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.
| Ferrucci, Leah M; Cartmel, Brenda; Clare, Rachel A et al. (2018) Cross-sectional assessment of ultraviolet radiation-related behaviors among young people after a diagnosis of melanoma or basal cell carcinoma. J Am Acad Dermatol 79:149-152 |
| Arbesman, Joshua; Ravichandran, Sairekha; Funchain, Pauline et al. (2018) Melanoma cases demonstrate increased carrier frequency of phenylketonuria/hyperphenylalanemia mutations. Pigment Cell Melanoma Res 31:529-533 |
| Perry, Curtis J; Muñoz-Rojas, Andrés R; Meeth, Katrina M et al. (2018) Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. J Exp Med 215:877-893 |
| Liu, Xiaoni; Zhang, Shang-Min; McGeary, Meaghan K et al. (2018) KDM5B Promotes Drug Resistance by Regulating Melanoma Propagating Cell Subpopulations. Mol Cancer Ther : |
| Sulkowski, Parker L; Scanlon, Susan E; Oeck, Sebastian et al. (2018) PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF. Mol Cancer Res 16:1241-1254 |
| Chen, Ling; Azuma, Takeshi; Yu, Weiwei et al. (2018) B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. Proc Natl Acad Sci U S A 115:3126-3131 |
| Krauthammer, Michael (2018) Unraveling the etiology of primary malignant melanoma of the esophagus. J Thorac Dis 10:S1074-S1075 |
| Das, Rituparna; Bar, Noffar; Ferreira, Michelle et al. (2018) Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest 128:715-720 |
| Weed, Jason; Gibson, Juliet; Lewis, Julia et al. (2017) FISH Panel for Leukemic CTCL. J Invest Dermatol 137:751-753 |
| Zhang, Yanchang; Cartmel, Brenda; Choy, Courtney C et al. (2017) Body mass index, height and early-onset basal cell carcinoma in a case-control study. Cancer Epidemiol 46:66-72 |
Showing the most recent 10 out of 172 publications
