Abstract B15: Combination chemotherapy in melanoma using EZH2 inhibitor

Abstract

Abstract Melanoma is the deadliest variety of skin cancer, which according to the American Cancer Society (ACS) will account for around 9710 deaths and diagnosis of around 76,100 new melanoma cases in the current year. According to the ACS, melanoma is also the fastest growing cancer, and hence it is vital to investigate the pathogenesis involved in the advanced stage of melanoma, and design effective therapeutics for its treatment. Aberrant activity of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been reported to be associated with different types of cancer. The EZH2 catalyzes the deposition of the repressive mark histone H3 lysine 27 trimethylation (H3K27me3) on the promoter of the target genes using the catalytic SET domain, thereby epigenetically silencing the expression of the target genes. This is because the H3K27me3 mark results in chromatin compaction which reduces the accessibility of various transcription factors to the gene, and hence adversely affects transcription. Several of such EZH2 target genes have been found to be tumor suppressor genes like RUNX3, DAB2IP, and E-cadherin, and silencing of such tumor suppressor genes is a chief mechanism by which EZH2 leads to cancer progression. Hence derepression of the tumor suppressor genes by inhibition of EZH2 could be an effective treatment strategy in different types of cancer. There has been no study till date investigating the role of EZH2 in melanoma. Our laboratory is investigating the role of EZH2 in the pathogenesis involved in the advanced stage of melanoma, to enable the design of effective therapeutic strategies for the treatment of melanoma. Drugs targeting epigenetic modifiers are becoming increasingly popular because of the fact that most epigenetic modifications and their effects can be reversed using these drugs. Our lab has strong evidence that metastatic (or advanced) melanoma is associated with upregulation of EZH2 and H3K27me3. We have also observed that EZH2 inhibition inhibits proliferation and invasion, and also induces apoptosis in metastatic melanoma cells. Recently our lab is performing combination chemotherapeutic studies in vitro, where EZH2 inhibitor GSK126 (S-adenosyl-methionine competitive inhibitor) is being used in combination with conventional chemotherapeutics like cisplatin and Bcl-2 inhibitors. Our results strongly suggest that when EZH2 inhibitor is used in combination with cisplatin or Bcl-2 inhibitor in metastatic melanoma cell lines, the inhibition is synergistic. This synergistic effect of GSK126 and cisplatin or Bcl-2 inhibitor has been found to be caspase-mediated. Citation Format: Deepanwita Sengupta, Nathan L. Avaritt, Alan J. Tackett. Combination chemotherapy in melanoma using EZH2 inhibitor. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B15.