MP70-16 SEMA3C DRIVES CANCER GROWTH AND TREATMENT RESISTANCE VIA COGNATE LIGAND-INDEPENDENT ACTIVATION

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2018MP70-16 SEMA3C DRIVES CANCER GROWTH AND TREATMENT RESISTANCE VIA COGNATE LIGAND-INDEPENDENT ACTIVATION Ario Takeuchi, Masaki Shiota, Junichi Inokuchi, Katsunori Tatsugami, and Masatoshi Eto Ario TakeuchiArio Takeuchi More articles by this author , Masaki ShiotaMasaki Shiota More articles by this author , Junichi InokuchiJunichi Inokuchi More articles by this author , Katsunori TatsugamiKatsunori Tatsugami More articles by this author , and Masatoshi EtoMasatoshi Eto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2260AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Our gene expression profiling data identified a member of the secreted class 3 semaphorins, SEMA3C, to be highly expressed in CRPC and AR pathway inhibitor-recurrent tumors. Increased expression of SEMA3C is associated with poor prognosis and tumor progression in a number of cancers. In prostate cancer, SEMA3C promotes cell migration and invasion in vitro and SEMA3C expression is a predictive marker for biochemical recurrence (BCR). Therefore, we investigated whether SEMA3C could be a key growth factor that drives CRPC progression and treatment resistance. METHODS The objective of this study was to evaluate SEMA3C as a therapeutic target for advanced prostate cancer and the physiological consequences of loss- and gain-of-function of SEMA3C. The expression of SEMA3C in a tissue microarray representing a total of 280 prostate cancer specimens was evaluated to determine association of SEMA3C expression with castration and treatment resistance. For in vivo orthotopic model, when mice bearing LNCaP tumors reached a tumor volume over 200 mm3 or serum PSA levels reached greater than 75 ng/ml, castration was performed via the scrotum under isoflurane anesthesia. Treatment commenced when PSA recovered to pre-castration levels. Mice were randomized into 4 groups for treatment with SEMA3C ASO or Scr with or without ENZ. For ASO treatment, Scr ASO or SEMA3C ASO was intra-peritoneally injected once daily for 7 days followed by three weekly treatments thereafter. For ENZ treatment, ENZ or vehicle was intragastrically administered once daily 5 days per week. RESULTS Here we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and c-MET in a cognate ligand-independent manner. High SEMA3C expression is associated with metastatic castration-resistant prostate cancer (CRPC). SEMA3C promotes cancer growth and castrate resistant progression while SEMA3C inhibition delays CRPC and Enzalutamide-resistant progression. Proteolytic processing of SEMA3C generates a dominant negative sema domain-containing decoy fragment that suppresses cell growth and RTK signaling. Intratumoral lentiviral delivery of this decoy protein inhibits CRPC progression. CONCLUSIONS SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e940 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Ario Takeuchi More articles by this author Masaki Shiota More articles by this author Junichi Inokuchi More articles by this author Katsunori Tatsugami More articles by this author Masatoshi Eto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...