CDCP1 is a novel target for radioligand therapy in metastatic castration resistant prostate cancer refractory to treatment with PSMA directed radioligands

Purpose: Radioligand therapy (RLT) is still relatively unexplored in metastatic castration resistant prostate cancer (mCRPC), with much of the focus having been on bone seeking radionuclides and PSMA-directed RLT. Herein, we evaluated if the cell surface cancer antigen CUB domain containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, particularly for subsets like neuroendocrine prostate cancer (NEPC) that would not be expected to respond to current options for RLT. Experimental Design: CDCP1 expression levels were evaluated in RNA-seq data from a mCRPC biopsy data set. Protein expression was assessed on immunoblot in a panel of twelve patient derived xenografts (PDX) from the LuCaP and Living Tumor Laboratory series. Receptor number per cell was defined using a saturation binding assay with 4A06, a recombinant human antibody we recently developed that targets the CDCP1 ectodomain. The feasibility of imaging and treating mCRPC in vivo was tested with ⁸⁹Zr-4A06 and ¹⁷⁷Lu-4A06 in mouse models. Results: CDCP1 expression was observed in 90% of mCRPC biopsies, including NEPC and in adenocarcinoma with negligible PSMA expression. Overall, no correlation was observed between CDPC1 and PSMA expression, and modest but significant anticorrelation was observed between CDCP1 and PTEN. Overall survival was not significantly different between patients whose tumors had low versus high CDCP1 expression. Full length and/or cleaved CDCP1 was expressed in six of seven NEPC PDX samples and expressed in four of five adenocarcinoma PDX samples, including LTL-484 which has low PSMA expression. Five subcutaneous prostate cancer models were detected using ⁸⁹Zr-4A06 PET. An antitumor assessment study showed that ¹⁷⁷Lu-4A06 significantly suppressed the growth of PSMA null DU145 tumors compared to control and extended overall survival. Conclusions: We provide the first evidence that CDCP1 can be targeted for RLT in mCRPC. Combined with the results showing widespread CDCP1 expression in mCRPC, these data position CDCP1-directed RLT as a potential complement or alternative to current the repertoire of RLTs.