A combinatorial approach using sorafenib and liposomal ceramide to inhibit malignant melanoma

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4754 Melanoma is the deadliest form of skin cancer killing one person in the US every hour. Current treatments for advanced disease are ineffective necessitating development of rationally based combinatorial approaches with a solid mechanistic underpinning. Thus, combinatorial therapeutics, targeting multiple processes regulating tumorigenesis are being explored. One protein under intense investigation as a therapeutic target in melanoma is B-Raf, which is mutated to a constitutively active form in ~60% of sporadic melanomas leading to MAP kinase activation. While targeting this protein using a nonspecific Raf kinase inhibitor called sorafenib (BAY 43-9006) is relatively ineffective in human patients, in combination with carboplatin and paclitaxel it can be beneficial. However, there is no rational basis for this combination of agents. In order to develop rational based combinatorial agents, we have evaluated the preclinical effectiveness and mechanistic basis for combining sorafenib with ceramide encapsulated in a liposomal formulation. Sorafenib alone decreases cell proliferation and vascular development in xenografted melanoma tumors by reducing signaling through the MAP kinase-signaling cascade. In contrast, ceramide is a lipid-derived second messenger that preferentially induces tumor apoptosis by inhibiting Akt3, which is a second kinase activated in ~70% of melanomas through amplification and/or PTEN loss. We have developed a liposomal delivery system for ceramide that increases cellular permeability and prevents degradation by ceramidases in the circulatory system. Combining sorafenib and liposomal ceramide increased rates of apoptosis (by 9 fold) and decreased cellular proliferation (by 16 fold) compared to control cells. The combined treatment resulted in a significant reduction in tumor development compared to single agents alone. Specifically, the drug combination led to a 30% reduction in tumor development compared to sorafenib treatment alone and a 58% decrease in tumor size compared to liposomal ceramide treatment. This combination of agents is also effective at inhibiting breast cancer tumor development to a similar extent. Thus, targeted inhibition of the MAP kinase and Akt signaling cascades using sorafenib and liposomal ceramide has potential to more effectively inhibit melanoma and breast cancer development than either agent alone.