Abstract 2704: Simultaneous targeting of androgen receptor (AR) and Eukaryotic Initiation Factor 4E (eIF4E) dependent translation initiation by RAMBA Retinamides promotes apoptosis and impedes cell growth, cell proliferation and matrix invasion in androgen sensitive and castration-resistant prostate cancers

Abstract

Abstract Introduction: Prostate cancer (PCa) remains the second most leading cause of cancer-related death in Western male population. Although initially counteracted by androgen deprivation therapy (ADT), PCa cells eventually progress to a hormone-independent state thereby limiting treatment options and rendering the discovery of new therapeutic approaches a clinical priority. Direct targeting of translational machinery has gained enormous attention in recent years for treating castration resistant prostate cancers (CRPC). The present study aims to investigate the effect of our novel retinoic acid metabolism blocking agents (RAMBA) retinamides (RRs) on eukaryotic translation initiation factor 4E (eIF4E) translational machinery and androgen receptor (AR) signaling in prostate cancers. Methods: Androgen-sensitive (LNCaP), androgen-resistant (PC-3, C4-2B and CWR22Rv1), enzalutamide resistant (MR49F) prostate cancer cells and normal prostatic epithelial cells (PWR-1E) were used analyzing the effect of RRs on prostate cancers. Results: 24 h treatment of PCa cells to RRs resulted in substantial down-regulation of androgen receptor (AR), degradation of MAPK-interacting kinases (MNK), and attenuation of eukaryotic translation initiation factor 4E (eIF4E) cap dependent translation initiation. Down-regulation of AR and MNK mediated eIF4E translation initiation by RRs in PCa cells were in turn associated with inhibition of cell growth and proliferation, induction of cell cycle arrest, increased apoptosis, and inhibition of matrix invasion and metastasis. Most importantly, the effects of our RRs on AR degradation, eIF4E translation initiation and subsequent oncogenic program were far more potent than the clinically relevant retinoids, established MNK inhibitors (CGP 57380 and/or cercosporamide) and the FDA approved PCa drugs (Casodex, Enzalutamide and Abiraterone acetate). Conclusion: RAMBA retinamides which can exclusively target the degradation of both AR and MNK- the two divergent axes in PCa, at pharmacologically feasible concentrations are novel therapeutic compounds for treatment of both androgen-sensitive and androgen-resistant prostate cancers. Citation Format: Vidya priyadarsini Ramamurthy, Senthilmurugan Ramalingam, Lalji Gediya, Vincent C.O Njar. Simultaneous targeting of androgen receptor (AR) and Eukaryotic Initiation Factor 4E (eIF4E) dependent translation initiation by RAMBA Retinamides promotes apoptosis and impedes cell growth, cell proliferation and matrix invasion in androgen sensitive and castration-resistant prostate cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2704. doi:10.1158/1538-7445.AM2014-2704