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.
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.
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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 May 23 [Epub ahead of print]
Ning Zhao, Shalini Chopra, Kai Trepka, Yung-Hua Wang, Sasank Sakhamuri, Nima Hooshdaran, Hyunjung Kim, Jie Zhou, Kevin K Leung, Emily A Egusa, Jun Zhu, Li Zhang, Adam Foye, Renuka Sriram, Emily Chan, Youngho Seo, Felix Y Feng, Eric J Small, Jonathan Chou, James A Wells, Rahul Aggarwal, Michael J Evans
University of California, San Francisco, San Francisco, CA, United States., University of California, San Francisco, San Franciso, United States., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, United States., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States.