PREDICTIVE AND THERAPEUTIC UTILITIES OF EPIGENETIC CHANGES IN CHROMATIN IN MELANO

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Aberrant changes in gene activity due to chromatin remodeling are frequent in cancer cells. They involve methylation/demethylation of cytosine at cytosine-guanine (CpG) pair rich islands in promoter regions and post-transcriptional modifications (acetylation/methylation) of histones. Aberrant gain or loss of DNA methylation causes altered expression of genes involved in tumorigenesis and maintenance of the malignant phenotype including tumor suppressors, apoptotic factors, DNA repair enzymes, adhesion molecules, and immunomodulators. The reversible nature of epigenetic changes in chromatin is the rationale for clinical development of the DNA demethylation agents 5-Aza-2'-deoxy-cytidine (5-Aza-CdR, also known as decitabine), its analogue 5-azacytidine, and the histone deacetylase (HDAC) inhibitors. Our goal is to identify epigenomic markers associated with growth arrest of melanoma cells and tumors. These markers can be the basis for an assay for predicting responses and tailoring treatment with epigenetic modifiers to responsive patients. In Aim 1 we will assess global changes in gene expression in response to decitabine in sensitive and resistant melanoma cells and determine gene-expression profiles that can predict growth suppression. In Aim 2 we will interrogate genome-wide changes in the patterns of DNA promoter methylation in sensitive and resistant melanoma cells in response to 5-Aza-CdR, and correlate it to the profiles of affected genes revealed in Aim 1. We will also determine the global changes in DNA methylation in melanoma tumors excised from patients undergoing treatment with 5-azacytidine and compare it to melanoma cells in culture. In Aim 3 we will verify the epigenetic modification (DNA methylation) in regulatory regions of 5-Aza-CdRresponsive genes deemed critical to inducing growth arrest. We will employ multiple bioinformatics methods to perform data mining and integration of the information derived from the chromatin modification and gene expression array data. We foresee that the information will help devise a cost-effective epigenetic-modifier test that can predict efficacy and monitor therapeutic responses to this class of agents in melanoma patients. This project includes a Phase I trial with 5-azacytidine, is multidisciplinary, involving the concerted efforts of basic scientists, molecular biologists, bioinformatics and clinical oncologists.