Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration in vitro. We provide in vivo data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC.
The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC.
Cancer research communications. 2023 Aug 03*** epublish ***
Lucie Van Emmenis, Sheng-Yu Ku, Kaitlyn Gayvert, Jonathan R Branch, Nicholas J Brady, Subhasree Basu, Michael Russell, Joanna Cyrta, Aram Vosoughi, Verena Sailer, Hussein Alnajar, Etienne Dardenne, Elena Koumis, Loredana Puca, Brian D Robinson, Michael D Feldkamp, Annmarie Winkis, Nathan Majewski, Brent Rupnow, Marco M Gottardis, Olivier Elemento, Mark A Rubin, Himisha Beltran, David S Rickman
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York., Janssen Research & Development, Spring House, Pennsylvania., Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Caryl and Israel Englander Institute for Precision Medicine, New York-Presbyterian Hospital, New York, New York.