Predictive and diagnostic methods for prostate cancer
The present invention generally relates to a method of diagnosing, prognosing and treating prostate cancer patients. Particularly, the present invention relates to a method of selecting patients with castration resistant prostate cancer (CrPC) for combination therapy comprising a selective dipeptidyl peptidase inhibitor and a PD-1 axis antagonist. The present invention provides a computational approach to identifying potential patients for CrPC. The present invention also relates to a method of treating castration resistant prostate cancer (CrPC) patients with said combination therapy.
1. A method for identifying an eligible prostate cancer patient to receive treatment for castration resistant prostate adenocarcinoma or castration resistant neuroendocrine prostate cancer, the method comprising:
(a) obtaining a biological sample or a data set of biological samples from a prostate cancer patient;
(b) determining an amplification and/or an expression level of one or more genes selected from the group consisting of DPP-8, DPP-9, FAP, and programmed death ligand-1 (PDL-1) or CD274 in the biological sample obtained from the prostate cancer patient; and,
(c) identifying the prostate cancer patient as the eligible prostate cancer patient if the amplification and/or the expression level of DPP-8, DPP-9, FAP, and programmed death ligand-1 (PDL-1) or CD274, exceeds a predetermined threshold level;
wherein the eligible prostate cancer patient is treated with a therapeutically effective amount of (i) talabostat or a pharmaceutically acceptable salt thereof, and (ii) a PD-1 axis antagonist.
2. The method of claim 1 , wherein the eligible prostate cancer patient has castration resistant prostate cancer (CrPC).
3. The method of claim 1 , wherein the amplification and/or expression level of the genes is determined by an amplification assay, a hybridization assay, an immunoassay, immunohistochemistry, a western blot, a northern blot, a probe-based quantitative amplification assay, a whole genomic sequencing, a whole proteomic sequencing, RNA sequencing, a polymerase chain reaction (PCR) or a quantitative real-time polymerase chain reaction (qRT-PCR).
4. The method of claim 1 , wherein the biological sample comprises tumor cells; tumor associated stromal cells; tumor associated fibroblasts; tumor associated macrophages; other immune related cells selected from tumor infiltrating lymphocytes including CD8+ T cells, MDSCs and Tregs; NK cells, circulating tumor DNA (ctDNA); circulating tumor cells or combination thereof.
5. A method for treating a subject with castration resistant prostate adenocarcinoma or castration-resistant neuroendocrine prostate cancer wherein the treatment comprises a combination therapy comprising administering talabostat or a pharmaceutically acceptable salt thereof; and a PD-1 axis antagonist, said method comprising:
(a) obtaining a biological sample from a subject with castration resistant prostate cancer (CrPC);
(b) determining the amplification and/or expression level of one or more genes selected from the group consisting of DPP-8, DPP-9, FAP, and programmed death ligand-1 (PDL-1) or CD274 in the biological sample obtained from the subject;
(c) selecting the subject as a suitable candidate for said treatment if based on an assessment that the amplification and/or expression level of the DPP-8, DPP-9, FAP, and programmed death ligand-1 (PDL-1) or CD274 exceeds a predetermined threshold level; and
(d) administering to the subject a therapeutically effective amount of (i) talabostat or a pharmaceutically acceptable salt thereof; and (ii) PD-1 axis antagonist.
6. The method of claim 5 , wherein the determining the amplification and/or expression level of the genes is determined by an amplification assay, a hybridization assay, an immunoassay, immunohistochemistry, a western blot, a northern blot, a whole genomic sequencing, a whole proteomic sequencing, RNA sequencing, a probe-based quantitative amplification assay, a polymerase chain reaction (PCR) or a quantitative real-time polymerase chain reaction (qRT-PCR).
7. The method of claim 5 , wherein the biological sample comprises tumor cells; tumor associated stromal cells; tumor associated fibroblasts, tumor associated macrophages; other immune related cells selected from tumor infiltrating lymphocytes including CD8+T cells, MDSCs and Tregs; NK cells, circulating tumor DNA (ctDNA);
circulating tumor cells or combination thereof.
8. The method of claim 5 , wherein the subject is human.
9. The method of claim 5 , wherein the PD-1 axis antagonist is selected from the group consisting of PD-1 antagonist, PDL-1 antagonist, and PDL-2 antagonist.
10. The method of claim 9 , wherein the PD-1 antagonist is selected from the group consisting of ANA011, AUNP-12, BGB-A317, KD033, pembrolizumab, MCLA-134, mDX400, MEDI0680, muDX400, nivolumab, PDR001, PF-06801591,REGN-2810, SHR-1210, STI-Al 110, TSR-042, and XCE853 and combinations thereof.
11. The method of claim 9 , wherein the PDL-1 antagonist is selected from the group consisting of avelumab, BMS-936559, CA-170, durvalumab, MCLA-145, SP142, STI-A1011, STI- A1012, STI-AIOIO, STI-A1014 and atezolizumab and combinations thereof.
12. The method of claim 9 , wherein the PDL-2 antagonist is selected from the group consisting of AMP-224 and rHIgM12B7 and combination thereof.
13. A method for treating a subject having castration-resistant prostate cancer adenocarcinoma or castration resistant neuroendocrine prostate cancer comprising: administering to the subject a therapeutically effective amount of (i) talabostat or a pharmaceutically acceptable salt thereof; and (ii) PD-1 axis antagonist.
14. The method of claim 13 , wherein the subject is human.
15. The method of claim 13 , wherein the PD-1 axis antagonist is selected from the group consisting of PD-1 antagonist, PDL-1 antagonist and PDL-2 antagonist.
16. The method of claim 15 , wherein the PD-1 antagonist is selected from the group consisting of ANA011, AUNP-12, BGB-A317, KD033, pembrolizumab, MCLA-134, mDX400, MED10680, muDX400, nivolumab, PDR001, PF-06801591, REGN-2810, SHR-1210, STI-Al 110, TSR-042, and XCE853 and combinations thereof.
17. The method of claim 15 , wherein the PDL-1 antagonist is selected from the group consisting of avelumab, BMS-936559, CA-170, durvalumab, MCLA-145, SP142, STI-A1011, STI-A1012, STI-A1010, STI-A1014 and atezolizumab and combinations thereof.
18. The method of claim 15 , wherein the PDL-2 antagonist is selected from the group consisting of AMP-224 and rHIgM12B7 and combinations thereof.
19. The method of claim 15 , wherein the PD-1 axis antagonist is a PD-1 antagonist.
20. The method of claim 16 , wherein the PD-1 antagonist is pembrolizumab.
21. The method of claim 16 , wherein the PD-1 antagonist is nivolumab.