Purpose: With the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated if the cell surface protein CUB domain containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA low subsets.
Experimental design: CDCP1 levels were evaluated using RNA-seq from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post enzalutamide or abiraterone treated mCRPC biopsies, 12 patient derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor bearing mice.
Results: CDCP1 expression was observed in 90% of mCRPC biopsies, including small cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared to PSMA. CDCP1 was expressed in ten of twelve PDX samples. Bmax values of ~22,000, ~6,200, and ~2,800 fmol/mg were calculated for PC3, DU145, and C4-2B human prostate cancer cells respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4-2B xenografts.
Conclusions: The data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine if CDCP1 is a viable drug target for mCPRC patients.