Aberrant changes in gene activity due to chromatin remodeling are frequent in cancer cells. They involvemethylation/demethylation of cytosine at cytosine-guanine (CpG) pair rich islands in promoter regions andpost-transcriptional modifications (acetylation/methylation) of histones. Aberrant gain or loss of DNAmethylation causes altered expression of genes involved in tumorigenesis and maintenance of the malignantphenotype including tumor suppressors, apoptotic factors, DNA repair enzymes, adhesion molecules, andimmunomodulators. The reversible nature of epigenetic changes in chromatin is the rationale for clinicaldevelopment of the DNA demethylation agents 5-Aza-2'-deoxy-cytidine (5-Aza-CdR, also known asdecitabine), its analogue 5-azacytidine, and the histone deacetylase (HDAC) inhibitors. Our goal is to identifyepigenomic markers associated with growth arrest of melanoma cells and tumors. These markers can be thebasis for an assay for predicting responses and tailoring treatment with epigenetic modifiers to responsivepatients.
In Aim 1 we will assess global changes in gene expression in response to decitabine in sensitiveand 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 sensitiveand resistant melanoma cells in response to 5-Aza-CdR, and correlate it to the profiles of affected genesrevealed in Aim 1. We will also determine the global changes in DNA methylation in melanoma tumorsexcised 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-CdRresponsivegenes deemed critical to inducing growth arrest. We will employ multiple bioinformatics methodsto perform data mining and integration of the information derived from the chromatin modification and geneexpression array data. We foresee that the information will help devise a cost-effective epigenetic-modifiertest 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 ofbasic scientists, molecular biologists, bioinformatics and clinical oncologists.
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