Faculty Collaboration Database

Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5-SN38 Antibody-drug Conjugate in Neuroendocrine Prostate Cancer. Clin Cancer Res 2021 Feb 01;27(3):759-774

Date

11/18/2020

Pubmed ID

33199493

Pubmed Central ID

PMC7854497

DOI

10.1158/1078-0432.CCR-20-3396

Scopus ID

2-s2.0-85100427026 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

PURPOSE: 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.

EXPERIMENTAL DESIGN: The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (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.

RESULTS: CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 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.

CONCLUSIONS: 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.

Author List

DeLucia DC, Cardillo TM, Ang L, Labrecque MP, Zhang A, Hopkins JE, De Sarkar N, Coleman I, da Costa RMG, Corey E, True LD, Haffner MC, Schweizer MT, Morrissey C, Nelson PS, Lee JK

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antibodies, Monoclonal, Humanized
Basic Helix-Loop-Helix Transcription Factors
Carcinoembryonic Antigen
Carcinoma, Neuroendocrine
Cell Line, Tumor
DNA Damage
Drug Resistance, Neoplasm
GPI-Linked Proteins
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Promoter Regions, Genetic
Prostate
Prostatic Neoplasms, Castration-Resistant
Xenograft Model Antitumor Assays