Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen.
Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody-drug conjugate labetuzumab govitecan in prostate cancer.
The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal mCRPC cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5+ prostate cancer cell lines and patient-derived xenografts models.
CEACAM5 expression was enriched in NEPC compared to other mCRPC subtypes and minimally overlapped with PSMA, PSCA, and Trop2 expression. We focused on a correlation between the expression of the pioneer transcription factor ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC.
Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Nov 16 [Epub ahead of print]
Diana C DeLucia, Thomas M Cardillo, Lisa S Ang, Mark P Labrecque, Ailin Zhang, James E Hopkins, Navonil De Sarkar, Ilsa Coleman, Rui M Gil da Costa, Eva Corey, Lawrence D True, Michael C Haffner, Michael T Schweizer, Colm Morrissey, Peter S Nelson, John K Lee
Human Biology, Fred Hutchinson Cancer Research Center., Immunomedics, Inc., Human Biology Division, Fred Hutchinson Cancer Research Center., Urology, University of Washington., Clinical Research, Fred Hutchinson Cancer Research Center., Fred Hutchinson Cancer Research Center., Division of Human Biology, Fred Hutchinson Cancer Research Center., Department of Urology, University of Washington., Department of Pathology, University of Washington., Department of Medicine, Division of Oncology, University of Washington., Division of Clinical Research, Fred Hutchinson Cancer Research Center., Human Biology Division, Fred Hutchinson Cancer Research Center .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/33199493