WO2010089707A1 - Procédé et trousses pour déterminer la sensibilité ou la résistance d'un cancer prostatique à une radiothérapie - Google Patents

Procédé et trousses pour déterminer la sensibilité ou la résistance d'un cancer prostatique à une radiothérapie Download PDF

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WO2010089707A1
WO2010089707A1 PCT/IB2010/050517 IB2010050517W WO2010089707A1 WO 2010089707 A1 WO2010089707 A1 WO 2010089707A1 IB 2010050517 W IB2010050517 W IB 2010050517W WO 2010089707 A1 WO2010089707 A1 WO 2010089707A1
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prostate cancer
gene
gene encoding
encoding seq
expression
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PCT/IB2010/050517
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English (en)
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Zelig Eshhar
Eytan Domany
Lilach Agemy
Itai Kella
Avi Orr-Urtreger
Anat Bar-Shira
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Yeda Research And Development Co. Ltd.
The Medical Research, Infrastructure, And Health Services Fund Of The Tel Aviv Medical Center
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Publication of WO2010089707A1 publication Critical patent/WO2010089707A1/fr

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

Definitions

  • the present invention in some embodiments thereof, relates to genetic markers of radiation- sensitivity or resistance of prostate cancer cells, and, more particularly, to methods and kits for predicting the sensitivity or the resistance of prostate cancer cells to radiation therapy and determining dosage and treatment regimens of prostate cancer.
  • Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer related death in the Western male population.
  • PSA serum prostate specific antigen
  • IR ionizing radiation
  • Resistant of cells to radiation therapy may be influenced by cellular and genetic factors, such as differential tissue-specific gene expression [e.g., p53, ataxia telangiectasia mutated (ATM) status (Canman, CE., et al., 1998; Chang, EH., 2000; Colletier, PJ., 2000; Fan, Z., et al., 2000; Lee, JM. and Bernstein, A. 1993)].
  • tissue-specific gene expression e.g., p53, ataxia telangiectasia mutated (ATM) status
  • ATM ataxia telangiectasia mutated
  • Exposure of cells to ionizing radiation results in immediate and widespread oxidative damage, by stimulating various signal transduction pathways such as protein kinase C (PKC), c-Jun NH2-terminal kinase (JNK), ceramide and mitogen- activated protein kinase (MAPK) activation.
  • PLC protein kinase C
  • JNK c-Jun NH2-terminal kinase
  • MEAK mitogen- activated protein kinase
  • the second one is an indirect effect in which recognition of DNA damage by sensor molecules (like ATM and ku 80), initiate signal transmitted to proteins that modulate the activity of gene regulated cellular responses.
  • sensor molecules like ATM and ku 80
  • the outcome of this dynamic combination under certain circumstances is arrest of cell cycle that is coupled with DNA repair leading to cell survival, apoptotic cell death or senescence.
  • DNA damage induced radiation include single-strand breaks (SSBs) and double-strand breaks (DSBs), sugar and base modifications, oxidative damage of bases, interstrand cross-links, DNA-protein cross-links and locally multiply damaged sites (LMDSs).
  • SSBs single-strand breaks
  • DSBs double-strand breaks
  • LMDSs locally multiply damaged sites
  • IR initiates a complicated series of transcriptional alterations in the cell, many of which are dependent upon genetic background, dose, dose rate, stage of cell cycle and time after irradiation.
  • Microarray technology has been used to identify markers which can predict resistance of cancerous cells to radiation therapy.
  • Hanna E., et al. (Cancer Research 61: 2376-2380, 2001) identified tumor-related genes as predictors of radiation response of squamous cell carcinoma and Kumagai K, et al., [Invest Ophthalmol Vis Sci. 47(6): 2300-4, 2006] identified upregulated and downregulated genes in RNA samples of radiation-sensitive and radiation-resistant cell lines of choroidal malignant melanomas.
  • Microarray studies performed on prostate cancer cells identified small clusters of genes discriminating recurrent versus nonrecurrent prostate cancer disease (Glinsky GV., et al., J. Clin. Invest. 113: 913-923, 2004).
  • the present inventors used microarrays to identify differentially expressed genes between IR resistance and IR sensitive human prostate cancer xenografts and cell lines (Lilach Agemy, Itai KeIa, Rafi Pfeffer, Eytan Domany, Avi Orr-Urtreger, Bar Shira Anat and Zelig Eshhar.
  • Fait S et al., 2003, Carcinogenesis, 24(11): 1837-1845; Kruse JJ, et al., 2004, Radiat Res., 161(l):28-38; Rosser CJ, et al., 2004, Cancer Gene Ther., l l(4):273-279; Kitahara O, et al., 2002, Neoplasia, 4(4):295- 303; Vallat L, et al., 2003, Blood, 101(11):4598-4606; Fukuda K, et al., 2004, Br J Cancer, 91(8):1543-1550; Fait S, et al., 2003, Carcinogenesis, 24(11):1837-1845; and Kruse JJ, et al., 2004, Radiat Res., 161(l):28-38.
  • a method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising comparing a level of expression in a prostate cancer sample of at least one gene selected from the group consisting H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, R
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, S100A16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO:
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, S100A16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185,
  • a microarray comprising no more than 500 oligonucleotides wherein each of the oligonucleotides is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, R
  • a method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2 and ZNF718, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy.
  • a method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy.
  • a method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy.
  • a method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy.
  • a method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:l l, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy.
  • a method of selecting a treatment regimen of a subject diagnosed with prostate cancer comprising: (a) predicting the sensitivity or the resistance of the prostate cancer of the subject to radiation therapy according to the method of the invention; and (b) selecting the treatment regimen based on the sensitivity or resistance of the prostate cancer to radiation therapy, thereby selecting the treatment regimen of a subject diagnosed with prostate cancer.
  • a method of selecting a treatment regimen of a subject diagnosed with prostate cancer comprising: (a) determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of S100A16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2 and ZNF718, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy; and (b) selecting the treatment regimen based on the sensitivity or resistance of the prostate cancer to radiation therapy.
  • a method of selecting a treatment regimen of a subject diagnosed with prostate cancer comprising: (a) determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy; and (b) selecting the treatment regimen based on the sensitivity or resistance of the prostate cancer to radiation therapy.
  • a method of selecting a treatment regimen of a subject diagnosed with prostate cancer comprising: (a) determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy; and (b) selecting the treatment regimen based on the sensitivity or resistance of the prostate cancer to radiation therapy.
  • a method of selecting a treatment regimen of a subject diagnosed with prostate cancer comprising: (a) determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy; and (b) selecting the treatment regimen based on the sensitivity or resistance of the prostate cancer to radiation therapy.
  • a method of selecting a treatment regimen of a subject diagnosed with prostate cancer comprising: (a) determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy; and (b) selecting the treatment regimen based on the sensitivity or resistance of the prostate cancer to radiation therapy.
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2 and ZNF718.
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203.
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218.
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218.
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197.
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy comprising at least 2 and no more than 500 isolated nucleic acid sequences selected from the group consisting of SEQ ID NOs:233-308.
  • kits for predicting a sensitivity or a resistance of prostate cancer to radiation therapy consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences selected from the group consisting of SEQ ID NOs:233-308 and optionally additional reagent(s) for facilitating detection of the expression level of at least one gene hybridizing to the isolated nucleic acid sequences, and/or packaging materials and/or instructions for use in predicting a sensitivity or a resistance of prostate cancer to radiation therapy.
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2 and ZNF718.
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203.
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218.
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218.
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197.
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer comprising at least 2 and no more than 500 isolated nucleic acid sequences selected from the group consisting of SEQ ID NOs:233-308.
  • kits for selecting a treatment regimen of a subject diagnosed with prostate cancer consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences selected from the group consisting of SEQ ID NOs:233-308 and optionally additional reagent(s) for facilitating detection of the expression level of at least one gene hybridizing to the isolated nucleic acid sequences, and/or packaging materials and/or instructions for use in selecting a treatment regimen of a subject diagnosed with prostate cancer.
  • a microarray comprising no more than 500 oligonucleotides wherein each of the oligonucleotides is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2 and ZNF718.
  • a microarray comprising no more than 500 oligonucleotides wherein each of the oligonucleotides is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198,
  • a microarray comprising no more than 500 oligonucleotides wherein each of the oligonucleotides is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218.
  • a microarray comprising no more than 500 oligonucleotides wherein each of the oligonucleotides is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218.
  • a microarray comprising no more than 500 oligonucleotides wherein each of the oligonucleotides is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197.
  • a decrease above a predetermined threshold in the level of expression of the at least one gene selected from the group consisting of IMP3, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, KRTCAP3, CSAG2, ZNF718, TP53, PTEN, DUSP6, TNFRSFlOD, and BTGl in the prostate cancer sample relative to the reference expression data of the at least one gene obtained from the at least one prostate cancer sensitive sample predict
  • an increase above a predetermined threshold in the level of expression of the at least one gene selected from the group consisting of IMP3, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, KRTCAP3, CSAG2, ZNF718, TP53, PTEN, DUSP6, TNFRSFlOD, and BTGl in the prostate cancer sample relative to the reference expression data of the at least one gene obtained from the at least one prostate cancer resistant sample predicts
  • the at least one gene is selected from the group consisting of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, MAGEA2, ZNF718, CASP8, LITAF, CASP4, CD24, GULPl, UCP2, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, and BTGl.
  • the at least one gene is selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51
  • the at least one gene is selected from the group consisting of H2AFJ, FTHl, PFN2, TFCP2, PSMB 8, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, KRTCAP3, LITAF, CASP4, CD24, GULPl, H
  • the at least one gene is selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, and ZNF718.
  • the at least one gene is selected from the group consisting of CASP8, LITAF, CASP4, CD24, GULPl, UCP2, H2AFJ, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, and BTGl.
  • the at least one gene is selected from the group consisting of FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB,
  • VDP VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST,
  • ID NO: 185 a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2,
  • SETD7 SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, and KRTC AP3.
  • the kit further comprising at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample.
  • the at least one prostate cancer sensitive sample comprises a radiation sensitive prostate cancer xenograft or a radiation sensitive prostate cancer cell line.
  • the at least one prostate cancer resistant sample comprises a radiation resistant prostate cancer xenograft or a radiation resistant prostate cancer cell line.
  • the kit further comprising a reference sample which comprises a cell sample of prostate cancer with known sensitivity or resistance to radiation therapy.
  • the reference sample comprises a radiation sensitive prostate cancer xenograft or a radiation sensitive prostate cancer cell line. According to some embodiments of the invention, the reference sample comprises a radiation resistant prostate cancer xenograft or a radiation resistant prostate cancer cell line.
  • the treatment regimen comprises a radiation therapy selected from the range of 45-80 Gy when the prostate cancer is radiation sensitive.
  • the alteration is upregulation of the expression level of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl and
  • the alteration is upregulation of the expression level of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201 and 202.
  • the alteration is upregulation of the expression level of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs:204-210.
  • the alteration is upregulation of the expression level of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs: 11-97 and 169-173.
  • the alteration is upregulation of the expression level of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169,
  • the alteration is upregulation of the level of expression of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of CSAG2, PPAPDClB, MAGEA2 and ZNF718.
  • the alteration is upregulation of the level of expression of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs: 101, 181, 114, 111 and 203.
  • the alteration is upregulation of the level of expression of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs:211-218.
  • the alteration is upregulation of the level of expression of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs:98-168 and 174-197.
  • the alteration is upregulation of the level of expression of the at least one polynucleotide in the cell of the prostate cancer relative to the reference cell, whereas the at least one polynucleotide is selected from the group consisting of SEQ ID NOs: 101, 114, 119, 174-197.
  • detecting the level of expression is effected using an RNA detection method.
  • detecting the level of expression is effected using a protein detection method.
  • each of the isolated nucleic acid sequences is selected from the group consisting of an oligonucleotide molecule, a cDNA molecule, a genomic DNA molecule and an RNA molecule.
  • each of the isolated nucleic acid sequences comprises at least 10 and no more than 50 nucleic acids.
  • each of the isolated nucleic acid sequences is bound to a solid support.
  • the kit further comprising at least one reagent suitable for detecting hybridization of the isolated nucleic acid sequences to at least one RNA transcript of the at least one gene.
  • the kit further comprising at least one reagent suitable for detecting hybridization of the isolated nucleic acid sequences and at least one RNA transcript corresponding to the at least one specific polynucleotide sequence selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2 and ZNF718.
  • the kit further comprising at least one reagent suitable for detecting hybridization of the isolated nucleic acid sequences and at least one RNA transcript corresponding to the at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203.
  • the kit further comprising at least one reagent suitable for detecting hybridization of the isolated nucleic acid sequences and at least one RNA transcript corresponding to the at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218.
  • the kit further comprising at least one reagent suitable for detecting hybridization of the isolated nucleic acid sequences and at least one RNA transcript corresponding to the at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218.
  • the kit further comprising at least one reagent suitable for detecting hybridization of the isolated nucleic acid sequences and at least one RNA transcript corresponding to the at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38,
  • the kit further comprising packaging materials packaging the at least one reagent and instructions for use in determining the sensitivity or the resistance of the prostate cancer to radiation therapy
  • the kit further comprising packaging materials packaging the at least one reagent and instructions for use in selecting the treatment regimen of the subject diagnosed with prostate cancer.
  • each of the oligonucleotides comprises at least 10 and no more than 40 nucleic acids.
  • IA-D are graphs depicting tumor growth following a single dose of in- vitro irradiation (FIG.s IA-B) or fractionated irradiation in vivo (FIGs. IC-D) of representative radiosensitive (FIGs. IA, 1C) and radioresistant (FIGs. IB and ID) prostate cancer xenografts.
  • Tissue of CWR22 or LAPC9 xenografts (80-100 mg) were implanted subcutaneously (s.c.) to SCID mice either without or after increasing doses of irradiation (0-160 Gy).
  • SPC super-paramagnetic clustering
  • FIG. 2A Dendrogram of the genes that includes clusters (each box represent a cluster) of size 3 and larger. The arrows mark the six clusters analyzed;
  • FIG. 2B Expression matrix of the 12 RNA samples obtained from 5 prostate cancer (PC) xenografts. Samples 1, 3, 5, 8 and 11 were obtained from non-irradiated (0 Gy) prostate cancer xenografts; Samples 2, 4, 6, 7, 9, 10 and 12 were obtained from irradiated prostate cancer xenografts with the following maximal irradiation doses: Sample 2 - 40 Gy; Sample 4 - 20 Gy; Sample 6 - 20 Gy; Sample 7 - 60 Gy; Sample 9 (80 Gy); Sample 10 - 160 Gy; and Sample 12 - 120 Gy.
  • PC prostate cancer
  • the genes (row) are normalized and ordered according to the dendrogram on the left (clustering operation).
  • the color represents induction (increase; red) or repression (decrease; blue).
  • the six clusters are marked by black lines at the right hand side of the matrix.
  • the 12 samples are divided according to their sensitivity to the IR (delineated at the matrix).
  • the "radiosensitive” group includes WISH-PC23 (columns 1 and 2) and CWR22 (columns 3 and 4) xenografts;
  • the "semi-radioresistant” group includes the LuCap35 (columns 5, 6 and 7) xenograft, and the "radioresistant” group includes the LAPC9 (columns 8, 9 and 10) and WISH-PC14 (columns 11 and 12) xenografts.
  • FIGs. 3A-D depict up regulated genes in the radioresistant samples.
  • Cluster 2 (FIGs. 3A-B), an expression matrix consists of 157 probesets (rows) and 12 samples (columns);
  • Cluster 3 (FIGs. 3C-D), an expression matrix consists of 66 probesets (rows) and 12 samples (columns).
  • FIGs. 3A and 3C - The probesets are centered and normalized, and ordered according to the sorter algorithm. The color represents increase (red) or decrease of gene expression (blue). The samples are ordered according to their sensitivity to radiation (see bottom of the expression matrix).
  • the sensitive group includes the WISH-PC23 (columns 1 and 2) and CWR22 (columns 3 and 4) xenografts
  • the semi-resistant group includes the LuCAP35 (columns 5, 6 and 7) xenograft
  • the resistant group includes the LAPC9 (columns 8, 9 and 10) and WISH-PC14 (columns 11 and 12) xenografts.
  • Samples 1, 3, 5, 8 and 11 were obtained from non-irradiated (0 Gy) prostate cancer xenografts; Samples 2, 4, 6, 7, 9, 10 and 12 were obtained from irradiated prostate cancer xenografts with the following maximal irradiation doses: Sample 2 - 40 Gy; Sample 4 - 20 Gy; Sample 6 - 20 Gy; Sample 7 - 60 Gy; Sample 9 (80 Gy); Sample 10 - 160 Gy; and Sample 12 - 120 Gy.
  • the sensitive, resistant and semi-sensitive groups are marked by red, black and green dots, respectively.
  • FIGs. 4A-D depict up regulated genes in the radiosensitive samples.
  • Cluster 5 is a method that enables visualization of high dimension vectors in a two or three dimensional plane; for
  • FIGs. 4A and 4C an expression matrix consists of 117 probesets (rows) and 12 samples (columns); Cluster 6 (FIGs. 4B and 4D), an expression matrix consists of 116 probesets (rows) and 12 samples (columns).
  • FIGs. 4A and 4C - The probesets are centered and normalized, and ordered according to the sorter algorithm. The color represents increase (red) or decrease of gene expression (blue). The samples are ordered according to their sensitivity to radiation (see bottom of the expression matrix).
  • the sensitive group includes the WISH-PC23 (columns 1 and 2) and CWR22 (columns 3 and 4) xenografts
  • the semi-resistant group includes the LuCap35 (columns 5, 6 and 7) xenograft
  • the resistant group includes the LAPC9 (columns 8, 9 and 10) and WISH- PC14 (columns 11 and 12) xenografts.
  • Samples 1, 3, 5, 8 and 11 were obtained from non-irradiated (0 Gy) prostate cancer xenografts; Samples 2, 4, 6, 7, 9, 10 and 12 were obtained from irradiated prostate cancer xenografts with the following maximal irradiation doses: Sample 2 - 40 Gy; Sample 4 - 20 Gy; Sample 6 - 20 Gy; Sample 7 - 60 Gy; Sample 9 (80 Gy); Sample 10 - 160 Gy; and Sample 12 - 120 Gy.
  • FIGs. 4B and 4D - depict principal component analysis (PCA), a visualization of the distance relation between the 12 samples.
  • the sensitive, resistant and semi- sensitive groups are marked by red, black and green dots, respectively.
  • FIGs. 5A-C depict uniting clusters 2, 3, 5 and 6.
  • FIG. 5A - An expression matrix consisting of 456 probesets (rows) and 12 samples (columns). The probesets are centered and normalized, and ordered according to the sorter algorithm. The color represents increase (red) or decrease in gene expression (blue). The samples are ordered according to their sensitivity to the IR (see bottom of the expression matrix).
  • the sensitive group includes the WISH-PC23 (columns 1 and 2) and CWR22 (columns 3 and 4) xenografts
  • the semi-resistant group includes the LuCap35 (columns 5, 6 and 7) xenograft
  • the resistant group includes the LAPC9 (columns 8, 9 and 10) and WISH- PC 14 (columns 11 and 12) xenografts.
  • FIG. 5B A visualization of the distance relation between the 12 samples by PCA analysis.
  • the sensitive, resistant and semi-resistant groups are marked by red, black and green dots, respectively.
  • FIG. 5C Representation of the distance relationship between the 12 samples by PCA analysis.
  • the Sensitive, Resistant and Semi-resistant samples are marked by red, black and green dots, respectively.
  • X, Y and Z axes represent the first, second and third principal components, respectively.
  • FIGs. 6A-D depict correlation of mRNA expression between gene chip analysis and Real Time PCR.
  • RNA samples from three individual mice, each of a different generation of the same xenograft, and the RNA sample (of the same xenograft) used on the Affymetrix chip were tested by Real Time PCR.
  • the data is presented as the relative expression value for LAPC9-resistant xenograft compared with sensitive xenografts (CWR22 or WISH PC23) or the intermediate phenotype (LuCAP35).
  • TPTl a control gene that was used for normalization for each sample.
  • FIG. 7 depicts clustering of genes whose expression differentiates between the radio- sensitive and the radio-resistant phenotypes, and are shared by both PC xenografts and cell lines.
  • the expression matrix contains 46 probe sets (corresponding to 42 genes) out of the 456 previously identified probesets that best distinguish between the radioresistant/sensitive phenotypes (using t-test, FDR 10 %) in the xenogratfs and in the cell line data.
  • the color bars at the bottom mark the Sensitive (red) and the Resistant (black) samples.
  • FIGs. 8A-B depict two hypothetical models for radioresistance/sensitivity of prostate cancer xenografts
  • FIG. 8 A - Model a one): two distinct subpopulations within a given xenograft
  • FIG. 8B - Model b two): each xenograft contains a homogeneous population of cells that have equal chance to survive/die after irradiation.
  • the present invention is of genetic markers which are differentially expressed in radiation sensitive or radiation resistant prostate cancer cells and which can be used to predict the sensitivity or the resistance of prostate cancer to radiation therapy. Specifically, the present invention can be used to select treatment regimens and dosage of subjects diagnosed with prostate cancer.
  • the present inventors have uncovered differentially expressed genes which are associated with radiation sensitive or radiation resistance prostate cancer and which can be used to predict the sensitivity or the resistance of prostate cancer to radiation therapy, select treatment regimen in subjects diagnosed with prostate cancer and determine a dosage of radiation therapy suitable for treating prostate cancer.
  • the present inventors have determined the radiosensitivity or radioresistance of prostatic adenocarcinoma xenografts and prostate cancer cell lines (Table 1, Figures IA-D, Example 1), and further subjected RNA derived from radiation sensitive or radiation resistance xenografts to microarray analysis.
  • Figures 2A-B, 3A-D, 4A-D and 5A-C and is described in Example 2 of the Examples section which follows, six stable gene clusters were observed. Of these, four clusters could divide the samples into major subgroups: IR-resistant and IR-sensitive phenotypes.
  • the four clusters consisted of 158 probsets [correspondent to 112 genes, including 14 expressed sequence tags (ESTs)] that showed more than 3 fold change in transcription (RNA expression level). 87 probesets displayed elevated expression (clusters 2 and 3, Tables 2 and 3, respectively), and 71 probesets displayed decreased expression (clusters 5 and 6, Tables 4 and 5, respectively) in the radioresistant xenografts relative to the radiosensitive xenografts.
  • Real Time PCR analysis of representative genes validated the gene array data ( Figures 6A-D, Example 3).
  • Tables 8 and 9 summarize the ratio of expression levels between several genes (CASP8, LITAF, CASP4, CD24, GULPl, UCP2, H2AFJ, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, BTGl) which are differentially expressed between IR resistant and sensitive prostate cancer cell samples phenotypes according to their functional affiliation.
  • a method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy is effected by comparing a level of expression in a prostate cancer sample of at least one gene selected from the group consisting H2AFJ, S100A16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF
  • the phrase "radiation therapy” refers to a high-energy radiation which is capable of at least causing a growth arrest of cancer cells and optimally killing the cancer cell and/or shrinking tumors.
  • the phrase “radiation therapy” refers to an ionizing radiation such as X-ray, beta particles and/or gamma rays. Radiation therapy may be applied to the cancer cells or the tumors from an external radiation source (e.g., machine) placed outside the body (external radiation therapy) or can be delivered via radioisotopes which are administered close to the cancer cells or the tumor (e.g., brachy therapy).
  • radiation therapy may be given at a single dose, or preferably, in fractions so that multiple doses are given for a period of several weeks.
  • radiation therapy is given over a 7 to 8 week period with a total of 65-80 Gray (Gy) delivered in fractions (e.g., in the range of 1.8 to 2 Gy) to the prostate.
  • the phrase "predicting a sensitivity or a resistance of prostate cancer to radiation therapy” refers to determining susceptibility of the prostate cancer cells to the radiation therapy, e.g., the degree of sensitivity or resistance of the prostate cancer to the radiation therapy.
  • radiation resistant prostate cancer refers to prostate cancer cells of which at least about 50 % of cells survive radiation therapy, e.g., being capable of growing and/or proliferating following radiation therapy.
  • a radiation resistant prostate cancer at least about 55 %, at least about 60 %, at least about 65 %, at least about 70 %, at least about 75 %, at least about 80 %, at least about 85 %, at least about 90 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, e.g., 100 % of the cells are capable of growing and/or proliferating following radiation therapy.
  • radiation sensitive prostate cancer refers to prostate cancer cells of which at least about 50 % of cells are growth arrest and/or killed as a result of radiation therapy.
  • a radiation sensitive prostate cancer at least about 55 %, at least about 60 %, at least about 65 %, at least about 70 %, at least about 75 %, at least about 80 %, at least about 85 %, at least about 90 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, e.g., 100 % of the cells are growth arrest and/or killed as a result of radiation therapy.
  • the growth and/or proliferation of prostate cancer cells can be determined in vitro (e.g., using known cell viability, proliferation, live/dead assays), ex vivo (e.g., by monitoring the ability of the cells to generate tumors in animals) and/or in vivo (e.g., by monitoring tumor growth in a subject).
  • the phrase "level of expression” refers to the degree of gene expression and/or gene product activity in a specific prostate cancer sample (e.g., a cell or a cell sample of the prostate cancer).
  • up-regulation or down-regulation of various genes can affect the level of the gene product (i.e., RNA and/or protein) in a specific sample.
  • RNA transcripts and polypeptide sequences of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195
  • probes which can be used to detect transcripts of these genes are provided in 6, 7, 8 and 9 in the Examples section which follows.
  • the level of expression can be determined in arbitrary absolute units, or in normalized units (relative to known expression levels of a control reference, e.g., a prostate cancer sample with known sensitivity or resistant to radiation therapy).
  • a control reference e.g., a prostate cancer sample with known sensitivity or resistant to radiation therapy.
  • the expression levels are normalized according to the chips' internal controls or by using quantile normalization such as RMA (Robust Multichip Average).
  • the at least one gene is selected from the group consisting of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, MAGEA2, ZNF718, CASP8, LITAF, CASP4, CD24, GULPl, UCP2, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, and BTGl.
  • the at least one gene is selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51
  • the at least one gene is selected from the group consisting of H2AFJ, FTHl, PFN2, TFCP2, PSMB 8, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, KRTCAP3, LITAF, CASP4, CD24, GULPl, H
  • the at least one gene is selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, and ZNF718.
  • the at least one gene is selected from the group consisting of CASP8, LITAF, CASP4, CD24, GULPl, UCP2, H2AFJ, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, and BTGl.
  • the at least one gene is selected from the group consisting of FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB,
  • VDP VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST,
  • ID NO: 185 a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2,
  • SETD7 SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, and KRTC AP3.
  • the method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy is effected by comparing the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218, in a prostate cancer sample to a reference expression data of the at least one polynucleotide sequence obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • the method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy is effected by comparing the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114,
  • 111 and 203 in a prostate cancer sample to a reference expression data of the at least one polynucleotide sequence obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • the method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy is effected by comparing the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218 in a prostate cancer sample to a reference expression data of the at least one polynucleotide sequence obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • the method of predicting a sensitivity or a resistance of prostate cancer to radiation therapy is effected by comparing the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197 in a prostate cancer sample to a reference expression data of the at least one polynucleotide sequence obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • the at least one gene comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least about 10 genes (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 genes), at least about 20 genes (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 genes), at least about 30 genes (e.g., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 genes), at least about 40 genes (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 genes), at least about 50 genes (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 genes), at least about 60 genes (e.g., 60, 61, 62, 63 or 64 genes) selected from the group consisting of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDC
  • the at least one gene can include H2AFJ, PSMB8, RHOQ, ACAA2, TUB A3 and Sl 0OA 16. Additionally or alternatively, the at least one gene can include METTL7A, MAGEA2, and KRTC AP3. Additionally or alternatively, the at least one gene can include H2AFJ, PSMB8, RHOQ, ACAA2, TUBA3, S100A16 and METTL7A, MAGEA2, and KRTC AP3.
  • the at least one gene comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least about 10 genes (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 genes), at least about 20 genes (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 genes), at least about 30 genes (e.g., 30, 31, 32 genes) selected from the group consisting of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, MAGEA2, ZNF718, CASP8, LITAF, CASP4, CD24, GULPl, UCP2, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3
  • H2AFJ e
  • the at least one gene can include H2AFJ, MAGEA2, ZNF718, CASP8, CASP4, CD24, UCP2, IFITM3, GUCY1A3. Additionally or alternatively, the at least one gene can include TP53, DUSP6, PTEN, TNFRSFlOD and IMP-3.
  • the at least one gene comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least about 10 genes (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 genes), at least about 20 genes (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 genes), at least about 30 genes (e.g., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 genes), at least about 40 genes (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 genes), e.g., 50 or 51 genes selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TU
  • the at least one gene comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least about 10 genes (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 genes), at least about 20 genes (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 genes), at least about 30 genes (e.g., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 genes), at least about 40 genes (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 genes), at least 50 genes (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58 or 59 genes) selected from the group consisting of H2AFJ, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16
  • H2AFJ FTH
  • the at least one gene comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least about 10 genes (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 genes), at least about 20 genes (e.g., 20, 21 genes) selected from the group consisting of CASP8, LITAF, CASP4, CD24, GULPl, UCP2, H2AFJ, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, and BTGl.
  • CASP8 LITAF
  • CASP4 CD24
  • GULPl UCP2, H2AFJ, HIST1H2BK, HIST1H2BD
  • ILlRl IFITM3, GUCY1A3, NRPl
  • AGTRl TP53
  • the at least one gene comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least about 10 genes (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 genes), at least about 20 genes (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 genes), at least about 30 genes (e.g., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 genes), at least about 40 genes (e.g., 40, 41 genes) selected from the group consisting of FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR
  • the method is effected by comparing the level of expression of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10 polynucleotide sequences, at least 11, e.g., 12 polynucleotide sequences selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203 in a prostate cancer sample to a reference expression data of the at least one polynucleotide obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • the method is effected by comparing the level of expression of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, e.g., 10 polynucleotide sequences selected from the group consisting of SEQ ID NOs:204-218 in a prostate cancer sample to a reference expression data of the at least one polynucleotide obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy. .
  • the method is effected by comparing the level of expression of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10 polynucleotide sequences, at least 20, at least 30, at least 40, at least 50 polynucleotide sequences selected from the group consisting of SEQ ID NOs: 11- 197 in a prostate cancer sample to a reference expression data of the at least one polynucleotide obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • the method is effected by determining the level of expression of at least one polynucleotide of clusters 2 and/or 3 (which genes are upregulated in radiation resistant prostate cancer cells) and/or of clusters 4 and/or 5 (which genes are downregulated in radiation resistant prostate cancer cells) and comparing the level of the at least one polynucleotide in a prostate cancer sample to a reference expression data of the at least one polynucleotide obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • the method is effected by comparing the level of expression of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10 polynucleotide sequences, at least 20, at least 30 polynucleotide sequences selected from the group consisting of SEQ ID NOs:l l, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197 in a prostate cancer sample to a reference expression data of the at least one polynucleotide obtained from at least one prostate cancer resistant sample and/or at least one prostate cancer sensitive sample, thereby predicting the sensitivity or the resistance of prostate cancer to radiation therapy.
  • detecting/determining the level of expression of the genes of some embodiments of the invention is effected using RNA or protein molecules which are extracted from a prostate cancer cell sample
  • prostate cancer sample refers to any cell content and/or cell secreted content which contains RNA and/or proteins of the prostate cancer cells.
  • Prostate cancer may be adenocarcinoma of the prostate or small cell carcinoma of the prostate.
  • the prostate cancer cell of the present invention is adenocarcinoma of the prostate. Examples include a prostate cancer biopsy (e.g., frozen tissue, cryosection, archival or fixed pathological specimens), blood sample, prostate cancer cell line, prostate cancer xenograft.
  • a "cell of the prostate cancer” may also optionally comprise a prostate cancer cell that has not been physically removed from the subject (e.g., in vivo detection).
  • the prostate cancer sample is a prostate cancer tissue biopsy which can be obtained using a scalpel or a syringe needle from a prostate cancer tumor.
  • Methods of extracting RNA or protein molecules from cells are well known in the art.
  • RNA or protein molecules are preferably characterized for the expression and/or activity level of various RNA and/or protein molecules using methods known in the arts.
  • methods of detecting transcribed RNA molecules in a cell sample include Northern blot analysis, RT-PCR, RNA in situ hybridization (using e.g., DNA or RNA probes to hybridize RNA molecules present in the cells or tissue sections), in situ RT-PCR (as described in Nuovo GJ, et al. Am J Surg Pathol. 1993, 17: 683-90; Karlinoth P, et al. Pathol Res Pract.
  • oligonucleotide microarray e.g., by hybridization of polynucleotide sequences derived from a sample to oligonucleotides attached to a solid surface [e.g., a glass wafer) with addressable location, such as Affymetrix microarray (Affymetrix®, Santa Clara, CA)].
  • Affymetrix microarray Affymetrix®, Santa Clara, CA
  • Non-limiting examples of methods of detecting the level and/or activity of specific protein molecules in a cell sample include Enzyme linked immunosorbent assay (ELISA), Western blot analysis, radio-immunoassay (RIA), Fluorescence activated cell sorting (FACS), immunohistochemical analysis, in situ activity assay (using e.g., a chromogenic substrate applied on the cells containing an active enzyme), in vitro activity assays (in which the activity of a particular enzyme is measured in a protein mixture extracted from the cells), quantitative two-dimensional (2-D) electrophoresis, dot blot analysis, protein array and the like.
  • ELISA Enzyme linked immunosorbent assay
  • RIA radio-immunoassay
  • FACS Fluorescence activated cell sorting
  • immunohistochemical analysis using e.g., a chromogenic substrate applied on the cells containing an active enzyme
  • in situ activity assay using e.g., a chromogenic substrate applied on the cells
  • reference expression data refers to the expression level of the gene in a prostate cancer sample with known sensitivity or resistant to radiation therapy, i.e., a radiation sensitive or a radiation resistance prostate cancer sample. Such as an expression level can be known from the literature, from the database, or from biological samples comprising RNA or protein molecules obtained from a reference cell.
  • reference cell refers to any cell of a prostate cancer with known sensitivity to radiation therapy, i.e., a radiation sensitive or a radiation resistance cell. Such a reference cell can be obtained from a blood sample of a subject diagnosed with prostate cancer, from a biopsy of prostate cancer, from a cell line or xenograft derived therefrom.
  • the reference expression data is obtained from at least one resistant prostate cancer sample (e.g., from one resistant prostate cancer sample), e.g., from at least 2, from at least 3, from at least 4, from at least 5, from at least 6, from at least 7, from at least 8, from at least 9, from at least 10, from at least 20, from at least 30, from at least 40, from at least 50, from at least 100 or more resistant prostate cancer samples.
  • at least one resistant prostate cancer sample e.g., from one resistant prostate cancer sample
  • the reference expression data is obtained from at least one resistant prostate cancer sample (e.g., from one resistant prostate cancer sample)
  • at least 2 from at least 3, from at least 4, from at least 5, from at least 6, from at least 7, from at least 8, from at least 9, from at least 10, from at least 20, from at least 30, from at least 40, from at least 50, from at least 100 or more resistant prostate cancer samples.
  • the reference expression data is obtained from at least one sensitive prostate cancer sample (e.g., from one sensitive prostate cancer sample), e.g., from at least 2, from at least 3, from at least 4, from at least 5, from at least 6, from at least 7, from at least 8, from at least 9, from at least 10, from at least 20, from at least 30, from at least 40, from at least 50, from at least 100 or more one sensitive prostate cancer samples.
  • the reference expression data may comprise an average of the expression level of several or all samples, and those of skills in the art are capable of averaging expression levels from 2 or more samples, using e.g., normalized expression values.
  • the reference expression data (or the reference cell) is obtained from a radiation sensitive prostate cancer xenograft or a radiation sensitive prostate cancer cell line.
  • Non-limiting examples of radiation sensitive prostate cancer xenograft include WISH-PC23 and CWR22.
  • Non-limiting examples of radiation sensitive prostate cancer cell line include LAPC4, LnCAP10995 (ATCC No. CRL- 10995), LnCAP1740 and 22RV-1 (ATCC No. CRL-2505).
  • Such xenografts and cell lines can be obtained from the American Type Culture Collection (Manassas, VA) or can be established in vitro from prostatic carcinoma essentially as described in the Examples section which follows.
  • the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-97 is determined and compared to the level of expression of the same polynucleotide sequences in a reference sample derived from a radiation sensitive prostate cancer (e.g., WISH-PC23, CWR22) or to an average level of expression of two or more radiation sensitive prostate cancer reference samples, wherein an upregulation (increase) in the expression level of the at least one polynucleotide sequence above a predetermined threshold relative to the reference sample is indicative of a radiation resistant prostate cancer.
  • a radiation sensitive prostate cancer e.g., WISH-PC23, CWR22
  • the level of expression of 71 polynucleotide sequences was downregulated in the radioresistant xenografts relative to the radiosensitive xenografts, in order to predict the sensitivity of the prostate cancer to radiation therapy, the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:98-168 is determined and compared to the level of expression of the same polynucleotide sequences in a reference sample derived from a radiation sensitive prostate cancer (e.g., WISH-PC23, CWR22) or to an average level of expression of two or more radiation sensitive prostate cancer reference samples, wherein downregulation (decrease) in the expression level of the at least one polynucleotide sequence above a predetermined threshold relative to the reference sample is indicative of a radiation resistant prostate cancer.
  • a radiation sensitive prostate cancer e.g., WISH-PC23, CWR22
  • the reference expression data (or the reference cell) is obtained from a radiation resistant prostate cancer xenograft or a radiation resistant prostate cancer cell line.
  • Non-limiting examples of radiation resistant prostate cancer xenograft include WISH-PC14 and LAPC9.
  • Non-limiting examples of radiation resistant prostate cancer cell line include PC-3 (ATCC No. CRL- 1435), DU- 145 (ATCC No. HTB-81) and CL- 1.
  • Such xenografts and cell lines can be obtained from the American Type Culture Collection (Manassas, VA) or can be established in vitro from prostatic carcinoma essentially as described in the Examples section which follows.
  • the expression level of 87 polynucleotide sequences was downregulated in the radiosensitive xenografts relative to the radioresistant xenografts, in order to predict the sensitivity of the prostate cancer to radiation therapy, the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-97 is determined and compared to the level of expression of the same polynucleotide sequences in a reference sample derived from a radiation resistant prostate cancer (e.g., WISH-PC14 and LAPC9) or to an average level of expression of two or more radiation resistant prostate cancer reference samples, wherein downregulation (decrease) in the expression level of the at least one polynucleotide sequence above a predetermined threshold relative to the reference sample is indicative of a radiation sensitive prostate cancer.
  • a radiation resistant prostate cancer e.g., WISH-PC14 and LAPC9
  • the level of expression of 71 polynucleotide sequences was upregulated (increased) in the radiosensitive xenografts relative to the radioresistant xenografts, in order to predict the sensitivity of the prostate cancer to radiation therapy, the level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:98-168 is determined and compared to the level of expression of the same polynucleotide sequences in a reference sample derived from a radiation resistant prostate cancer (e.g., WISH-PC14 and LAPC9) or to an average level of expression of two or more radiation resistant prostate cancer reference samples, wherein upregulation (increase) in the expression level of the at least one polynucleotide sequence above a predetermined threshold relative to the reference sample is indicative of a radiation sensitive prostate cancer.
  • a radiation resistant prostate cancer e.g., WISH-PC14 and LAPC9
  • an alteration above a predetermined threshold refers to a fold increase or decrease (i.e., degree of upregulation or downregulation, respectively) which is higher than a predetermined threshold such as at least twice, at least three times, at least four time, at least five times, at least six times, at least seven times, at least eight times, at least nine times, at least 20 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, at least 1000 times, at least 2000 times, at least 3000 times relative to the reference sample.
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs: 14, 15, 17, 24, 26, 29, 35, 45, 49, 60, 64, 65, 80, 82, 83 and 96 is at least 10 times higher in radiation resistant prostate cancer cells as compared to radiation sensitive prostate cancer cells
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs:22, 28, 36, 42, 84 or the polynucleotides set forth by SEQ ID NOs:21 and 44 is at least 50 or 150 times, respectively, higher in radiation resistant prostate cancer cells as compared to radiation sensitive prostate cancer cells.
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173 is higher in radiation resistant prostate cancer cells as compared to radiation sensitive prostate cancer cells.
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs:91, 198, 83, 199, 200, 201 or 202 is higher in radiation resistant prostate cancer cells as compared to radiation sensitive prostate cancer cells.
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs:99, 104, 112, 113, 114, 118, 122, 125, 129, 130, 132, 135, 136, 138, 146, 152, 153, 156, 158, 159, 164, 165 and 166 is at least 10 times higher in radiation sensitive prostate cancer cells as compared to radiation resistant prostate cancer cells
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs: 107, 108, 109, 117, 139, 143, 147, 157, 162 and 167, the polynucleotides set forth by SEQ ID NOs: 101, 105, 111, 140 and 145, or the polynucleotides set forth by SEQ ID NOs: 141, 142 and 144 is at least 50, 150 or 1000 times, respectively, higher in radiation sensitive prostate cancer cells as
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs: 101, 114, 119, 174-197 is higher in radiation sensitive prostate cancer cells as compared to radiation resistant prostate cancer cells.
  • the level of expression of the polynucleotide sequences set forth by SEQ ID NOs: 101, 181, 114, 111 or 203 is higher in radiation sensitive prostate cancer cells as compared to radiation resistant prostate cancer cells.
  • a decrease above a predetermined threshold in the level of expression of the at least one gene selected from the group consisting of IMP3, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, KRTCAP3, CSAG2, ZNF718, TP53, PTEN, DUSP6, TNFRSFlOD, and BTGl in the prostate cancer sample relative to the reference expression data of the at least one gene obtained from the at least one prostate cancer sensitive sample predict
  • an increase above a predetermined threshold in the level of expression of the at least one gene selected from the group consisting of IMP3, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6orfl51, a gene encoding SEQ ID NO:195, LOC646208, KRTCAP3, CSAG2, ZNF718, TP53, PTEN, DUSP6, TNFRSFlOD, and BTGl in the prostate cancer sample relative to the reference expression data of the at least one gene obtained from the at least one prostate cancer resistant sample predicts
  • the method of predicting the sensitivity or resistance of prostate cancer to radiation therapy enables the classification of prostate cancer cells to radiation resistant or radiation sensitive cells.
  • some prostate cancer cells may have a semi-resistant or a semi- sensitive phenotype with respect to radiation therapy. Accordingly, such prostate cancer cells may share an expression profile with radiation resistant and radiation sensitive prostate cancer cells.
  • a non-limiting example of a prostate cancer cell sample with a semi-resistant radiation therapy phenotype is the LuCaP35 prostate cancer xenograft described in the Examples section which follows.
  • Determination of the radiosensitivity or radioresistance of a prostate cancer cell sample can be used to select the treatment regimen of a subject being diagnosed with prostate cancer.
  • a method of selecting a treatment regimen of a subject diagnosed with prostate cancer is effected by (a) predicting the sensitivity or the resistance of the prostate cancer of the subject to radiation therapy according to the method of the invention and (b) selecting the treatment regimen based on the sensitivity or resistance of the prostate cancer to radiation therapy.
  • a presence of a radiation sensitive prostate cancer is indicative of selecting radiation therapy as the treatment regimen of the subject diagnosed with prostate cancer.
  • the method of selecting a treatment regimen of a subject diagnosed with prostate cancer is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy, whereas a presence of a radiation sensitive prostate cancer is indicative of selecting radiation therapy as the treatment regimen of the subject diagnosed with prostate cancer.
  • the method of selecting a treatment regimen of a subject diagnosed with prostate cancer is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy, whereas a presence of a radiation sensitive prostate cancer is indicative of selecting radiation therapy as the treatment regimen of the subject diagnosed with prostate cancer.
  • the method of selecting a treatment regimen of a subject diagnosed with prostate cancer is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy, whereas a presence of a radiation sensitive prostate cancer is indicative of selecting radiation therapy as the treatment regimen of the subject diagnosed with prostate cancer.
  • the method of selecting a treatment regimen of a subject diagnosed with prostate cancer is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to radiation therapy, whereas a presence of a radiation sensitive prostate cancer is indicative of selecting radiation therapy as the treatment regimen of the subject diagnosed with prostate cancer.
  • the term "subject” refers to a male mammal, preferably human being, who is diagnosed with prostate cancer. It will be appreciated that the diagnosis of prostate cancer (e.g., determining presence of cancer, classifying disease, determining the severity of the disease) can take place at early stages of the disease (e.g., when the cancer is confined to the prostate tissue) as well as at advanced stages of the disease, when the cancer has spread beyond the prostate tissue.
  • diagnosis of prostate cancer e.g., determining presence of cancer, classifying disease, determining the severity of the disease
  • early stages of the disease e.g., when the cancer is confined to the prostate tissue
  • advanced stages of the disease when the cancer has spread beyond the prostate tissue.
  • the presence of radiation sensitive prostate cancer cells of a subject is indicative of selecting radiotherapy as a preferred treatment regimen.
  • the presence of radiation resistant prostate cancer cells of a subject suggests that the tumor is refractory to IR and therefore the subject should preferably be subjected to alternative treatment (e.g., radical prostectomy, with or without radiation therapy, with or without hormonal therapy such as androgen suppression (ablation) which is achieved, for example, with a gonadotropin-releasing-hormone agonist with or without antiandrogen therapy and the like).
  • alternative treatment e.g., radical prostectomy, with or without radiation therapy, with or without hormonal therapy such as androgen suppression (ablation) which is achieved, for example, with a gonadotropin-releasing-hormone agonist with or without antiandrogen therapy and the like.
  • the classification of prostate cancer cells as being sensitive or resistant to radiation therapy may also affect the selection of optimal dosage for treating the prostate cancer in the subject.
  • a method of determining an optimal dosage of radiation therapy for treatment of prostate cancer is effected by (a) predicting the sensitivity or the resistance of the prostate cancer of the subject to radiation therapy according to the method of the invention; and (b) selecting the optimal dosage of radiation therapy for the treatment of prostate cancer, thereby determining the optimal dosage of the radiation therapy for the treatment of the prostate cancer.
  • the method of determining an optimal dosage of radiation therapy for treatment of prostate cancer is effected by (a) determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218 (e.g., a polynucleotide selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203; a polynucleotide selected from the group consisting of SEQ ID NOs:204-218; or a polynucleotide selected from the group consisting of SEQ ID NOs:l l, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197), wherein an alteration above a predetermined threshold in the level of expression of the
  • a presence of radiation sensitive prostate cancer is indicative of using a dosage of the radiation therapy selected from the range of about 45-80 Gy, e.g., about 65-80 Gy, e.g., about between 65-78 Gy;
  • a presence of radiation sensitive prostate cancer is indicative for using a combination of external beam radiation and brachy therapy.
  • an external beam radiation therapy can involve the administration of a dosage of about 45 Gy (e.g., in fractions of about 2 Gy, for 5 times/week, 4-5 weeks) and brachy therapy can involve an internal radiation of more than 100 Gy (see Pisansky TM., 2006).
  • a presence of radiation resistant prostate cancer is indicative of using a dosage of radiation therapy selected from the range of about 75-80 Gy combined with radiotherapy to the pelvic lymph nodes and/or neoadjuvant or adjuvant androgen suppression therapy (see Pisansky TM., 2006).
  • a presence of radiation resistant prostate cancer is indicative of treating the subject with radical prostectomy, with or without radiation therapy.
  • an efficient radiation therapy which is selected according to the method described hereinabove
  • a radical prostatectomy may increase the prognosis of a subject diagnosed with prostate cancer.
  • the presence of prostate cancer cells which are resistant to radiation therapy may indicative poor prognosis of the subject being diagnosed with prostate cancer.
  • a method of predicting a prognosis of a subject diagnosed with prostate cancer following radiation therapy is effected by predicting the sensitivity or the resistance of the prostate cancer of the subject to radiation therapy according to the method of the invention; wherein a presence of radiation resistance prostate cancer is indicative of poor prognosis of the subject; thereby determining the prognosis of the subject diagnosed with prostate cancer following radiation therapy.
  • the method of predicting a prognosis of a subject diagnosed with prostate cancer following radiation therapy is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11- 218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to the radiation therapy; wherein a presence of radiation resistance prostate cancer is indicative of poor prognosis of the subject; thereby determining the prognosis of the subject diagnosed with prostate cancer following radiation therapy.
  • the method of predicting a prognosis of a subject diagnosed with prostate cancer following radiation therapy is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to the radiation therapy; wherein a presence of radiation resistance prostate cancer is indicative of poor prognosis of the subject; thereby determining the prognosis of the subject diagnosed with prostate cancer following radiation therapy.
  • the method of predicting a prognosis of a subject diagnosed with prostate cancer following radiation therapy is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs:204- 218, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to the radiation therapy; wherein a presence of radiation resistance prostate cancer is indicative of poor prognosis of the subject; thereby determining the prognosis of the subject diagnosed with prostate cancer following radiation therapy.
  • the method of predicting a prognosis of a subject diagnosed with prostate cancer following radiation therapy is effected by determining in a cell of the prostate cancer a level of expression of at least one polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197, wherein an alteration above a predetermined threshold in the level of expression of the at least one polynucleotide sequence in the cell relative to a level of expression of the at least one polynucleotide sequence in a reference cell is indicative of the sensitivity or the resistance of the prostate cancer to the radiation therapy; wherein a presence of radiation resistance prostate cancer is indicative of poor prognosis of the subject; thereby determining the prognosis of the subject diagnosed with prostate cancer following radiation therapy.
  • the kit of the some embodiments of the invention is for predicting a sensitivity or a resistance of prostate cancer to radiation therapy.
  • the kit comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, S100A16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185
  • the kit of the some embodiments of the invention is for selecting a treatment regimen of a subject diagnosed with prostate cancer.
  • the kit comprising at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, S100A16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUBA3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl,
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, PSMB8, RHOQ, ACAA2, TUBA3 and S100A16 and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of METTL7A, MAGEA2, and KRTCAP3 and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, PSMB 8, RHOQ, ACAA2, TUB A3, S100A16 and METTL7A, MAGEA2, and KRTCAP3 and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, MAGEA2, ZNF718, CASP8, LITAF, CASP4, CD24, GULPl, UCP2, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, and BTGl and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described herein
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, S100A16, MALL, SMARCAl, HPCALl and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, MAGEA2, ZNF718, CASP8, CASP4, CD24, UCP2, IFITM3, GUCY1A3 and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of TP53, DUSP6, PTEN, TNFRSFlOD and IMP-3 and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAM118A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of Sl 0OA 16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, and ZNF718 and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of CASP8, LITAF, CASP4, CD24, GULPl, UCP2, H2AFJ, HIST1H2BK, HIST1H2BD, ILlRl, IFITM3, GUCY1A3, NRPl, AGTRl, TP53, DUSP6, PTEN, TNFRSFlOD, IMP-3, RAB26, and BTGl and additional reagent(s) as described below for facilitating detection of the expression level of the at least one gene, and/or packaging materials and instructions for use as described hereinbelow.
  • the kit consisting essentially of at least 2 and no more than 500 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one gene selected from the group consisting of FTHl, PFN2, PSMB8, TFCP2, RHOQ, CASP8, ACAA2, SMARCAl, UCP2, TUBA3, MALL, CKLFSF3, GDAPl, S100A16, PPIB, VDP, CDC40, METTL7A, MAGEA2, ELL3, RAB26, FAMl 18A, TRAG3, CNST, PPAPDClB, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2, SETD7, ARRDC4, SLAINl, C6or
  • the kit comprises at least 2 and no more than 500 isolated nucleic acid sequences, preferably, at least 4 and no more than 500 isolated nucleic acid sequences, preferably, at least 4 and no more than 400 isolated nucleic acid sequences, preferably, at least 10 and no more than 300 isolated nucleic acid sequences, preferably, at least 10 and no more than 198 isolated nucleic acid sequences, preferably, at least 20 and no more than 157 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218.
  • the kit comprises at least 2 and no more than 500 isolated nucleic acid sequences, preferably, at least 4 and no more than 500 isolated nucleic acid sequences, preferably, at least 4 and no more than 400 isolated nucleic acid sequences, preferably, at least 10 and no more than 300 isolated nucleic acid sequences, preferably, at least 10 and no more than 198 isolated nucleic acid sequences, preferably, at least 20 and no more than 157 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203.
  • the kit comprises at least 2 and no more than 500 isolated nucleic acid sequences, preferably, at least 4 and no more than 500 isolated nucleic acid sequences, preferably, at least 4 and no more than 400 isolated nucleic acid sequences, preferably, at least 10 and no more than 300 isolated nucleic acid sequences, preferably, at least 10 and no more than 198 isolated nucleic acid sequences, preferably, at least 20 and no more than 157 isolated nucleic acid sequences, wherein each of the at least 2 and no more than 500 isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218.
  • the isolated nucleic acid sequences included in the kit of the present invention can be single- stranded or double- stranded, naturally occurring or synthetic nucleic acid sequences such as oligonucleotides, RNA molecules, genomic DNA molecules, cDNA molecules and/or cRNA molecules.
  • the isolated nucleic acid sequences of the kit can be composed of naturally occurring bases, sugars, and covalent internucleoside linkages (e.g., backbone), as well as non-naturally occurring portions, which function similarly to respective naturally occurring portions.
  • Synthesis of the isolated nucleic acid sequences of the kit can be performed using enzymatic synthesis or solid-phase synthesis.
  • Equipment and reagents for executing solid-phase synthesis are commercially available from, for example, Applied Biosystems. Any other means for such synthesis may also be employed; the actual synthesis of the oligonucleotides is well within the capabilities of one skilled in the art and can be accomplished via established methodologies as detailed in, for example: Sambrook, J. and Russell, D. W. (2001), "Molecular Cloning: A Laboratory Manual”; Ausubel, R. M. et al, eds.
  • each of the isolated nucleic acid sequences included in the kit of present invention comprises at least 10 and no more than 50 nucleic acids, more preferably, at least 15 and no more than 45, more preferably, between 15-40, more preferably, between 20-35, more preferably, between 20-30, even more preferably, between 20-25 nucleic acids.
  • the kit preferably includes at least one reagent as described hereinabove which is suitable for facilitating detection of the expression level of the at least one gene of the invention (as described above), e.g., the polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11-218; at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203; at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218; or at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197.
  • Examples include reagents suitable for hybridization or annealing of a specific polynucleotide of the kit to a specific target polynucleotide sequence (e.g., RNA transcript derived from the prostate cancer cell sample or a cDNA derived therefrom) such as formamide, sodium chloride, and sodium citrate), reagents which can be used to labeled polynucleotides (e.g., radiolabeled nucleotides, biotinylated nucleotides, digoxigenin-conjugated nucleotides, fluorescent-conjugated nucleotides) as well as reagents suitable for detecting the labeled polynucleotides (e.g., antibodies conjugated to fluorescent dyes, antibodies conjugated to enzymes, radiolabeled antibodies and the like).
  • a specific target polynucleotide sequence e.g., RNA transcript derived from the prostate cancer cell sample or a cDNA derived therefrom
  • the kit of the present invention comprises at least one reagent suitable for detecting the expression level and/or activity of at least one polypeptide encoded by at least one polynucleotide selected from the group consisting of SEQ ID NOs: 11-218; at least one polypeptide encoded by at least one polynucleotide selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203; at least one polypeptide encoded by at least one polynucleotide selected from the group consisting of SEQ ID NOs:204-218; or at least one polypeptide encoded by at least one polynucleotide selected from the group consisting of SEQ ID NOs:l l, 30, 38, 44, 59, 62, 65, 82, 83, 91, 169, 170, 171, 172, 173, 101, 114, 119, 174-197.
  • the kit may comprise at least one reagent suitable for detecting the expression level and/or activity of at least one polypeptide selected from the group consisting of: S100A16 (GenBank Accession No. NP_525127.1; SEQ ID NO:219), MALL (GenBank Accession No. NP_005425.1; SEQ ID NO:220), SMARCAl (GenBank Accession No. NP_003060.2; SEQ ID NO:221), HPCALl (GenBank Accession Nos. NP_002140.2, and NP_602293.1; SEQ ID NOs:222, and 223), FUNDCl (GenBank Accession No. NP_776155.1; SEQ ID NO:224), CSAG2 (GenBank Accession No.
  • a reagent can be, for example, an antibody capable of specifically binding to at least one epitope of the polypeptide.
  • the reagent included in the kit can be a specific substrate capable of binding to an active site of the polypeptide.
  • the kit may also include reagents such as fluorescent conjugates, enzymes, secondary antibodies and the like which are suitable for detecting the binding of a specific antibody and/or a specific substrate to the polypeptide.
  • the kit includes a reference cell which comprises a cell sample of prostate cancer with a known sensitivity (sensitive or resistant prostate cancer sample) to radiation therapy as described hereinabove.
  • the kit of the present invention preferably includes packaging material packaging the at least one reagent and a notification in or on the packaging material.
  • a notification identifies the kit for use in predicting the sensitivity or the resistance of prostate cancer to radiation therapy, selecting a treatment regimen of a subject diagnosed with prostate cancer, determining an optimal dosage of radiation therapy for treatment of prostate cancer and/or predicting a prognosis of a subject diagnosed with prostate cancer following radiation therapy.
  • the kit may also include appropriate buffers and preservatives for improving the shelf life of the kit.
  • isolated nucleic acid sequences included in the kit of the present invention can be bound to a solid support e.g., a glass wafer in a specific order, i.e., in the form of a microarray.
  • isolated nucleic acid sequences can be synthesized directly on the solid support using well-known prior art approaches (Seo TS, et al, 2004, Proc. Natl. Acad. Sci. USA, 101: 5488-93.).
  • the isolated nucleic acid sequences are attached to the support in a location specific manner such that each specific isolated nucleic acid sequence has a specific address on the support (i.e., an addressable location) which denotes the identity (i.e., the sequence) of that specific isolated nucleic acid sequence.
  • the microarray comprising no more than 500 oligonucleotides wherein each of the oligonucleotides is capable of specifically recognizing at least one gene selected from the group consisting of H2AFJ, S100A16, ANXA2P2, MALL, SMARCAl, HPCALl, FUNDCl, CSAG2, PPAPDClB, MAGEA2, ZNF718, FTHl, PFN2, TFCP2, PSMB8, RHOQ, CASP8, ACAA2, UCP2, TUB A3, CKLFSF3, GDAPl, PPIB, VDP, CDC40, METTL7A, ELL3, RAB26, FAMl 18A, TRAG3, CNST, CLN8, WDR5B, a gene encoding SEQ ID NO: 184, a gene encoding SEQ ID NO: 185, a gene encoding SEQ ID NO: 186, IDHl, ZNF124, RWDD2, COX7A2,
  • the microarray comprises no more than 500 isolated nucleic acid sequences, wherein each of the isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:l l-218.
  • the microarray comprises no more than 500 isolated nucleic acid sequences, wherein each of the isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:91, 198, 83, 199, 200, 201, 202, 101, 181, 114, 111 and 203.
  • the microarray comprises no more than 500 isolated nucleic acid sequences, wherein each of the isolated nucleic acid sequences is capable of specifically recognizing at least one specific polynucleotide sequence selected from the group consisting of SEQ ID NOs:204-218.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • the term "treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
  • the WISH-PC23 adenocarcinoma xenograft was established from prostatic carcinoma harvested during palliative trans urethral resection of the prostate performed in a patient with local progression of adenocarcinoma of the prostate, Gleason score 6 (3+3).
  • the patient was previously treated with external beam radiotherapy and total androgen blockade.
  • LuCaP35 xenograft was developed and provided by R.L.
  • Vessella (University of Washington School of Medicine, Seattle, Washington, USA); LAPC9 was developed and provided by Charles L Sawyers (University of California, Los Angeles, USA); CWR22 was developed by Case Western Reserve University and provided by the University of North Carolina-Chapel Hill. All xenografts were maintained by serial transfers in 4-10-week-old SCID mice (c.b-17/Icr Beige). Mice were grown in the pathogen-free facilities of the Weizmann Institute of Science. All of the surgical procedures were performed under ketamin + xylazine anesthesia (127.5 and 4.5 mg/kg respectively) according to the IACUC regulations.
  • Cell culture - Cells were grown in RPMI 1640 media supplemented with 2 mM glutamine, 100 ⁇ g/mL penicillin, 100 ⁇ g/mL streptomycin, and 10 % FCS (CL-I supplemented with charcoal stripped FCS). Special supplement to cell lines used in these studies were as follows: LNCaP1740, LNCaP10995 and LAPC4 were grown with 10 "9 M testosterone and insulin (Sigma). DU-145 were grown with insulin (Sigma). Cells cultured in RPMI-based media were incubated in a humidified 37 0 C incubator with a 5 % CO 2 atmosphere.
  • Xenograft irradiation - Single-cell suspensions of xenograft fragments were prepared by dissociating and mincing the xenografts through a stainless still mesh followed by separation over Ficoll-Paque 400.
  • the cell suspensions or the tumor tissues were irradiated by a Cobalt 60 source, emitting 65 cGy/min (Gammabeam-150, MDS Nordion).
  • mice received fractionated radiation using the Caesium 137 source, operating at a dose rate of 100 centiGy/min (Gammacell 40 Exactor, MDS Nordion). Treatment was given daily for five consecutive days per week, followed by a two day break, for the total number of fraction as indicated. Tumor growth was followed for up to 1 year after irradiation.
  • Samples were collected from 12 xenografts; either un-irradiated or from xenografts 2-6 months after their irradiation (depend on the tumor establishment after IR) using the highest tolerated dose: CWR22 (un-irradiated and survivors of 20Gy), WISH PC-23 (un-irradiated and survivors of 40Gy), LuCAP35 (un-irradiated and survivors of 20Gy and 60Gy), LAPC9 (un-irradiated and survivors of 80Gy and 160Gy) and WISH PC- 14 (un-irradiated and survivors of 120Gy). Samples of irradiated xenografts that developed in mice were kept frozen in liquid nitrogen until their processing for gene array.
  • the microarray consists of sets of DNA probes, each chosen carefully to record expression of a specific gene.
  • the set of probes relating to a specific gene is referred to as a probeset, where, each probe that is part of a probeset is a sequence of 20-25 bases taken from the transcribed region of the gene.
  • the expression value of a given probeset is calculated as the average expression level of all the probes in the probeset. Note that some genes have more than one probeset.
  • GeneChips were prepared, hybridized, and scanned according to the manufacturer's instruction. Briefly, 10 ⁇ g total RNA was reverse transcribed with a poly-(T) primer containing a T7 promoter, and the cDNA made double-stranded. An in vitro transcription was done to produce biotinylated cRNA, which was then hybridized to the GeneChips. The chips were washed and stained with streptavidin phycoerythrin using an Affymetrix FS-450 fluidics station, and data was collected with Affymetrix GeneChip Scanner 3000.
  • Clustering analysis of the gene array data was performed as follows. First, probesets that were present (P ⁇ 0.05) at least in one sample (out of 12) were selected. 31690 (out of 54,613) probeset passed this filter. Next, the 3 filtering process was performed as following:
  • the 2000 most variable probe-sets measured based on the 12 samples.
  • the gene clustering operation was performed using the Super-Paramagnetic Clustering algorithm (Blatt M, Wiseman S, Domany E. Superparamagnetic clustering of data; 1996. 3251-3254).
  • the SPIN algorithm Tsafrir D, Tsafrir I, Ein-Dor L, Zuk O, Notterman DA, Domany E. Sorting points into neighborhoods (SPIN): data analysis and visualization by ordering distance matrices; 2005. 2301-2308) was used.
  • Statistical Analysis was performed using JMP statistical software (SAS Institute, Inc., Cary, NC). Tumor volume data were analyzed by the Fit model, to test the effect of different doses of irradiation during the experimental period.
  • PCR - RNA was reverse transcribed to cDNA from 1 ⁇ g of total RNA by using the Reverse Transcription System kit (Promega Crop.), which was then subjected to Q-RT-PCR performed essentially according to the manufacturer's instructions.
  • Specific primer pairs were designed using LightCycler probe design software (Roche) and were used to amplify specific genes in the presence of 3 mM MgCl 2 .
  • PCR was performed in duplicate/triplicate in a total volume of 10 ⁇ l of LightCycler HotStart DNA SYBR Green I mix (Roche) containing primer and 2.5 ⁇ l of cDNA.
  • PCR amplification was preceded by incubation of the mixture for 10 minutes at 95 0 C, and the amplification step consisted of 35-45 cycles of denaturation, annealing, and extension. Denaturation was performed for 10 seconds at 95 0 C, annealing was performed at 60 0 C for 10 seconds, and the extension was performed at 72 0 C for 14 seconds, with fluorescence detection at 72 0 C after each cycle. After the final cycle, melting point analyses of all samples were performed within the range of 70-99 0 C with continuous fluorescence detection. A standard curve was generated from one sample in each run.
  • TPTl 5 1 -GCACATCCTTGCTAATTTCA-3 1 (SEQ ID NO:1) and 3'-CAAGCAGAAGCCAGTTAT-S' (SEQ ID NO:2); 207 bp RT-PCR product] were used for sample normalization. Results for each gene are presented as the relative expression of LAPC9 xenograft levels.
  • the primers used in these studies were as follows: human RAB26 [5 1 -AGTGGACAGACTTTGCC-3 1 (SEQ ID NO:3) and 3'- GCACG ATGTGATTAGCCAG-S 1 (SEQ ID NO:4); 193 bp RT-PCR product], human H2A variant 2 [5 1 -TGTTGGAGTACCTTACGG-3 1 (SEQ ID NO:5) and 3'- GCGTCAGGGTCATTTG-S 1 (SEQ ID NO:6); 236 bp RT-PCR product], human PTEN [5 1 -AGTGGCTAAAGAGCTTTG-3 1 (SEQ ID NO:7) and 3'-
  • ATGGTATATGGTCCAGAGT-S 1 (SEQ ID NO:8); 196 bp RT-PCR product], and human UCP2 [5 1 -GATACCAAAGCACCGTC-3 1 (SEQ ID NO:9) and 3'- GAAGTGAAGAAGTGGCAAGG-S 1 (SEQ ID NO: 10), 196 bp RT-PCR product].
  • EXAMPLE 1 EXAMPLE 1
  • the present inventors have determined the effect of different doses of IR in-vitro (single dose) and in-vivo (both single and fractionated doses) of human PC xenografts and classified the xenografts and cell lines to radiosensitive and radioresistant groups, as follows.
  • human prostate cancer xenografts established in the present inventors' laboratory (WISH PC- 14, WISH PC-2, WISH PC-23) as well other adenocarcinoma xenografts from other laboratories (CWR22, LuCAP35 and LAPC9), and cell lines (CL-I, LNCaP10995, LNCaP1740, LAPC4, PC-3, 22RV-1 and DU- 145) show variability in their resistance to radiation in the range of 4-160 Gy.
  • Table 1 Maximal irradiation dose at which prostate adenocarcinoma grew following a single dose irradiation or a fractionated dose.
  • Tissue or cells of the prostate cancer xenografts (80-100 mg/5xl ⁇ 6 cells/) were put in dishes and irradiated at various doses 5, 10, 40, 80 or 160 Gy before their subcutaneous implantation into SCID mice.
  • the cells or xenograft beads were then injected/implanted s.c. to SCID mice.
  • cells derived from xenografts or small pieces were implanted into the right hind thigh of SCID mice.
  • mice After reaching a size of around 200 mm 3 , mice were shielded except for their tumor bearing leg and were sub-lethally irradiated by daily doses (five sessions per week) for the total dose as indicated. The values shown represent maximal irradiation dose in which PC xenografts or in-vivo cells grew. Samples were taken from all xenografts before and after irradiation.
  • mice were treated according to a protocol clinically applied to prostate cancer patients, including a total of 65-78 Gy delivered in 1.8-2 Gy doses over a 7 to 8 week period.
  • the human PC xenografts were injected into the hind limb of SCID mice and when tumor volume reached the volume of 150-200 mm 3 , mice were irradiated using the Caesium 137 source at the indicated doses.
  • the total dose administered was close to the maximal dose obtained by single dose irradiation.
  • RNA from non-irradiated and irradiated PC xenografts of both irradiation resistant and sensitive phenotypes was subjected to gene microarray (Affymetrix, U133P2) containing probes corresponding to 54,613 human transcripts and clustering analysis as described under General Materials and Experimental Methods hereinabove.
  • Gene expression profiling of 12 experimental samples was performed, four of which were derived from radiation-sensitive xenografts: CWR22 (unirradiated and cells surviving 20 Gy) and WISH PC-23 (unirradiated cells, and those surviving 40 Gy), and five samples were processed from radiation-resistant xenografts: LAPC9 (unirradiated and cells surviving of 80 Gy and 160 Gy) and WISH PC- 14 (unirradiated and cells surviving of 120 Gy).
  • Another xenograft sample was LuCAP35 (un-irradiated and surviving of 20 Gy and 60 Gy) which represented an intermediate level of IR sensitivity (Table 1, hereinabove).
  • Unsupervised analysis of the data was conducted to search for clusters shared by either IR resistant or sensitive PC xenografts.
  • the 3,730 probesets that passed one of the four filtering processes were clustered (employing the Super-Paramagnetic Clustering algorithm (SPC) [Blatt M, Wiseman S, Domany E. Superparamagnetic clustering of data. Physical Review Letters 1996;76(18):3251-3254] based on the phenotypes of the xenograft samples.
  • SPC Super-Paramagnetic Clustering algorithm
  • PCA principal component analysis
  • the 3,730 probe sets yielded six stable clusters ( Figure 2b). Because the same gene expression profiles have been obtained for none and irradiated cells (see comparison below) the analysis used data from both samples. The samples were then clustered, one at a time, based on each stable gene cluster of the 6 clusters shown in Figure 2b.
  • Clusters 2, 3, 5 and 6 Four gene clusters (clusters 2, 3, 5 and 6; Figures 3A, 3C, 4A and 4C) were identified displaying different behavior between the resistant versus the sensitive xenografts in non-irradiated cells
  • Two clusters (Clusters 2 and 3) showed higher expression levels in the resistant xenografts (WISH-PC14 and LAPC9; Figures 3a and c), while the other two clusters (Clusters 5 and 6) were more highly expressed in the IR sensitive xenografts (CWR22 and WISH-PC23; Figures 4A and C).
  • the LuCAP35 cell line displayed a non-uniform behavior; for some groups of genes it clustered with the IR resistant samples (clusters 2 and 6; Figures 3A and 4C) while for others it clustered with the sensitive samples (clusters 3 and 5; Figures 3C and 4A).
  • Cluster 2 consisted of 157 probe-sets and cluster 3 consisted of 66 probe-sets that were highly expressed in the resistant samples.
  • the up-regulated genes that were highly expressed in the IR resistant samples included a number of genes involved in cell survival and death such as the cell growth genes SNN, KLK2, ACPP; angiogenesis factors AGTRl, ILlRl, ZNF323, FMNL2, KLF13 and PTK7; DNA repair genes, e.g. H2AFJ, HIST1H2BK, HIST1H2BD and SMARCAl; cell death genes
  • CASP8 and 4 LITAF, GULP and UCP2; and an inhibition of cell growth gene IFITM3.
  • Figures 5A-C display a united expression profile of these clusters.
  • the LuCAP35 xenograft displayed a non-uniform behavior, while in some cases it clustered with the resistant samples and in some cases it clustered with the sensitive samples.
  • LuCap35 displays a radioresistant behavior in cluster 2 and radiosensitive behavior in cluster 3 ( Figures 5a-b).
  • Gene clusters that appear in Figures 5A-B consist of probe sets that are highly expressed in the resistant samples ( Figures 3A-D) together with the opposite pattern seen in the clusters displayed in Figures 4A-D, in which the sensitive samples characterized by high expression levels compared to the resistant samples.
  • LuCap35 xenograft also displayed inconsistent behavior, and was clustered with the sensitive samples in Figure 5 A and with the resistant samples in Figure 5B.
  • the PCA analysis shown in Figure 5C clearly shows the same differences that have been seen in the clustering analysis. It demonstrates that the groups representing the resistant xenografts (WISH-PC14 and LAPC9), the sensitive ones (CWR22 and WISH-PC23) and LuCAP35 each differ in their gene expression profiles. This observation may reflect the inherent properties of the response to irradiation. Altogether, the data presented so far identify 456 probesets (113 genes) that differentiate between the IR resistant and IR sensitive phenotypes.
  • the genes identified herein can serve as the cohort of genes whose pattern of expression in a given prostate cancer biopsy should serve as a genetic signature to predict the response of the tumor to ionizing irradiation.
  • Table 2 depicts the genes of cluster 2 which were upregulated in radiation resistant prostate cancer cells (or downregulated in radiation sensitive prostate cancer cells).
  • Table 2 Cluster 2 genes upregulated in radiation resistant prostate cancer
  • Table 3 depicts the genes of cluster 3 which were upregulated in radiation resistant prostate cancer cells (or downregulated in radiation sensitive prostate cancer cells).
  • Table 3 Cluster 3 genes upregulated in radiation resistant prostate cancer
  • Table 4 depicts the genes of cluster 5 which were downregulated in radiation resistant prostate cancer cells (or upregulated in radiation sensitive prostate cancer cells).
  • Table 4 Cluster 5 genes downregulated in radiation resistant prostate cancer
  • Table 5 depicts the genes of cluster 6 which were downregulated in radiation resistant prostate cancer cells (or upregulated in radiation sensitive prostate cancer cells).
  • these results demonstrate, for the first time, the identification of gene markers which differentiate between radiosensitive and radioresistant prostate cancer cells.
  • these gene markers can be used to predict the response of the prostate cancer tumors to ionizing irradiation and thus can serve as a tool for selecting the suitable treatment regimen for each prostate cancer patient (e.g., chemotherapy, surgery, radiation therapy or combination thereof).
  • these gene markers can be used to determine the dosing of radiation therapy in prostate cancer patients.
  • Q-RT-PCR Quantitative RT-PCR
  • Figures 6a-d depict the relative expression of each of the tested genes [H2AFJ (Figure 6A), UCP2 ( Figure 6B), PTEN (Figure 6C) and RAB26 ( Figure 6D)] in the LAPC9 resistant xenograft as compared to the expression in the CWR22 or WISH PC-23 sensitive xenografts of the LuCAP35 semiresistant xenograft.
  • H2AFJ and UCP2 the genes that were upregulated in resistant xenografts
  • a significantly higher expression was found as compared with the expression of the same genes in the GeneChip analysis.
  • Table 6 Presented are the Affymetrix probe set and sequence identifiers and the genes (and sequence identifiers of their encoded transcripts and polypeptides) which are differentially expressed between radiation resistance and sensitive prostate cancer xenografts and cell lines. Also provided are the average ratios between the expression level of resistance to sensitive for the prostate cancer xenografts and for cell lines.
  • the resistance xenografts were LAPC9 and WISH14; the sensitive xenografts were WISH23 and CWR22; the resistance cell lines were CL-I, DU- 145, and PC-3; the sensitive cell lines were LNCaP1740, LNCaP10995 and LAPC4.
  • polynucleotides set forth by SEQ ID NOs:91, 198, 83, 199, 200, 201 and 202 which are upregulated in radiation resistance prostate cancer samples and are downregulated in radiation sensitive prostate cancer samples
  • polynucleotides set forth by SEQ ID NO: 101, 181, 114, 111 and 203 which are downregulated in radiation resistance prostate cancer samples and are upregulated in radiation sensitive prostate cancer samples.
  • Table 7 Presented are the Affymetrix probe set identifiers and genes along with the sequence identifiers (SEQ ID NO:) of their encoded transcripts and polypeptides which are differentially expressed between radiation resistance and sensitive prostate cancer samples (xenografts and cell lines). Also provided are the average ratios between the expression level of resistance to sensitive (R/S) for the prostate cancer samples (xenografts and cell lines).
  • the resistance xenografts were LAPC9 and WISH14; the sensitive xenografts were WISH23 and CWR22; the resistance cell lines were CL-I, DU-145, and PC-3 ; the sensitive cell lines were LNCaP1740, LNCaP10995, LAPC4 and 22RvI.
  • S100A16 [GenBank Accession No. NM_080388.1 (SEQ ID NO:204) for the polynucleotide, and NP_525127.1 (SEQ ID NO:219) for the polypeptide].
  • ANXA2P2 [GenBank Accession No. NR_003573.1 (SEQ ID NO:205) for the polynucleotide].
  • MALL GeneBank Accession No. NM_005434.3 (SEQ ID NO:206) for the polynucleotide, and NP_005425.1 (SEQ ID NO:220) for the polypeptide].
  • SMARCAl GeneBank Accession No. NM_003069.2 (SEQ ID NO:207) for the polynucleotide, and NP_003060.2 (SEQ ID NO:221) for the polypeptide].
  • HPCALl transcript variant 1 [GenBank Accession No. NM_002149.2 (SEQ ID NO:208) for the polynucleotide, and NP_002140.2 (SEQ ID NO:222) for the polypeptide]
  • HPCALl transcript variant 2 [GenBank Accession No. NM_134421.1 (SEQ ID NO:209) for the polynucleotide, and NP_602293.1 (SEQ ID NO:223) for the polypeptide].
  • CSAG2 [GenBank Accession No. NM_004909.3 (SEQ ID NO:211) for the polynucleotide, and NP_004900.2 (SEQ ID NO:225) for the polypeptide].
  • PPAPDClB transcript variant 1 [GenBank Accession No. NMJ)Ol 102559 (SEQ ID NO:212), for the polynucleotide, and NPJ)01096029.1 (SEQ ID NO:226) for the polypeptide]
  • PPAPDClB transcript variant 2 [GenBank Accession No. NMJB2483 (SEQ ID NO:213), for the polynucleotide, and NP_115872.2 (SEQ ID NO:227) for the polypeptide]
  • PPAPDClB transcript variant 3 [GenBank Accession No.
  • NMJ NMJOl 102560 (SEQ ID NO:214), for the polynucleotide, and NPJ)01096030.1 (SEQ ID NO:228) for the polypeptide].
  • MAGEA2 transcript variant 1 [GenBank Accession No. NMJJ05361 (SEQ ID NO: 214), for the polynucleotide, and NPJ)01096030.1 (SEQ ID NO:228) for the polypeptide].
  • MAGEA2 transcript variant 1 [GenBank Accession No. NMJJ05361 (SEQ ID NO:214), for the polynucleotide, and NPJ)01096030.1 (SEQ ID NO:228) for the polypeptide].
  • MAGEA2 transcript variant 2 [GenBank Accession No. NM_175742 (SEQ ID NO:216) for the polynucleotide, and NP_786884.1 (SEQ ID NO:230) for the polypeptide]
  • MAGEA2 transcript variant 3 [GenBank Accession No. NM_175743 (SEQ ID NO:217) for the polynucleotide, and NP_786885.1 (SEQ ID NO:231) for the polypeptide].
  • ZNF718 [GenBank Accession No. NM_001039127 (SEQ ID NO:218) for the polynucleotide, and NP_001034216.1 (SEQ ID NO:232) for the polypeptide].
  • Tables 8 and 9, hereinbelow, summarize the ratio of expression levels between several genes which are differentially expressed between IR resistant and sensitive prostate cancer cell samples phenotypes according to their functional affiliation.
  • the Affymetrix probe set identifiers and genes along with the sequence identifiers (SEQ ID NO:) of their encoded transcripts and polypeptides which are upregulated in radiation resistant prostate cancer samples as compared to radiation sensitive prostate cancer cell samples.
  • the apoptosis genes include CASP8, LITAF, CASP4, CD24, GULPl, UCP2; the DNA repair genes include H2AFJ, HIST1H2BK and, HIST1H2BD; the proliferation related genes include ILlRl; the inhibition of cell growth related genes include IFITM3; the angiogenesis related genes include GUCYl A3, NRPl and AGTRl.
  • Affymetrix probe set identifiers and genes along with the sequence identifiers (SEQ ID NO:) of their encoded transcripts and polypeptides which are upregulated in radiation sensitive prostate cancer samples as compared to radiation resistant prostate cancer cell samples.
  • Model a ( Figure 8A): Existence of two distinct subpopulations within a given xenograft.
  • the cell population within each xenograft consists of a mixture of two types- IR sensitive (S) and IR resistant (R) cells.
  • S IR sensitive
  • R IR resistant
  • Model b ( Figure 8B): Each xenograft is homogeneous, and all cells within a xenograft have about the same chance to survive/die after irradiation. According to this model, each tumor contains a cell population that responds uniformly to radiation. Thus, every cell in a given xenograft has nearly the same probability of dying from IR. The probability of dying is greater for a sensitive cell, than for a resistant one.
  • IR radiation resistant and radiation sensitive human prostate cancer.
  • IR has been used therapeutically to treat primary prostate tumors and its bone metastases.
  • the experimental system was based on human PC xenografts whose radioresistant/sensitive phenotype was previously determined (Table 1).
  • tumor xenografts are better representative of the patient's prostate cancer cell sample than cell lines.
  • the inventors identified four gene clusters displaying different expression behavior across the resistant and the sensitive xenografts ( Figures 3A-D and 4A-D). Two clusters showed higher expression levels in the resistant xenografts and the other two clusters showed higher expression levels in the sensitive xenografts.
  • the expression of 113 genes was significantly changed (p ⁇ 0.01 and at least 3 fold) in sensitive compared to resistant xenografts.
  • genes derived from the PC xenografts to the data obtained using PC cell lines 41 genes shared a similar pattern in distinguishing between the irradiation sensitive and resistant phenotypes ( Figure 7; Table 6).
  • These genes represent a primary list of genes whose expression may represent a genetic signature to predict the outcome of a given prostate tumor to radiotherapy.
  • the genes in the list represent several cellular mechanisms (such as DNA repair, cell death (apoptosis, oncosis), angiogenesis and cell growth (Tables 2, 3, 4 and 5).
  • TP53 and PTEN were previously reported to be related to radioresistance [Colletier PJ, et al, 2000, Int J Radiat Oncol Biol Phys 48(5):1507-1512; Lee JM, and Bernstein A. 1993. Proc Natl Acad Sci U S A ;90(12):5742-5746; Fan Z, et al., 2000, Cancer Gene Ther,7(10):1307-1314; and Rosser CJ, et al., 2004. Cancer Gene Ther l l(4):273-279].
  • Kitahara et al examined the molecular profiles of radioresistant cervical squamous cell calenoma versus sensitive cancers and showed that the expression of 62 genes could predict IR resistant versus sensitive tumors [Kitahara O, et al., 2002, Neoplasia, 4(4):295-303].
  • Vallat et al compared the gene expression of B-cell chronic lympocytic leukemia (B- CLL) cells that were either sensitive or resistant to radiation. Sixteen genes were differentially regulated by at least 2 fold in the resistant cells [Vallat L, et al., 2003, Blood 101(11):4598-4606].
  • Fukuda et al studied six oesophageal cancer cell lines that were treated with continuous fractionated irradiation and compared expression profiles of each parent to its radioresistant clones using an cDNA microarray. Nineteen up- regulated and 28 down-regulated genes were common to radioresistant cell lines [Fukuda K, et al., 2004, Br J Cancer, 91(8):1543-1550].
  • the study of the cervical cancer (Kitahara O., et al., 2002) response to IR suggested that radioresistance is maintained via increased expression of a DNA repair component (XRCC5/Ku80), while in leukemia it is potentially mediated by upregulation of anti-apoptotic (e.g.
  • the gene identified in the present study show an increased expression of DNA repair associated genes such as H2AFJ, HIST1H2BK, HIST1H2BD and loss of the two tumor suppressor genes (PTEN and p53) in the radioresistant samples.
  • the radiosensitive PC xenografts an increase in growth factors related to the EGF gene family (CFCl), RAS oncogene family (RAB26) and IGF-2 binding protein 3 (Table 3).
  • CFCl EGF gene family
  • RAS oncogene family RAS oncogene family
  • IGF-2 binding protein 3 Table 3
  • radioresistant and radiosensitive prostate cancer xenografts serve as a predictive tool, to determine right at early diagnosis, which PC patient will benefit from irradiation or resort to other treatment.

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Abstract

L'invention concerne des procédés et des trousses permettant de déterminer la sensibilité ou la résistance d'un cancer prostatique à une radiothérapie. Le procédé consiste à déterminer le taux d'expression de polynucléotides et/ou de leurs produits génétiques qui sont exprimés différemment par des tumeurs prostatiques sensibles ou résistantes aux rayonnements. L'invention concerne également des procédés et des trousses servant à sélectionner le régime de traitement d'un sujet souffrant d'un cancer prostatique et/ou à sélectionner la dose optimale de radiothérapie.
PCT/IB2010/050517 2009-02-04 2010-02-04 Procédé et trousses pour déterminer la sensibilité ou la résistance d'un cancer prostatique à une radiothérapie WO2010089707A1 (fr)

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WO2013096903A3 (fr) * 2011-12-22 2015-06-18 The Regents Of The University Of Colorado, A Body Corporate Procédés de prédiction de la réponse clinique à une thérapie par rayonnement dans des patients atteints d'un cancer
KR20180040420A (ko) * 2016-10-12 2018-04-20 울산대학교 산학협력단 Psmb8을 측정하는 제제를 포함하는 수술전 화학방사선치료 반응성 예측용 조성물 및 이의 용도
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