PREDICTIVE AND THERAPEUTIC UTILITIES OF EPIGENETIC CHANGES IN CHROMATIN IN MELANO

Yale University, New Haven CT

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Abstract

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