Abstract A31: Revisited use of tamoxifen for improving melanoma therapy

Abstract

Abstract The rapid increase in the incidence of malignant melanoma, a highly aggressive, drug-resistant cancer, has not been accompanied by significant therapeutic breakthroughs for decades, despite the introduction of biochemotherapies. The Dartmouth regimen, of which tamoxifen is a standard component, has also had little impact on outcome. Therefore, examination of alternative melanoma vulnerabilities is essential. Sphingolipid (SL) metabolism is an area of cancer science that has recently risen to prominence. This is because ceramide, the aliphatic backbone of SL's, can act as a powerful tumor censor. However, cancer cells rapidly inactivate ceramide via two major metabolic routes: glycosylation to form glucosylceramide and hydrolysis, which generates sphingosine 1-phosphate, a mitogenic SL. These actions severely blunt ceramide anticancer properties, thwarting potential utility in treatment. Our previous work has shown that tamoxifen is a potent inhibitor of ceramide metabolism at glycosylation and hydrolysis. Herein, we exploit these unique actions and pair tamoxifen with a cell-permeable ceramide, C6-ceramide, and demonstrate that this novel drug duo, unlike the single agents, was highly effective in inhibiting melanoma cell (A375 and cell lines established from patients) proliferation, inducing caspase-dependent apoptosis, promoting cell cycle arrest, diminishing cellular adhesion and migration, reducing cell surface expression of integrins, and downregulating expression of the main source of drug resistance in melanoma, survivin, all essential elements of a drug regimen useful for limiting melanoma growth. Because integrin expression often correlates with conversion of melanoma growth from radial to vertical, we propose that tamoxifen can serve as an effective adjuvant to C6-ceramide for countering metastatic potential. Whereas the role of tamoxifen in the Dartmouth regimen has always remained elusive, its role as a ceramide sensitizer is clear and presents novel inroads for improving melanoma therapy. Citation Format: Samy A.F Morad, Lance C. Bridges, Myles C. Cabot. Revisited use of tamoxifen for improving melanoma therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A31.