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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA121974-02
Application #
7454465
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$327,633
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
Miller, Chad J; Muftuoglu, Yagmur; Turk, Benjamin E (2017) A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases. Biochem Pharmacol 142:39-45
Kluger, Harriet M; Zito, Christopher R; Turcu, Gabriela et al. (2017) PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clin Cancer Res 23:4270-4279

Showing the most recent 10 out of 172 publications