Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5-SN38 Antibody-drug Conjugate in Neuroendocrine Prostate Cancer.

Autor:	DeLucia DC; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Cardillo TM; Immunomedics, Inc., Morris Plains, New Jersey., Ang L; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Labrecque MP; Department of Urology, University of Washington School of Medicine, Seattle, Washington., Zhang A; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Hopkins JE; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., De Sarkar N; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Coleman I; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., da Costa RMG; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Corey E; Department of Urology, University of Washington School of Medicine, Seattle, Washington., True LD; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington., Haffner MC; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington., Schweizer MT; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington., Morrissey C; Department of Urology, University of Washington School of Medicine, Seattle, Washington., Nelson PS; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Urology, University of Washington School of Medicine, Seattle, Washington.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington., Lee JK; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. jklee5@fredhutch.org.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Feb 01; Vol. 27 (3), pp. 759-774. Date of Electronic Publication: 2020 Nov 16.
DOI:	10.1158/1078-0432.CCR-20-3396
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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