Abstract 3540: Novel targeted combinational therapies for melanoma

Abstract

Abstract The BRAFV600E mutation is frequently observed in over 60% of melanomas. Development of the small molecule inhibitor PLX4032, which specifically targets the mutated BRAF protein, offers a novel therapeutic approach by effectively blocking the activation of key signaling molecules of the mitogen-activated protein kinase (MAPK) pathway, such as Mek and Erk, effectively leading to arrest in cell proliferation. Provided that MAPK signaling targets the micropthalmia transcription factor (MITF), which is linked to the expression of various melanoma associated antigens (MAAs), we hypothesized that the inhibition of BRAFV600E can modulate the expression of MAAs. Since MAAs are essential in the development of a melanoma vaccine, due to their increased immunogenicity, altering their expression can be a useful immunotherapeutic approach to targeting melanoma. Using patient derived melanoma cell lines, which express various MAAs; our laboratory has developed a vaccinia virus based immunotherapeutic vaccine. These melanoma cell lines have been characterized by their status of BRAFV600E mutation and found to be either homozygous or heterozygous for the mutation. Inhibition of two key MAPK pathway molecules, namely Mek and Erk, denotes that the melanoma cell lines are responsive to PLX4032. Phenotypically, the cells’ invasive and migratory properties were also modulated upon treatment with PLX4032. Moreover, we observed that the expression of various MAAs was enhanced upon treatment with PLX4032. An amplification of gp100, MART-1 and tyrosinase expression on the RNA level as well as on the protein level was observed. Lastly, expression of MMAs was conserved in vivo following the analysis of melanoma cell xenografts in BALB/c nude mice. Based on our observations in that PLX4032 modulates MMA expression, further studies are warranted to determine the clinical effectiveness of combinational immunologic therapy using BRAFV600E inhibitors with our vaccinia virus melanoma cell line derived preparation. Citation Format: Robert Suriano, Neha Y. Tuli, Jan Geliebter, Raj K. Tiwari, Marc Wallack. Novel targeted combinational therapies for melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3540. doi:10.1158/1538-7445.AM2015-3540