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 treating a subject with a castration resistant prostate adenocarcinoma cancer or a castration-resistant neuroendocrine prostate cancer, comprising:
administering to the subject a therapeutically effective amount of talabostat or a pharmaceutically acceptable salt thereof, and
administering to the subject a therapeutically effective amount of PD-1 axis antagonist.
2 . The method of claim 1 , wherein prior to treatment a biological sample from the subject was determined to have an 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 that exceeded a predetermined threshold level.
3 . The method of claim 2 , 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 2 , 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 . The method of claim 1 , wherein the subject is human.
6 . The method of claim 1 , wherein the PD-1 axis antagonist is selected from the group consisting of PD-1 antagonist, PDL-1 antagonist, and PDL-2 antagonist.
7 . The method of claim 6 , 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.
8 . The method of claim 6 , 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.
9 . The method of claim 6 , wherein the PDL-2 antagonist is selected from the group consisting of AMP-224 and rHIgM12B7 and combination thereof.
10 . The method of claim 6 , wherein the PD-1 axis antagonist is a PD-1 antagonist.
11 . The method of claim 10 , wherein the PD-1 antagonist is pembrolizumab.
12 . The method of claim 10 , wherein the PD-1 antagonist is nivolumab.
13 . 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.
14 . The method of claim 5 , wherein the PD-1 axis antagonist is a PD-1 antagonist.
15 . The method of claim 5 , wherein the PD-1 axis antagonist is pembrolizumab.
16 . The method of claim 5 , wherein the PD-1 axis antagonist is nivolumab.
17 . The method of claim 1 , wherein the PD-1 axis antagonist is administered at a dose from about 0.01 to 30 mg/kg.
18 . The method of claim 1 , wherein the total daily amount of talabostat administered to the subject is from about 100 micrograms to 2.0 milligrams.