Englander Institute for Precision Medicine

The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.

TitleThe Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.
Publication TypeJournal Article
Year of Publication2023
AuthorsVan Emmenis L, Ku S-Y, Gayvert K, Branch JR, Brady NJ, Basu S, Russell M, Cyrta J, Vosoughi A, Sailer V, Alnajar H, Dardenne E, Koumis E, Puca L, Robinson BD, Feldkamp MD, Winkis A, Majewski N, Rupnow B, Gottardis MM, Elemento O, Rubin MA, Beltran H, Rickman DS
JournalCancer Res Commun
Date Published2023 Aug
KeywordsCadherins, Cell Membrane, Humans, Male, Neuroendocrine Tumors, Prostate, Prostatic Neoplasms

UNLABELLED: 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.

SIGNIFICANCE: 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.

Alternate JournalCancer Res Commun
PubMed ID37546702
PubMed Central IDPMC10401480
Grant ListP50 CA211024 / CA / NCI NIH HHS / United States
R01 CA230913 / CA / NCI NIH HHS / United States
R37 CA241486 / CA / NCI NIH HHS / United States

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