Predictive and diagnostic methods for prostate cancer

Abstract

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.

What is claimed is: 
     
         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.