title: Evaluation of Epigenetic Drug Targeting of Heterogenous Tumor Cell Fractions Using Potential Biomarkers of Response in Ovarian Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 intratumor heterogeneity.
  
  
  RESULTS
  Differentially regulated genes during tumor progression were identified through the previously mentioned 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 cycling, 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.
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune, Maharashtra, India.
authors.forename: Anand Kamal
authors.initials: AK
authors.lastname: Singh
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune, Maharashtra, India.
authors.forename: Nishi
authors.initials: N
authors.lastname: Chandra
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune, Maharashtra, India. sabapat@nccs.res.in.
authors.forename: Sharmila A
authors.initials: SA
authors.lastname: Bapat
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage; D001550:Benzamidines / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D003474:Curcumin / Q000008:administration & dosage; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage; D011506:Proteins / Q000235:genetics; D047491:Retinoid X Receptor gamma / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001550:Benzamidines; D014408:Biomarkers, Tumor; C000604717:CBB1007; D006877:Hydroxamic Acids; D010879:Piperazines; D011506:Proteins; D047491:Retinoid X Receptor gamma; C103637:mesoderm specific transcript protein; C012589:trichostatin A; D003577:Cytochrome P-450 Enzyme System; C472456:PTGIS protein, human; D003474:Curcumin; D001374:Azacitidine