EphB4-EphrinB2 receptor-ligand pair as a novel target in prostate cancer (PC).

275 Background: Studies have shown that EphB4 (B4), a receptor kinase, is upregulated in PC. The ligand for B4, EphrinB2 (B2) has not been studied in PC thus far. In our PTEN null mouse PC model, B4 and B2 are both upregulated in PC, but not in normal prostate. Furthermore, Soluble B4-albumin (sB4) decoy receptor blocks B4-B2 bidirectional signaling, inhibits PI3K/AKT signaling and is currently in phase II clinical trials in multiple tumor types. We thus studied B2 expression in human PCs and normal tissues. Methods: B2 levels were studied in 180 clinically localized human PCs and normal prostates. Tissue staining was performed with specific monoclonal antibody, using LEICA platform. B2 expressions in tumor vessel, tumor cell and stromal cells were scored by a pathologist. In addition, a CRPC patient was treated with sB4 under an IND approved by the FDA and IRB. The patient’s prostate cancer was diagnosed in 2014, Gleason’s score 4+3, treated with radical prostatectomy (pT3bN0) with subsequent metastases bone/bone marrow and progression on sipuleucel T, enzalutamide, abiraterone, docetaxel, cabazitaxel, and carboplatin. Tumor and blood samples were obtained and analyzed after informed consent. Results: B2 was not expressed in any of the 40 normal prostate gland or normal vessels in bladder, pancreas, small intestine, liver, adrenal glands, skeletal muscle, and bone marrow tissues. B2 was expressed 50% of the human prostate cancer tissues, being positive in tumor cells and negative in vascular and stromal cells. Expression was correlated with Gleason score (p = 0.003). B2 was also upregulated in PC cell lines that are characterized for genomic, and epigenomic alterations to study mechanisms of B2 induction. Metastatic tumor tissue from the CRPC patient showed high elevation of B2. After a 4-week course of sB4, PSA level declined by 45% (from 2284 to 1257). PI3K and AR levels in tumor tissue declined compared to baseline. PI3K/AKT/pS6 and AR levels in tumor tissue ex-vivo studies were also reduced with sB4 exposure. Conclusions: B2 is expressed in half of PCs and our experiments suggest a significant role for the EphB4-EphrinB2 pair through regulation of PI3K and AR signaling. Given the central role of AR in PC, sB4 may offer a novel approach to targeting AR.