Singh , A.K. and Chandra , N. and Bapat , S.A. (2015) Evaluation of epigenetic drug targeting of heterogenous tumor cell fractions using potential biomarkers of response in ovarian cancer. Clinical Cancer Research.

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Abstract

PURPOSE: Resolution of aberrant epigenetic changes leading to altered gene expression during transformation and tumor progression is pertinent for mechanistic understanding of disrupted pathways in cancer. Such changes provide for biomarkers that can be applied in drug screening and improved disease management. EXPERIMENTAL DESIGN: Genome-wide profiling and analyses of promoter DNA methylation, histone modifications and gene expression of an in vitro progression model of serous ovarian adenocarcinoma were carried out. Similar in silico analyses and comparison of methylation and gene expression of early and late grade ovarian cancer samples in The Cancer Genome Atlas assigned a clinical relevance to our study. Candidate biomarkers were evaluated for epigenetic drug treatments in experimental animal models on a background of differing tumor cell responses arising from intra-tumor heterogeneity. RESULTS: Differentially regulated genes during tumor progression were identified through the above analyses as candidate biomarkers. In examining the tumor suppressor PTGIS as a potential biomarker for treatment with either 5-Aza-dC or TSA , 5-Aza-dC effectively stabilized cell cyling, restricted genetic instability and derepressed PTGIS expression, while TSA led to emergence of drug resistant progenitors lacking PTGIS expression. Profiling MEST and RXRγ for Curcumin and CBB1007 respectively indicated an inability of Curcumin and CBB1007 in restricting residual tumor regenerative capabilities. CONCLUSIONS: Our study provides novel insights into epigenetic regulation in ovarian cancer progression and potential biomarkers for evaluating efficacy of epigenetic drugs in restricting residual tumor regeneration. Such approaches may assign a new functional interpretation of drug efficacy and cell tumor responses in ovarian cancer.

Item Type:	Article
Subjects:	Cancer Biology
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	01 Sep 2015 09:06
Last Modified:	19 Feb 2016 08:41
URI:	http://nccs.sciencecentral.in/id/eprint/195

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