GENE EXPRESSION MARKERS FOR PREDICTING OVERALL SURVIVAL IN SUBJECTS TREATED WITH SIPULEUCEL-T
Gene expression profiling in patients with mCRPC identifying genes that predict overall survival in response to treatment with sipuleucel-T, the method comprising the steps of (a) determining a gene expression level of a first biomarker; (b) determining a gene expression level of at least one additional biomarker different from the first biomarker; and (c) transforming the expression level of the first biomarker and the at least one additional biomarker into a first score corresponding to a probability of overall survival in response to treatment with sipuleucel-T.
1 . A method of predicting the overall survival of a subject with mCRPC comprising:
(a) determining a gene expression level of a first biomarker;
(b) determining a gene expression level of at least one additional biomarker different from the first biomarker; and
(c) transforming the expression level of the first biomarker and the at least one additional biomarker into a first score corresponding to a probability of overall survival in response to treatment with sipuleucel-T.
2 . The method of claim 1 wherein the first biomarker is selected from the group consisting of SYNGR3, AURKC, CHI3L2, SNTB1, ZNF268, COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
3 . The method of claim 2 wherein the at least one additional biomarker is selected from the group consisting of SYNGR3, AURKC, CHI3L2, SNTB1, ZNF268, COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
4 . The method of claim 1 wherein the gene expression level of the first biomarker and the at least one additional biomarker is normalized to obtain a normalized expression level before transforming the expression level into the first score.
5 . The method of claim 1 wherein the first score is determine using an overall survival measure based on PSA level, LDH level, Alkaline phosphatase level, Hemoglobin level, Total Gleason Score, ECOG status, and a composite gene expression score, wherein the first biomarker is SNTB1, the additional biomarkers are SYNGR3, AURKC, ZNF268, and CHI3L2, and wherein the composite gene expression score is determined using the log expressions of SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2.
6 . The method of claim 1 wherein the first score is determine using an overall survival measure based on PSA level, LDH level, Alkaline phosphatase level, Hemoglobin level, Total Gleason Score, ECOG status, and a composite gene expression score, wherein the first biomarker is COL1A1, the additional biomarkers are LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2, and wherein the composite gene expression score is determined using the log expressions of COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
7 . The method of claim 5 further comprising the step of:
(d) administering sipuleucel-T to the subject based on the composite gene expression score that is higher or lower than an expression threshold relative to a control group of subjects that do not meet the expression threshold.
8 . The method of claim 6 further comprising the step of:
(d) administering sipuleucel-T to the subject based on the composite gene expression score that is higher or lower than an expression threshold relative to a control group of subjects that do not meet the expression threshold.
9 . A kit for determining in a biological sample an expression product level of at least one of the genes selected from the group consisting of SYNGR3, AURKC, CHI3L2, SNTB1, ZNF268, COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2, the kit comprising a plurality of oligonucleotide primers, wherein the plurality of primers consist essentially of at least one pair of oligonucleotide primers for amplification of at least one of the genes selected from the group consisting of SYNGR3, AURKC, CHI3L2, SNTB1, ZNF268, COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2, wherein the expression product is RNA or cDNA.
10 . The kit of claim 9 wherein the plurality of primers consist essential of at least one pair of oligonucleotide primers for the genes COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2 and the expression product levels of the genes COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2 are determined.
11 . The kit of claim 10 further comprising a device for converting the expression product levels of COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2 into an indicator of overall survival, the device including a measure based on PSA level, LDH level, Alkaline phosphatase level, Hemoglobin level, Total Gleason Score, ECOG status, and a composite gene expression score of the expression levels of the genes COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
12 . The kit of claim 9 wherein the plurality of primers consist essential of at least one pair of oligonucleotide primers for the genes SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2 and the expression product levels of the genes SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2 are determined
13 . The kit of claim 12 further comprising a device for converting the expression product levels of SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2 into an indicator of overall survival, the device including a measure based on PSA level, LDH level, Alkaline phosphatase level, Hemoglobin level, Total Gleason Score, ECOG status, and a composite gene expression score of the expression levels of the genes SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2.
14 . The kit of claim 9 wherein the biological sample is selected from the group consisting of whole blood, peripheral blood mononuclear cells (PBMCs), circulating tumor cells (CTCs), and tumor tissue.
15 . A method of predicting a reduction in risk of death following treatment of a mCRPC subject with sipuleucel-T, the method comprising:
(a) converting RNA from a biological sample of the subject to cDNA through reverse transcription;
(b) hybridizing the cDNA with a plurality of oligonucleotide primers, wherein said plurality of primers comprises at least one pair of oligonucleotide primers for a gene selected from the group consisting of: SYNGR3, AURKC, CHI3L2, SNTB1, ZNF268, COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2;
(c) performing PCR on the cDNAs; and
(d) determining an increase or decrease of an expression product of at least one tested gene in the biological sample from the subject.
16 . The method of claim 19 further comprising a device for converting the expression product level of COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2 into a composite gene expression score to determine a prediction of overall survival, the device including a measure based on PSA level, LDH level, Alkaline phosphatase level, Hemoglobin level, Total Gleason Score, ECOG status, and the composite gene expression score of the expression levels of the genes COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
17 . The method of claim 15 further comprising a device for converting the expression product level of SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2 into a composite gene expression score to determine a prediction of overall survival, the device including a measure based on PSA level, LDH level, Alkaline phosphatase level, Hemoglobin level, Total Gleason Score, ECOG status, and the composite gene expression score of the expression levels of the genes SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2.
18 . The method of claim 15 , wherein the biological sample is selected from the group consisting of whole blood, peripheral blood mononuclear cells (PBMCs), circulating tumor cells (CTCs), and tumor tissue.
19 . The method of claim 15 , wherein the plurality of oligonucleotide primers consists essentially of at least one pair of oligonucleotide primers for each of the genes COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
20 . The method of claim 15 , wherein the plurality of oligonucleotide primers consists essentially of at least one pair of oligonucleotide primers for each of the genes SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2.
21 . A combination of biomarkers for predicting overall survival after treatment with sipuleucel-T, comprising at least two of SYNGR3, SNTB1, AURKC, ZNF268, CHI3L2, COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
22 . The combination of biomarkers of claim 21 , wherein the at least two biomarkers are selected from the group consisting of COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.
23 . The combination of biomarkers of claim 21 , wherein the at least two biomarkers are selected from the group consisting of SNTB1, SYNGR3, AURKC, ZNF268, and CHI3L2.