Data from CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease

• DOI: 10.1158/1078-0432.c.6532265.v1
• Publication Date: 2023-04-01T02:45:39Z
• Authors: Ning Zhao; Shalini Chopra; Kai Trepka; Yung-Hua Wang; Sasank Sakhamuri; Nima Hooshdaran; Hyunjung Kim; Jie Zhou; Shion A. Lim; 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
• Keywords: DU145; Enzalutamide; Radioligand

<div>AbstractPurpose:<p>With the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, part due to low PSMA expression 30% of patients. Herein, we evaluated whether cell surface protein CUB domain-containing 1 (CDCP1) can be exploited treat mCRPC RLT, including PSMA-low subsets.</p>Experimental Design:<p>CDCP1 levels were using RNA sequencing from 119 biopsies. CDCP1 assessed 17 post–enzalutamide- or abiraterone-treated biopsies, 12 patient-derived xenografts (PDX), and lines. 4A06, recombinant human antibody that targets ectodomain, was labeled Zr-89 Lu-177 tested tumor-bearing mice.</p>Results:<p>CDCP1 observed 90% small-cell neuroendocrine (SCNC) adenocarcinomas FOLH1 (PSMA) levels. Fifteen evaluable biopsies (85%) demonstrated membranous expression, 4 (23%) had higher H-scores compared PSMA. expressed 10 PDX samples. <i>B</i><sub>max</sub> values approximately 22,000, 6,200, 2,800 fmol/mg calculated PC3, DU145, C4–2B cells, respectively. <sup>89</sup>Zr-4A06 PET detected six xenografts, tumors. <sup>177</sup>Lu-4A06 significantly suppressed growth DU145 xenografts.</p>Conclusions:<p>The data provide first evidence supporting CDCP1-directed RLT mCRPC. Expanded studies warranted determine drug target mCPRC.</p></div>