probes to identify marker nucleic acid molecules, and fragments of marker nucleic acid molecules, e.g., those suitable for use as PCR primers for the amplification of a specific product or mutation of marker nucleic acid molecules.
  • nucleic acid molecule is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs.
  • the nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA.
  • an “isolated” nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule.
  • an “isolated” nucleic acid molecule preferably a protein-encoding sequences
  • is free of sequences which naturally flank the nucleic acid i.e., sequences located at the 5′ and 3′ ends of the nucleic acid in the genomic DNA of the organism from which the nucleic acid is derived.
  • the isolated nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived.
  • an “isolated” nucleic acid molecule such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized.
  • a nucleic acid molecule that is substantially free of cellular material includes preparations having less than about 30%, 20%, 10%, or 5% of heterologous nucleic acid (also referred to herein as a “contaminating nucleic acid”).
  • a nucleic acid molecule of the present invention can be isolated using standard molecular biology techniques and the sequence information in the database records described herein. Using all or a portion of such nucleic acid sequences, nucleic acid molecules of the invention can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook et al., ed., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).
  • a nucleic acid molecule of the invention can be amplified using cDNA, mRNA, or genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques.
  • the nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis.
  • nucleotides corresponding to all or a portion of a nucleic acid molecule of the invention can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.
  • an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule which has a nucleotide sequence complementary to the nucleotide sequence of a marker nucleic acid or to the nucleotide sequence of a nucleic acid encoding a marker protein.
  • a nucleic acid molecule which is complementary to a given nucleotide sequence is one which is sufficiently complementary to the given nucleotide sequence that it can hybridize to the given nucleotide sequence thereby forming a stable duplex.
  • a nucleic acid molecule of the invention can comprise only a portion of a nucleic acid sequence, wherein the full length nucleic acid sequence comprises a marker nucleic acid or which encodes a marker protein.
  • Such nucleic acids can be used, for example, as a probe or primer.
  • the probe/primer typically is used as one or more substantially purified oligonucleotides.
  • the oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 15, more preferably at least about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 or more consecutive nucleotides of a nucleic acid of the invention.
  • Probes based on the sequence of a nucleic acid molecule of the invention can be used to detect transcripts or genomic sequences corresponding to one or more markers of the invention.
  • the probes hybridize to nucleic acid sequences that traverse splice junctions.
  • the probe comprises a label group attached thereto, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor.
  • Such probes can be used as part of a diagnostic test kit or panel for identifying cells or tissues which express or mis-express the protein, such as by measuring levels of a nucleic acid molecule encoding the protein in a sample of cells from a subject, e.g., detecting mRNA levels or determining whether a gene encoding the protein or its translational control sequences have been mutated or deleted.
  • the invention further encompasses nucleic acid molecules that differ, due to degeneracy of the genetic code, from the nucleotide sequence of nucleic acids encoding a marker protein (e.g., protein having the sequence provided in the sequence listing), and thus encode the same protein.
  • a marker protein e.g., protein having the sequence provided in the sequence listing
  • DNA sequence polymorphisms that lead to changes in the amino acid sequence can exist within a population (e.g., the human population). Such genetic polymorphisms can exist among individuals within a population due to natural allelic variation and changes known to occur in cancer. An allele is one of a group of genes which occur alternatively at a given genetic locus. In addition, it will be appreciated that DNA polymorphisms that affect RNA expression levels can also exist that may affect the overall expression level of that gene (e.g., by affecting regulation or degradation).
  • allelic variant refers to a nucleotide sequence which occurs at a given locus or to a polypeptide encoded by the nucleotide sequence.
  • the terms “gene” and “recombinant gene” refer to nucleic acid molecules comprising an open reading frame encoding a polypeptide corresponding to a marker of the invention.
  • Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of a given gene.
  • Alternative alleles can be identified by sequencing the gene of interest in a number of different individuals. This can be readily carried out by using hybridization probes to identify the same genetic locus in a variety of individuals. Any and all such nucleotide variations and resulting amino acid polymorphisms or variations that are the result of natural allelic variation and that do not alter the functional activity are intended to be within the scope of the invention.
  • an isolated nucleic acid molecule of the invention is at least 15, 20, 25, 30, 40, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 550, 650, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3500, 4000, 4500, or more nucleotides in length and hybridizes under stringent conditions to a marker nucleic acid or to a nucleic acid encoding a marker protein.
  • hybridizes under stringent conditions is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% (65%, 70%, preferably 75%) identical to each other typically remain hybridized to each other.
  • stringent conditions are known to those skilled in the art and can be found in sections 6.3.1-6.3.6 of Current Protocols in Molecular Biology , John Wiley & Sons, N.Y. (1989).
  • a preferred, non-limiting example of stringent hybridization conditions are hybridization in 6 ⁇ sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2 ⁇ SSC, 0.1% SDS at 50-65° C.
  • Nucleic acid therapeutics are well known in the art. Nucleic acid therapeutics include both single stranded and double stranded (i.e., nucleic acid therapeutics having a complementary region of at least 15 nucleotides in length that may be one or two nucleic acid strands) nucleic acids that are complementary to a target sequence in a cell. Nucleic acid therapeutics can be delivered to a cell in culture, e.g., by adding the nucleic acid to culture media either alone or with an agent to promote uptake of the nucleic acid into the cell. Nucleic acid therapeutics can be delivered to a cell in a subject, i.e., in vivo, by any route of administration. The specific formulation will depend on the route of administration.
  • the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person.
  • Such conditions can, for example, be stringent conditions, where stringent conditions may include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. for 12-16 hours followed by washing.
  • Sequences can be “fully complementary” with respect to each when there is base-pairing of the nucleotides of the first nucleotide sequence with the nucleotides of the second nucleotide sequence over the entire length of the first and second nucleotide sequences.
  • a first sequence is referred to as “substantially complementary” with respect to a second sequence herein
  • the two sequences can be fully complementary, or they may form one or more, but generally not more than 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the ability to hybridize under the conditions most relevant to their ultimate application.
  • a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as “fully complementary” for the purposes described herein.
  • “Complementary” sequences may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled.
  • Such non-Watson-Crick base pairs includes, but not limited to, G:U Wobble or Hoogstein base pairing.
  • a polynucleotide that is “substantially complementary to at least part of” a messenger RNA refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding filamin B, LY9, a keratin, tubulin-beta 3, or PSA) including a 5′ UTR, an open reading frame (ORF), or a 3′ UTR.
  • a polynucleotide is complementary to at least a part of filamin B, LY9, a keratin, tubulin-beta 3, or PSA mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding filamin B, LY9, a keratin, tubulin-beta 3, or PSA.
  • Nucleic acid therapeutics typically include chemical modifications to improve their stability and to modulate their pharmacokinetic and pharmacodynamic properties.
  • the modifications on the nucleotides can include, but are not limited to, LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-C— allyl, 2′-fluoro, 2′-deoxy, 2′-hydroxyl, and combinations thereof.
  • Nucleic acid therapeutics may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage.
  • the phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or antisense strand or both (in nucleic acid therapeutics including a sense strand) in any position of the strand.
  • the internucleotide linkage modification may occur on every nucleotide on the sense strand or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand or antisense strand; or the sense strand or antisense strand may contain both internucleotide linkage modifications in an alternating pattern.
  • the alternating pattern of the internucleotide linkage modification on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may have a shift relative to the alternating pattern of the internucleotide linkage modification on the antisense strand.
  • Antisense nucleic acid therapeutic agent single stranded nucleic acid therapeutics, typically about 16 to 30 nucleotides in length and are complementary to a target nucleic acid sequence in the target cell, either in culture or in an organism.
  • Patents directed to antisense nucleic acids, chemical modifications, and therapeutic uses are provided, for example, in U.S. Pat. No. 5,898,031 related to chemically modified RNA-containing therapeutic compounds, and U.S. Pat. No. 6,107,094 related methods of using these compounds as therapeutic agent.
  • U.S. Pat. No. 7,432,250 related to methods of treating patients by administering single-stranded chemically modified RNA-like compounds; and U.S. Pat. No.
  • the duplex region is 15-30 nucleotide pairs in length. In some embodiments, the duplex region is 17-23 nucleotide pairs in length, 17-25 nucleotide pairs in length, 23-27 nucleotide pairs in length, 19-21 nucleotide pairs in length, or 21-23 nucleotide pairs in length.
  • each strand has 15-30 nucleotides.
  • RNAi agent double stranded RNAi agent
  • double-stranded RNA (dsRNA) molecule also referred to as “dsRNA agent,” “dsRNA”, “siRNA”, “iRNA agent,” as used interchangeably herein, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary, as defined below, nucleic acid strands.
  • an RNAi agent can also include dsiRNA (see, e.g., US Patent publication 20070104688, incorporated herein by reference).
  • each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide.
  • an “RNAi agent” may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims.
  • the two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop.” Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker.”
  • the RNA strands may have the same or a different number of nucleotides.
  • RNAi agent may comprise one or more nucleotide overhangs.
  • siRNA is also used herein to refer to an RNAi agent as described above.
  • the agent is a single-stranded antisense RNA molecule.
  • An antisense RNA molecule is complementary to a sequence within the target mRNA. Antisense RNA can inhibit translation in a stoichiometric manner by base pairing to the mRNA and physically obstructing the translation machinery, see Dias, N. et al., (2002) Mol Cancer Ther 1:347-355.
  • the antisense RNA molecule may have about 15-30 nucleotides that are complementary to the target mRNA.
  • the antisense RNA molecule may have a sequence of at least 15, 16, 17, 18, 19, 20 or more contiguous nucleotides complementary to the filamin B or LY9 sequences provided herein.
  • antisense strand refers to the strand of a double stranded RNAi agent which includes a region that is substantially complementary to a target sequence (e.g., a human TTR mRNA).
  • a target sequence e.g., a human TTR mRNA
  • region complementary to part of an mRNA encoding transthyretin refers to a region on the antisense strand that is substantially complementary to part of a TTR mRNA sequence. Where the region of complementarity is not fully complementary to the target sequence, the mismatches are most tolerated in the terminal regions and, if present, are generally in a terminal region or regions, e.g., within 6, 5, 4, 3, or 2 nucleotides of the 5′ and/or 3′ terminus.
  • sense strand refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand.
  • the invention also includes molecular beacon nucleic acids having at least one region which is complementary to a nucleic acid of the invention, such that the molecular beacon is useful for quantitating the presence of the nucleic acid of the invention in a sample.
  • a “molecular beacon” nucleic acid is a nucleic acid comprising a pair of complementary regions and having a fluorophore and a fluorescent quencher associated therewith. The fluorophore and quencher are associated with different portions of the nucleic acid in such an orientation that when the complementary regions are annealed with one another, fluorescence of the fluorophore is quenched by the quencher.
  • One aspect of the invention pertains to isolated marker proteins and biologically active portions thereof, as well as polypeptide fragments suitable for use as immunogens to raise antibodies directed against a marker protein or a fragment thereof.
  • the native marker protein can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques.
  • a protein or peptide comprising the whole or a segment of the marker protein is produced by recombinant DNA techniques.
  • Alternative to recombinant expression such protein or peptide can be synthesized chemically using standard peptide synthesis techniques.
  • an “isolated” or “purified” protein or biologically active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized.
  • the language “substantially free of cellular material” includes preparations of protein in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly produced.
  • protein that is substantially free of cellular material includes preparations of protein having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a “contaminating protein”).
  • the protein or biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • the protein is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly such preparations of the protein have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest.
  • Biologically active portions of a marker protein include polypeptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of the marker protein, which include fewer amino acids than the full length protein, and exhibit at least one activity of the corresponding full-length protein.
  • biologically active portions comprise a domain or motif with at least one activity of the corresponding full-length protein.
  • a biologically active portion of a marker protein of the invention can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acids in length.
  • other biologically active portions, in which other regions of the marker protein are deleted can be prepared by recombinant techniques and evaluated for one or more of the functional activities of the native form of the marker protein.
  • Preferred marker proteins are encoded by nucleotide sequences provided in the sequence listing.
  • Other useful proteins are substantially identical (e.g., at least about 40%, preferably 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to one of these sequences and retain the functional activity of the corresponding naturally-occurring marker protein yet differ in amino acid sequence due to natural allelic variation or mutagenesis.
  • the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence).
  • the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
  • the percent identity between the two sequences is calculated using a global alignment.
  • the percent identity between the two sequences is calculated using a local alignment.
  • the two sequences are the same length. In another embodiment, the two sequences are not the same length.
  • the determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • a preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the BLASTN and BLASTX programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-410.
  • Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402, which is able to perform gapped local alignments for the programs BLASTN, BLASTP and BLASTX.
  • PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules.
  • the default parameters of the respective programs e.g., BLASTX and BLASTN
  • BLASTX and BLASTN BLASTX and BLASTN
  • Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package.
  • a PAM120 weight residue table When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Yet another useful algorithm for identifying regions of local sequence similarity and alignment is the FASTA algorithm as described in Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444-2448. When using the FASTA algorithm for comparing nucleotide or amino acid sequences, a PAM120 weight residue table can, for example, be used with a k-tuple value of 2.
  • the percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, only exact matches are counted.
  • an antibody and “antibodies” as used interchangeably herein refer to immunoglobulin molecules as well as fragments and derivatives thereof that comprise an immunologically active portion of an immunoglobulin molecule, (i.e., such a portion contains an antigen binding site which specifically binds an antigen, such as a marker protein, e.g., an epitope of a marker protein).
  • An antibody which specifically binds to a protein of the invention is an antibody which binds the protein, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the protein.
  • Examples of an immunologically active portion of an immunoglobulin molecule include, but are not limited to, single-chain antibodies (scAb), F(ab) and F(ab′) 2 fragments.
  • An isolated protein of the invention or a fragment thereof can be used as an immunogen to generate antibodies.
  • the full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments for use as immunogens.
  • the antigenic peptide of a protein of the invention comprises at least 8 (preferably 10, 15, 20, or 30 or more) amino acid residues of the amino acid sequence of one of the proteins of the invention, and encompasses at least one epitope of the protein such that an antibody raised against the peptide forms a specific immune complex with the protein.
  • Preferred epitopes encompassed by the antigenic peptide are regions that are located on the surface of the protein, e.g., hydrophilic regions. Hydrophobicity sequence analysis, hydrophilicity sequence analysis, or similar analyses can be used to identify hydrophilic regions.
  • an isolated marker protein or fragment thereof is used as an immunogen.
  • the invention provides polyclonal and monoclonal antibodies.
  • Preferred polyclonal and monoclonal antibody compositions are ones that have been selected for antibodies directed against a protein of the invention.
  • Particularly preferred polyclonal and monoclonal antibody preparations are ones that contain only antibodies directed against a marker protein or fragment thereof. Methods of making polyclonal, monoclonal, and recombinant antibody and antibody fragments are well known in the art.
  • the present invention pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically.
  • diagnostic assays for determining the level of expression of one or more marker proteins or nucleic acids, in order to determine whether an individual is at risk of developing a disease or disorder, such as, without limitation, an oncological disorder, e.g., prostate cancer.
  • Such assays can be used for prognostic or predictive purposes to thereby prophylactically treat an individual prior to the onset of the disorder.
  • Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs or other compounds administered either to inhibit an oncological disorder, e.g., prostate cancer, or to treat or prevent any other disorder (i.e. in order to understand any carcinogenic effects that such treatment may have)) on the expression or activity of a marker of the invention in clinical trials.
  • agents e.g., drugs or other compounds administered either to inhibit an oncological disorder, e.g., prostate cancer, or to treat or prevent any other disorder (i.e. in order to understand any carcinogenic effects that such treatment may have)
  • agents e.g., drugs or other compounds administered either to inhibit an oncological disorder, e.g., prostate cancer, or to treat or prevent any other disorder (i.e. in order to understand any carcinogenic effects that such treatment may have)
  • agents e.g., drugs or other compounds administered either to inhibit an oncological disorder, e.g., prostate cancer, or to treat or prevent any other disorder (i.e. in
  • An exemplary method for detecting the presence or absence or change of expression level of a marker protein or nucleic acid in a biological sample involves obtaining a biological sample (e.g. an oncological disorder-associated body fluid) from a test subject and contacting the biological sample with a compound or an agent capable of detecting the polypeptide or nucleic acid (e.g., mRNA, genomic DNA, or cDNA).
  • a biological sample e.g. an oncological disorder-associated body fluid
  • a compound or an agent capable of detecting the polypeptide or nucleic acid e.g., mRNA, genomic DNA, or cDNA.
  • the detection methods of the invention can thus be used to detect mRNA, protein, cDNA, or genomic DNA, for example, in a biological sample in vitro as well as in vivo.
  • Methods provided herein for detecting the presence, absence, change of expression level of a marker protein or nucleic acid in a biological sample include obtaining a biological sample from a subject that may or may not contain the marker protein or nucleic acid to be detected, contacting the sample with a marker-specific binding agent (i.e., one or more marker-specific binding agents) that is capable of forming a complex with the marker protein or nucleic acid to be detected, and contacting the sample with a detection reagent for detection of the marker—marker-specific binding agent complex, if formed.
  • a marker-specific binding agent i.e., one or more marker-specific binding agents
  • the methods provided herein for detecting an expression level of a marker in a biological sample includes the steps to perform the assay.
  • the level of the marker protein or nucleic acid in the sample is none or below the threshold for detection.
  • the methods include formation of either a transient or stable complex between the marker and the marker-specific binding agent.
  • the methods require that the complex, if formed, be formed for sufficient time to allow a detection reagent to bind the complex and produce a detectable signal (e.g., fluorescent signal, a signal from a product of an enzymatic reaction, e.g., a peroxidase reaction, a phosphatase reaction, a beta-galactosidase reaction, or a polymerase reaction).
  • a detectable signal e.g., fluorescent signal, a signal from a product of an enzymatic reaction, e.g., a peroxidase reaction, a phosphatase reaction, a beta-galactosidase reaction, or a polymerase reaction.
  • all markers are detected using the same method. In certain embodiments, all markers are detected using the same biological sample (e.g., same body fluid or tissue). In certain embodiments, different markers are detected using various methods. In certain embodiments, markers are detected in different biological samples.
  • the marker to be detected is a protein. Proteins are detected using a number of assays in which a complex between the marker protein to be detected and the marker specific binding agent would not occur naturally, for example, because one of the components is not a naturally occurring compound or the marker for detection and the marker specific binding agent are not from the same organism (e.g., human marker proteins detected using marker-specific binding antibodies from mouse, rat, or goat).
  • the marker protein for detection is a human marker protein.
  • the human markers for detection are bound by marker-specific, non-human antibodies, thus, the complex would not be formed in nature.
  • the complex of the marker protein can be detected directly, e.g., by use of a labeled marker-specific antibody that binds directly to the marker, or by binding a further component to the marker-marker-specific antibody complex.
  • the further component is a second marker-specific antibody capable of binding the marker at the same time as the first marker-specific antibody.
  • the further component is a secondary antibody that binds to a marker-specific antibody, wherein the secondary antibody preferably linked to a detectable label (e.g., fluorescent label, enzymatic label, biotin).
  • the secondary antibody When the secondary antibody is linked to an enzymatic detectable label (e.g., a peroxidase, a phosphatase, a beta-galactosidase), the secondary antibody is detected by contacting the enzymatic detectable label with an appropriate substrate to produce a colorimetric, fluorescent, or other detectable, preferably quantitatively detectable, product.
  • an enzymatic detectable label e.g., a peroxidase, a phosphatase, a beta-galactosidase
  • the secondary antibody is detected by contacting the enzymatic detectable label with an appropriate substrate to produce a colorimetric, fluorescent, or other detectable, preferably quantitatively detectable, product.
  • Antibodies for use in the methods of the invention can be polyclonal, however, in a preferred embodiment monoclonal antibodies are used.
  • An intact antibody, or a fragment or derivative thereof e.g., Fab or F(ab′) 2
  • the marker present in the biological sample for detection is an enzyme and the detection reagent is an enzyme substrate.
  • the enzyme can be a protease and the substrate can be any protein that includes an appropriate protease cleavage site.
  • the enzyme can be a kinase and the substrate can be any substrate for the kinase.
  • the substrate which forms a complex with the marker enzyme to be detected is not the substrate for the enzyme in a human subject.
  • the marker-marker-specific binding agent complex is attached to a solid support for detection of the marker.
  • the complex can be formed on the substrate or formed prior to capture on the substrate.
  • the marker for detection is attached to a solid support, either directly or indirectly.
  • the marker is typically attached indirectly to a solid support through an antibody or binding protein.
  • the marker is typically attached directly to the solid support.
  • the marker is resolved in a gel, typically an acrylamide gel, in which a substrate for the enzyme is integrated.
  • the marker is a nucleic acid. Nucleic acids are detected using a number of assays in which a complex between the marker nucleic acid to be detected and a marker-specific probe would not occur naturally, for example, because one of the components is not a naturally occurring compound.
  • the analyte comprises a nucleic acid and the probe comprises one or more synthetic single stranded nucleic acid molecules, e.g., a DNA molecule, a DNA-RNA hybrid, a PNA, or a modified nucleic acid molecule containing one or more artificial bases, sugars, or backbone moieties.
  • the synthetic nucleic acid is a single stranded is a DNA molecule that includes a fluorescent label. In certain embodiments, the synthetic nucleic acid is a single stranded oligonucleotide molecule of about 12 to about 50 nucleotides in length. In certain embodiments, the nucleic acid to be detected is an mRNA and the complex formed is an mRNA hybridized to a single stranded DNA molecule that is complementary to the mRNA.
  • an RNA is detected by generation of a DNA molecule (i.e., a cDNA molecule) first from the RNA template using the single stranded DNA that hybridizes to the RNA as a primer, e.g., a general poly-T primer to transcribe poly-A RNA.
  • the cDNA can then be used as a template for an amplification reaction, e.g., PCR, primer extension assay, using a marker-specific probe.
  • a labeled single stranded DNA can be hybridized to the RNA present in the sample for detection of the RNA by fluorescence in situ hybridization (FISH) or for detection of the RNA by northern blot.
  • FISH fluorescence in situ hybridization
  • in vitro techniques for detection of mRNA include northern hybridizations, in situ hybridizations, and rtPCR.
  • in vitro techniques for detection of genomic DNA include Southern hybridizations.
  • Techniques for detection of mRNA include PCR, northern hybridizations and in situ hybridizations. Methods include both qualitative and quantitative methods.
  • a general principle of such diagnostic, prognostic, and monitoring assays involves preparing a sample or reaction mixture that may contain a marker, and a probe, under appropriate conditions and for a time sufficient to allow the marker and probe to interact and bind, thus forming a complex that can be removed and/or detected in the reaction mixture.
  • assays can be conducted in a variety of ways known in the art, e.g., ELISA assay, PCR, FISH.
  • Marker levels can be detected based on the absolute expression level or a normalized or relative expression level. Detection of absolute marker levels may be preferable when monitoring the treatment of a subject or in determining if there is a change in the prostate cancer status of a subject. For example, the expression level of one or more markers can be monitored in a subject undergoing treatment for prostate cancer, e.g., at regular intervals, such a monthly intervals. A modulation in the level of one or more markers can be monitored over time to observe trends in changes in marker levels.
  • Expression levels of one or more of filamin B, LY9, or keratin 19 in the subject may be higher than the expression level of those markers in a normal sample, but may be lower than the prior expression level, thus indicating a benefit of the treatment regimen for the subject.
  • rates of change of marker levels can be important in a subject who is not subject to active treatment for prostate cancer (e.g., watchful waiting). Changes, or not, in marker levels may be more relevant to treatment decisions for the subject than marker levels present in the population. Rapid changes in marker levels in a subject who otherwise appears to have a normal prostate may be indicative of an abnormal prostate state, even if the markers are within normal ranges for the population.
  • determinations may be based on the normalized expression level of the marker.
  • Expression levels are normalized by correcting the absolute expression level of a marker by comparing its expression to the expression of a gene that is not a marker, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene, or epithelial cell-specific genes. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, e.g., a non-cancer sample, or between samples from different sources.
  • the expression level can be provided as a relative expression level as compared to an appropriate control, e.g., population control, adjacent normal tissue control, earlier time point control, etc.
  • the samples used in the baseline determination will be from non-cancer cells.
  • the choice of the cell source is dependent on the use of the relative expression level.
  • Using expression found in normal tissues as a mean expression score aids in validating whether the marker assayed is cancer specific (versus normal cells).
  • the mean expression value can be revised, providing improved relative expression values based on accumulated data. Expression data from cancer cells provides a means for grading the severity of the cancer state.
  • the invention provides methods for detecting an abnormal prostate state in a subject by
  • each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate-cancer related protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
  • detecting an abnormal prostate state comprises diagnosing prostate cancer status in a subject. In certain embodiments, an abnormal prostate state comprises identifying a predisposed to developing prostate cancer.
  • the invention provides methods for monitoring the treatment of prostate cancer in a subject by
  • each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
  • each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
  • the invention provides method of selecting for administration of active treatment or against administration of active treatment of prostate cancer in a subject by
  • each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
  • each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
  • one or more prostate-cancer related markers is two or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is three or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is four or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is five or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is six or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is seven or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is eight or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is nine or more markers.
  • an increase in the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample as compared to the level of expression of the one or more prostate-cancer related markers in a normal control sample is an indication that the subject is afflicted with prostate cancer.
  • no increase in the detected expression level of one or more of filamin B, LY9, and keratin 19 in the biological sample as compared to the expression level in a normal control sample is an indication that the subject is not afflicted with prostate cancer or not predisposed to developing prostate cancer.
  • an increase in the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample as compared to the level of expression of the one or more prostate-cancer related markers in a normal control sample is an indication that the subject is predisposed to developing prostate cancer.
  • no increase in the detected level of expression of any of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers in the first sample is an indication that the therapy is efficacious for treating prostate cancer in the subject.
  • the monitoring methods provided herein further comprise comparing the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the first sample or the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample with the expression of the one or more prostate-cancer related markers in a control sample.
  • an increase in the level of expression of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers in the first sample is an indication for selection of active treatment of prostate cancer in the subject.
  • no increase in the detected level of expression of any of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers in the first sample is an indication against selection of active treatment of prostate cancer in the subject.
  • an increased expression level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the expression level in the first sample is an indication that the therapy is not efficacious in the treatment of prostate cancer.
  • the one or more prostate-cancer related markers is selected from the group of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers is selected from the group of keratin 7, keratin 8, and keratin 15. In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers is selected from the group of keratin 7, keratin 15, and keratin 19. In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers is keratin 7 or keratin 15.
  • the one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the biological sample is compared to the level of the one or more prostate-cancer related markers in a normal control sample is indicative of a modulation in prostate cancer status.
  • modulation of the level of expression of the one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample is indicative of a change in prostate cancer status in response to treatment of the prostate cancer in the subject.
  • the methods further comprise comparing the level of expression of one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample; or the level of expression of one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample to the level of expression of one or more prostate-cancer related markers in a normal control sample.
  • the diagnostic methods provided herein further comprise detecting the level of expression of prostate specific antigen (PSA) in the biological sample and preferably further comprise comparing the level of expression of PSA in the biological sample to a PSA expression level in a normal control sample.
  • PSA prostate specific antigen
  • the combination of PSA level with one or more of the prostate-cancer maker levels increases the predictive value of the method.
  • the monitoring methods provided herein further comprise detecting the level of expression of prostate specific antigen (PSA) in the first sample and the second sample, and preferably further comprising comparing the level of expression of PSA in the first sample with the level of expression of PSA in the second sample.
  • PSA prostate specific antigen
  • the change in PSA level in combination with the change in prostate-cancer maker level increases the predictive value of the method.
  • the diagnostic and monitoring methods provided herein further comprise comparing the detected level of the one or more prostate markers in the biological samples with one or more control samples wherein the control sample is one or more of a sample from the same subject at an earlier time point than the biological sample, a sample from a subject with benign prostatic hyperplasia (BPH), a sample from a subject with non-metastatic prostate cancer, a sample from a subject with metastatic prostate cancer, a sample from a subject with androgen sensitive prostate cancer, a sample from a subject with androgen insensitive prostate cancer, a sample from a subject with aggressive prostate cancer, and sample obtained from a subject with non-aggressive prostate cancer.
  • BPH benign prostatic hyperplasia
  • Comparison of the marker levels in the biological samples with control samples from subjects with various normal and abnormal prostate states facilitates the differentiation between various prostate states including normal prostate and prostate cancer, benign prostate hyperplasia and prostate cancer, benign prostate hyperplasia and normal prostate, androgen dependent and androgen independent prostate cancer, aggressive prostate cancer and non-aggressive prostate cancer, aggressive prostate cancer and non-aggressive prostate cancer, or between any two or more prostate states including normal prostate, prostate cancer, benign prostate hyperplasia, androgen dependent prostate cancer, androgen independent prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, and non-metastatic prostate cancer.
  • the diagnostic and monitoring methods provided herein further comprising detecting the size of the prostate tumor in the subject.
  • the monitoring methods provided herein further comprise detecting a change in the size or relative aggressiveness of the tumor.
  • the size of the prostate tumor in the subject is detected prior to administering the at least a portion of a treatment regimen to the subject.
  • the size of the prostate tumor in the subject is detected after administering the at least a portion of a treatment regimen to the subject.
  • Certain monitoring methods further comprise comparing the size of the prostate tumor in the subject prior to administering the at least a portion of a treatment regimen to the subject to the size of the prostate tumor in the subject after administering the at least a portion of a treatment regimen to the subject.
  • diagnostic and monitoring methods provided herein further comprising obtaining a subject sample.
  • diagnostic and monitoring methods provided herein further comprising selecting a treatment regimen for the subject based on the level expression of one or more of the prostate-cancer related markers provided in claims 1 .
  • diagnostic and monitoring methods provided herein further comprising selecting a subject for having or being suspected of having prostate cancer.
  • diagnostic and monitoring methods provided herein further comprising treating the subject with a regimen including one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, and chemotherapy.
  • the diagnostic and monitoring methods provided herein further comprising selecting the one or more specific treatment regimens for the subject based on the results of the diagnostic and monitoring methods provided herein.
  • the treatment method is maintained based on the results from the diagnostic or prognostic methods.
  • the treatment method is changed based on the results from the diagnostic or prognostic methods.
  • a change the treatment regimen comprises changing a hormone based therapy treatment.
  • treatments for prostate cancer include one or more of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, or chemotherapy based on the results of a method of any one of claims 1 - 64 for an interval prior to performing a subsequent diagnostic, prognostic, or monitoring method provided herein.
  • the method of detecting a level comprises isolating a component of the biological sample.
  • the method of detecting a level comprises labeling a component of the biological sample.
  • the method of detecting a level comprises amplifying a component of a biological sample.
  • the method of detecting a level comprises forming a complex with a probe and a component of a biological sample. In certain embodiments, forming a complex with a probe comprises forming a complex with at least one non-naturally occurring reagent. In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises processing the biological sample. In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level of at least two markers comprises a panel of markers. In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises attaching the marker to be detected to a solid surface.
  • the invention provides methods of selecting for administration of active treatment or against administration of active treatment of prostate cancer in a subject comprising:
  • selecting for administration of active treatment or against administration of active treatment of prostate cancer is based on the presence or absence of changes in the level of expression of one or more markers between the first sample and the second sample.
  • the method further comprising obtaining a third sample obtained from the subject, detecting a level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the third sample, and comparing the level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the third sample with the level of the one or more markers in the first sample or the one or more markers in the second sample.
  • an increased level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample is an indication that the therapy is not efficacious in the treatment of prostate cancer.
  • an increased of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample is an indication for selecting active treatment for prostate cancer.
  • the method further comprises comparing the level of one or more markers selected from the group consisting of filamin B, LY9, and keratin 19 in the first sample or the level of one or more markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample with the level of one or more of filamin B, LY9, and keratin 19 in a control sample.
  • the method comprises detecting the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample; detecting the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample; and comparing the level of the one or more of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample with the one or more of the level of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample.
  • the method comprises detection of a subset of keratins such as keratin 7, keratin 8, and keratin 15; keratin 7, 15, and 19; and keratin 7 or keratin 15.
  • the method further comprises comparing the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample; or the level of expression of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample to the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in a control sample.
  • no change in the level of expression of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 between the first sample and the second sample is an indication for selecting against active treatment for prostate cancer.
  • the methods further comprise detecting the level of prostate specific antigen (PSA) in the first sample and the second sample, and then preferably further comprising comparing the level of PSA in the first sample with the level of PSA in the second sample.
  • PSA prostate specific antigen
  • a decrease in the level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample in combination with a decrease in the level of PSA in the second sample as compared to the level of PSA in the first sample has greater predictive value that the therapy is efficacious in treating prostate cancer in the subject than analysis of a single marker alone.
  • a decrease in the level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample in combination with a decrease in the level of expression of PSA in the second sample as compared to the level of PSA in the first sample has greater predictive value that for selecting against active treatment for prostate cancer than analysis of a single marker alone.
  • Monitoring the influence of agents (e.g., drug compounds) on the level of expression of a marker of the invention can be applied not only in basic drug screening or monitoring the treatment of a single subject, but also in clinical trials.
  • agents e.g., drug compounds
  • the effectiveness of an agent to affect marker expression can be monitored in clinical trials of subjects receiving treatment for an oncological disorder.
  • the present invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of one or more selected markers of the invention (e.g., filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, optionally in combination with PSA) in the pre-administration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression of the marker(s) in the post-administration samples; (v) comparing the level of expression of the marker(s) in the pre-administration sample with the level of expression of the marker(s) in the post
  • kits for diagnosing, prognosing, or monitoring a disease or disorder, recurrence of a disorder, or survival of a subject being treated for a disorder (e.g., an abnormal prostate state, BPH, an oncologic disorder, e.g., prostate cancer).
  • a disorder e.g., an abnormal prostate state, BPH, an oncologic disorder, e.g., prostate cancer.
  • kits include one or more of the following: a detectable antibody that specifically binds to a marker of the invention, a detectable antibody that specifically binds to a marker of the invention, reagents for obtaining and/or preparing subject tissue samples for staining, and instructions for use.
  • kits for detecting the presence of a marker protein or nucleic acid in a biological sample can be used to determine if a subject is suffering from or is at increased risk of developing an abnormal prostate state.
  • the kit can comprise a labeled compound or agent capable of detecting a marker protein or nucleic acid in a biological sample and means for determining the amount of the protein or mRNA in the sample (e.g., an antibody which binds the protein or a fragment thereof, or an oligonucleotide probe which binds to DNA or mRNA encoding the protein).
  • Kits can also include instructions for use of the kit for practicing any of the methods provided herein or interpreting the results obtained using the kit based on the teachings provided herein.
  • kits can also include reagents for detection of a control protein in the sample not related to the abnormal prostate state, e.g., actin for tissue samples, albumin in blood or blood derived samples for normalization of the amount of the marker present in the sample.
  • the kit can also include the purified marker for detection for use as a control or for quantitation of the assay performed with the kit.
  • Kits include panel of reagents for use in a method to diagnose prostate cancer in a subject (or to identify a subject predisposed to developing prostate cancer, etc.), the panel comprising at least two detection reagents, wherein each detection reagent is specific for one prostate cancer-specific protein, wherein said prostate cancer-specific proteins are selected from the prostate cancer-specific protein sets provided herein.
  • the kit can comprise, for example: (1) a first antibody (e.g., attached to a solid support) which binds to a first marker protein; and, optionally, (2) a second, different antibody which binds to either the first marker protein or the first antibody and is conjugated to a detectable label.
  • the kit includes (1) a second antibody (e.g., attached to a solid support) which binds to a second marker protein; and, optionally, (2) a second, different antibody which binds to either the second marker protein or the second antibody and is conjugated to a detectable label.
  • the first and second marker proteins are different.
  • the first and second markers are markers of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and PSA.
  • the kit comprises a third antibody which binds to a third marker protein which is different from the first and second marker proteins, and a second different antibody that binds to either the third marker protein or the antibody that binds the third marker protein wherein the third marker protein is different from the first and second marker proteins.
  • the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a marker protein or (2) a pair of primers useful for amplifying a marker nucleic acid molecule.
  • the kit can further include, for example: (1) an oligonucleotide, e.g., a second detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a second marker protein or (2) a pair of primers useful for amplifying the second marker nucleic acid molecule.
  • the first and second markers are different.
  • the first and second markers are markers of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and PSA.
  • neither the first marker nor the second marker is PSA.
  • the kit can further include, for example: (1) an oligonucleotide, e.g., a third detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a third marker protein or (2) a pair of primers useful for amplifying the third marker nucleic acid molecule wherein the third marker is different from the first and second markers.
  • the kit includes a third primer specific for each nucleic acid marker to allow for detection using quantitative PCR methods.
  • the kit can include markers, including labeled markers, to permit detection and identification of one or more markers of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and optionally PSA, by chromatography.
  • markers including labeled markers, to permit detection and identification of one or more markers of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and optionally PSA, by chromatography.
  • kits for chromatography methods include compounds for derivatization of one or more markers of the invention.
  • kits for chromatography methods include columns for resolving the markers of the method.
  • Reagents specific for detection of a marker of the invention allow for detection and quantitation of the marker in a complex mixture, e.g., serum, tissue sample.
  • the reagents are species specific.
  • the reagents are not species specific.
  • the reagents are isoform specific.
  • the reagents are not isoform specific.
  • the reagents detect total keratin 8, keratin 18, filamin B, PSA, or LY9.
  • kits for the diagnosis, monitoring, or characterization of prostate cancer comprise at least one reagent specific for the detection of the level of expression of at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9.
  • the kits further comprise instructions for the diagnosis, monitoring, or characterization of prostate cancer based on the level of expression of the at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9.
  • kits further comprise instructions to detect the level of PSA in a sample in which the at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 is detected.
  • the kits further comprise at least one reagent for the specific detection of PSA.
  • kits comprising at least one reagent specific for the detection of a level of expression of at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 and at least one reagent specific for the detection of a level of expression of PSA.
  • kits can also comprise, e.g., a buffering agents, a preservative, a protein stabilizing agent, reaction buffers.
  • the kit can further comprise components necessary for detecting the detectable label (e.g., an enzyme or a substrate).
  • the kit can also contain a control sample or a series of control samples which can be assayed and compared to the test sample.
  • the controls can be control serum samples or control samples of purified proteins or nucleic acids, as appropriate, with known levels of target markers.
  • Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.
  • kits of the invention may optionally comprise additional components useful for performing the methods of the invention.
  • the invention provides panels of reagents for detection of one or more prostate-related marker in a subject sample and at least one control reagent.
  • the control reagent is to detect the marker for detection in the biological sample wherein the panel is provided with a control sample containing the marker for use as a positive control and optionally to quantitate the amount of marker present in the biological sample.
  • the panel includes a detection reagent for a maker not related to an abnormal prostate state that is known to be present or absent in the biological sample to provide a positive or negative control, respectively.
  • the panel can be provided with reagents for detection of a control protein in the sample not related to the abnormal prostate state, e.g., actin for tissue samples, albumin in blood or blood derived samples for normalization of the amount of the marker present in the sample.
  • the panel can be provided with a purified marker for detection for use as a control or for quantitation of the assay performed with the panel.
  • the panel includes reagents for detection of two or more markers of the invention (e.g., 2, 3, 4, 5, 6, 7, 8, 9), preferably in conjunction with a control reagent.
  • each marker is detected by a reagent specific for that marker.
  • the panel further includes a reagent for the detection of PSA.
  • the panel includes replicate wells, spots, or portions to allow for analysis of various dilutions (e.g., serial dilutions) of biological samples and control samples.
  • the panel allows for quantitative detection of one or more markers of the invention.
  • the panel is a protein chip for detection of one or more markers. In certain embodiments, the panel is an ELISA plate for detection of one or more markers. In certain embodiments, the panel is a plate for quantitative PCR for detection of one or more markers.
  • the panel of detection reagents is provided on a single device including a detection reagent for one or more markers of the invention and at least one control sample. In certain embodiments, the panel of detection reagents is provided on a single device including a detection reagent for two or more markers of the invention and at least one control sample. In certain embodiments, multiple panels for the detection of different markers of the invention are provided with at least one uniform control sample to facilitate comparison of results between panels.
  • the invention also provides methods (also referred to herein as “screening assays”) for identifying modulators, i.e., candidate or test compounds or agents (e.g., proteins, peptides, peptidomimetics, peptoids, small molecules or other drugs), which modulate the state of the diseased cell by modulating the expression and/or activity of a marker of the invention, i.e., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, or LY9; optionally in combination with PSA.
  • Such assays typically comprise a reaction between a marker of the invention and one or more assay components.
  • the other components may be either the test compound itself, or a combination of test compounds and a natural binding partner of a marker of the invention.
  • Compounds identified via assays such as those described herein may be useful, for example, for modulating, e.g., inhibiting, ameliorating, treating, or preventing the disease.
  • Compounds identified for modulating the expression level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, or LY9; optionally in combination with PSA, are preferably further tested for activity useful in the treatment of cancer, preferably prostate cancer, e.g., inhibiting tumor cell growth, inhibiting tumor angiogenesis, inducing tumor cell apoptosis, etc.
  • test compounds used in the screening assays of the present invention may be obtained from any available source, including systematic libraries of natural and/or synthetic compounds.
  • Test compounds may also be obtained by any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive; see, e.g., Zuckermann et al., 1994 , J. Med. Chem. 37:2678-85); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the ‘one-bead one-compound’ library method; and synthetic library methods using affinity chromatography selection.
  • the biological library and peptoid library approaches are limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, 1997 , Anticancer Drug Des. 12
  • the screening methods of the invention comprise contacting a cell, e.g., a diseased cell, especially a prostate cancer cell, with a test compound and determining the ability of the test compound to modulate the expression and/or activity of filamin B, LY9, or keratin 19, optionally in combination with PSA, in the cell.
  • a cell e.g., a diseased cell, especially a prostate cancer cell
  • the expression and/or activity of filamin B, LY9, or keratin 19; optionally in combination with PSA can be determined using any methods known in the art, such as those described herein.
  • the invention provides assays for screening candidate or test compounds which are substrates of a marker of the invention or biologically active portions thereof. In yet another embodiment, the invention provides assays for screening candidate or test compounds which bind to a marker of the invention or biologically active portions thereof. Determining the ability of the test compound to directly bind to a marker can be accomplished, for example, by any method known in the art.
  • This invention further pertains to novel agents identified by the above-described screening assays. Accordingly, it is within the scope of this invention to further use an agent identified as described herein in an appropriate animal model.
  • an agent capable of modulating the expression and/or activity of a marker of the invention identified as described herein can be used in an animal model to determine the efficacy, toxicity, or side effects of treatment with such an agent.
  • an agent identified as described herein can be used in an animal model to determine the mechanism of action of such an agent.
  • this invention pertains to uses of novel agents identified by the above-described screening assays for treatment as described above.
  • Extracellular Keratins are known to influence the cell proliferation and metastasis of epithelial derived prostate cancers. Androgen refractory prostate cancers exhibit differential expression keratin 8 (K8) when compared to normal tissue. Modulation and degradation of keratins is in turn mediated by mitochondrial generation of Reactive Oxygen Species (ROS).
  • ROS Reactive Oxygen Species
  • the discovery platform involves discovery across a hierarchy of systems including in vitro human cell based models and human serum samples from prostate cancer patients and downstream data integration and mathematical modeling employing an Artificial Intelligence (AI) based informatic module.
  • AI Artificial Intelligence
  • LnCAP cell line and metastatic, androgen refractory PC3 cell line were treated with ubidecarenone (coenzyme Q10) in order to engage the mitochondrial machinery.
  • Proteomic signatures were captured using a 2D LC-MS orbitrap technology.
  • Total protein signatures were input to an AI based informatics module to generate causal protein networks ( FIGS. 2A-C ).
  • Wet lab assays that specifically measure mitochondrial ROS, ATP and caspase 3 activation confirmed changes in intracellular levels of these markers.
  • An interrogative systems biology based discovery platform was used to obtain mechanistic insights into understanding mitochondrial role in behavior of prostate cancer cells.
  • the Platform technology which is described in detail in WO2012119129, involves discovery across a hierarchy of systems including in vitro human cell based models and human serum samples from prostate cancer patients and downstream data integration and mathematical modeling employing an Artificial Intelligence (AI) based informatics module.
  • AI Artificial Intelligence
  • the results provided herein demonstrate the modulation of filamin B and LY9, and potential causal association in androgen refractory prostate cancer that was inferred using the Platform technology.
  • the application provides potential mechanisms of filamin B and LY9 regulation in response to modulation of mitochondrial function was deciphered by the Platform technology and provides validation of the markers in patient serum samples.
  • human prostate cancer cells PC3 (androgen insensitive, metastatic) and LnCap (androgen sensitive) were modeled in cancer microenvironments including hypoxia, reduced environments, and hyperglycemia and in presence of coenzyme Q10.
  • Normal cells human dermal fibroblasts (HDFa) and SV40 transformed human liver cells (THLE2)
  • HPFa human dermal fibroblasts
  • THLE2 SV40 transformed human liver cells
  • Proteomics of cellular proteins and proteins secreted in the supernatant were carried out by LCMS. Data were input into the Bayesian Network Inference (BNI) algorithms REFSTM.
  • BNI Bayesian Network Inference
  • human serum samples were procured from a commercial vendor that sources human serum. Twenty samples were from normal donors and 20 samples were from patients diagnosed with prostate cancer. Prostate cancer samples were from patients with different prognosis and aggressiveness of cancers reported. Clinical characteristics of the subjects are provided in the table.
  • Prostate Cancer Control Group Median Age 61 (47-86) 58 (45-72) Ethnicity Caucasian 75% 85% African American 15% 10% Hispanic 10% 5% Tumor Stage Stage I 20% Stage II 35% Stage III 5% Stage IV 40%
  • Example 4 The same human serum samples used in Example 4 were further tested to detect the presence of LY9.
  • a commercially available ELISA test for LY9 was procured from commercial source. The assay was performed using the manufactures' instructions. The results from the assay are shown in FIG. 7 . The results show the differential levels of LY9 in patients with a diagnosis for prostate cancer as compared to control subjects without prostate cancer. As shown, samples from subjects with prostate cancer were found to have higher levels of LY9 as compared to normal subjects. Results from assays of expression levels of both filamin B and LY9 in human serum with results expressed as ng/ml of protein are shown in FIGS. 8A-C . Additional samples can be analyzed to further refine the results.
  • each filamin B, LY9, and PSA are all elevated in serum samples from subjects with prostate cancer
  • the ROC curve analysis was performed comparing each of the three markers individually to the combination of all three markers using a linear scoring function, and comparing the combination of filamin B and LY9, and the combination of filamin B and PSA, against the combination of all three markers using a non-linear scoring function to determine which combinations of the markers were more effective than each single marker for the detection of prostate cancer in a subject.
  • the combination of all three markers was more predictive than any of the markers alone ( FIG. 10A ).
  • the combination of filamin B with PSA, either with or without LY9, was more predictive than the combination of filamin B with LY9 ( FIG. 10B ). Additional samples can be analyzed to further refine the results.
  • the AUC results are summarized in the table.
  • filamin B levels and LY9 levels can be used to distinguish subjects who are or are not suffering from prostate cancer. Further, as demonstrated in Examples 6 and 7, the analysis of both filamin B and PSA, optionally further in combination with LY9, is more sensitive than an analysis based on either marker alone.
  • a series of subject samples are obtained from an appropriate source, e.g., a commercial source, wherein the samples were obtained from subjects with different stages of prostate cancer, e.g., aggressive prostate cancer, androgen sensitive, androgen insensitive, metastatic; or from subjects not suffering from prostate cancer, e.g., subjects with normal prostate or subjects with BPH.
  • the samples are analyzed for the expression level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA.
  • the level of the expression of the makers correlate with the presence or absence of disease, and with the severity of prostate cancer. For example, an increase in the expression level of one or more of keratin 19, filamin B, LY9, and PSA, as compared to a normal sample from a subject not suffering from prostate cancer, is indicative of prostate cancer in the subject.
  • Expression levels of keratins 7, 8, and 15 may also be particularly useful in the stratification of subjects with prostate cancer.
  • a subject sample e.g., blood
  • a new subject sample is obtained.
  • all subject samples are tested for the expression level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA.
  • the subject samples are matched to the medical records of the subjects to correlate marker levels with prostate cancer status at the time of diagnosis, rate of progression of disease, response of subjects to one or more interventions, and transitions between androgen dependent and independent status.
  • Expression levels of keratins 7, 8, and 15 may also be particularly useful in the diagnosis and monitoring of subjects with prostate cancer.
  • PSA remains the only generally accepted biomarker for prostate cancer.
  • prostate cancer is most commonly a slow growing tumor in men of advanced age, treatment of the cancer may do more harm to the subject than the tumor itself would. Therefore, the tests together for the expression level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA are used for the detection an monitoring of prostate cancer.
  • the level of the expression of the makers are used in detection, including in routine, preventative, screening methods in men having an increased risk of prostate cancer (e.g., increased age, family history, race, etc.) or in monitoring of subjects diagnosed with prostate cancer prior to or during treatment may be useful to better identify subjects in need of further, potentially more invasive, diagnostic tests, e.g., prostate exam or biopsy, digital rectal exam; or more aggressive treatment. Detection of levels of expression of the markers, or various combinations thereof, may also be indicative of a good or poor response to a specific treatment regimen prior to changes in other signs or symptoms, e.g., loss of tumor response to hormone therapy.
  • a serum sample from a subject is tested for the level of expression of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA.
  • the levels are compared to one or more appropriate controls, e.g., other normal subjects, subjects with prostate cancer.
  • Detection of an abnormal level of one or more of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 8, keratin 15, and keratin 19; indicates that the subject should be considered for further tests for the presence of prostate cancer.
  • Changes in the level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 8, keratin 15, and keratin 19, in the subject may be more indicative of a change in prostate cancer status than comparison to a population control.
  • determining a therapeutic regimen for a subject with prostate cancer not yet being actively treated for prostate cancer can be tested at regular intervals to determine if there is a change in the level of expression of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA.
  • An modulation in the level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 8, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA indicates that the subject should be considered for further tests to monitor the prostate cancer and more active therapeutic interventions should be considered.
  • a subject undergoing treatment for prostate cancer is tested prior to the initiation of the treatment and during and/or after the treatment to determine if the treatment results in a decrease in the level of expression of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA.
  • a decrease in the level of keratin 19, filamin B, LY9, or PSA is indicative of response to treatment.
  • Expression levels of keratins 7, 8, and 15 may also be particularly useful in the diagnosis and monitoring of subjects with prostate cancer.
  • filamin B levels and LY9 levels can be used to distinguish subjects who are or are not suffering from prostate cancer. Further, as demonstrated in Examples 6 and 7, the analysis of both filamin B and PSA, optionally further in combination with LY9, is more sensitive than an analysis based on either marker alone.
  • a series of subject samples are obtained from an appropriate source, e.g., a commercial source, wherein the samples were obtained from subjects with different stages of prostate cancer, e.g., aggressive prostate cancer, androgen sensitive, androgen insensitive, metastatic; or from subjects not suffering from prostate cancer, e.g., subjects with normal prostate or subjects with BPH.
  • the samples are analyzed for the expression level of filamin B and PSA, and optionally the level of LY9, and further with one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19.
  • the level of filamin B, LY9, and PSA alone and in various combinations, optionally with other markers, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19, correlate with the presence or absence of disease, and with the severity of prostate cancer.
  • markers e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19, correlate with the presence or absence of disease, and with the severity of prostate cancer.
  • a subject sample e.g., blood
  • a new subject sample is obtained.
  • all subject samples are tested for the level of filamin B, PSA, and optionally in further combination with one or more of LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3.
  • the subject samples are matched to the medical records of the subjects to correlate filamin B, PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, or tubulin-beta 3 levels, as appropriate, with prostate cancer status at the time of diagnosis, rate of progression of disease, response of subjects to one or more interventions, and transitions between androgen dependent and independent status.
  • PSA remains the only generally accepted biomarker for prostate cancer.
  • prostate cancer is most commonly a slow growing tumor in men of advanced age, treatment of the cancer may do more harm to the subject than the tumor itself would.
  • elevated levels of LY9 have been demonstrated to be associated with prostate cancer.
  • the tests together particularly filamin B and PSA, optionally in combination with one or more of LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19, in detection, including in routine, preventative, screening methods in men having an increased risk of prostate cancer (e.g., increased age, family history, race, etc.) or in monitoring of subjects diagnosed with prostate cancer prior to or during treatment may be useful to better identify subjects in need of further, potentially more invasive, diagnostic tests, e.g., prostate exam or biopsy, digital rectal exam; or more aggressive treatment.
  • Detection of levels of expression of filamin B, PSA, LY9 keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19, may also be indicative of a good or poor response to a specific treatment regimen prior to changes in other signs or symptoms, e.g., loss of tumor response to hormone therapy.
  • a serum sample from a subject is tested for the level of expression of both filamin B and PSA, and optionally one or more of LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19.
  • the levels are compared to one or more appropriate controls, e.g., other normal subjects, subjects with prostate cancer.
  • Detection of an abnormal level of one or more of filamin B, PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19 indicates that the subject should be considered for further tests for the presence of prostate cancer.
  • Changes in the level of filamin B, optionally in combination with one or more of PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, or tubulin-beta 3, especially keratin 19 with PSA in the subject may be more indicative of a change in prostate cancer status than comparison to a population control.
  • determining a therapeutic regimen for a subject with prostate cancer not yet being actively treated for prostate cancer can be tested at regular intervals to determine if there is a change in the level of expression of filamin B, PSA, LY9 keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3.
  • An increase in the level of filamin B, PSA, keratin 19, or LY9 indicates that the subject should be considered for further tests to monitor the prostate cancer and more active therapeutic interventions should be considered.
  • a subject undergoing treatment for prostate cancer is tested prior to the initiation of the treatment and during and/or after the treatment to determine if the treatment results in a change in the level of expression of one or more of filamin B, PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3.
  • a decrease in the level of filamin B, PSA, keratin 19, or LY9 is indicative of response to treatment.

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