An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer

Project: Research project

Description

Project Summary/Abstract
Platinum resistance in ovarian cancer is associated with accumulation of epigenetic changes leading to
transcriptional silencing of tumor suppressor and chemo-responsiveness-associated genes. A clinical trial
designed and conducted previously demonstrated that methylome-targeted interventions reverse platinum
resistance and induce clinical responses. Building upon this work, we propose to extend the ovarian cancer
epigenome analysis by using MBDCap-sequencing and bioinformatics and to test the effects of SGI-110, a
novel DNA methyl transferase inhibitor (DNMTI). The hypothesis to be tested is that platinum resistance in
ovarian cancer is uniquely reflected in DNA methylation changes and can be reversed by DNMTI. To
address this hypothesis, tumor and plasma samples collected from an ongoing randomized phase II clinical trial
comparing SGI-110 and carboplatin to FDA-approved strategies for platinum-resistant ovarian cancer will be
analyzed. Clinical specimens from ~100 patients will be available for analysis. Three aims are proposed. For
Aim 1, DNMTI-induced changes in the ovarian cancer methylome will be measured by using MethylCap-seq on
tumor biopsies obtained before and after SGI-110. The objective of this Aim is to investigate whether SGI-110
induces global methylome changes affecting networks of genes associated with chemo-responsiveness. The
objective of Aim 2 is to determine whether DNMT expression levels differ in recurrent vs. primary tumors and
whether expression levels at enrollment or changes induced by DNMTIs correlate with clinical benefit. For Aim
3, the objective is to determine whether specific genes methylation levels at enrollment and changes induced by
DNMTIs correlate with clinical benefit. This project will identify critical DNA methylation events that govern the
development of platinum resistance. The proposed studies are highly innovative based on the use of state-of-
the-art MBDCap-Seq and bioinformatics applied to a question of high clinical relevance. Successful completion
of the correlative work integrated in this trial will identify predictive markers of response to methylome-targeting
strategies. This study will bring epigenetic interventions to the forefront of therapy for ovarian cancer impacting
treatment strategies and outcomes for this deadly cancer. Successful completion of this study will move
forward the field of epigenome-targeted therapy for solid tumors and will provide key information for biologically-
directed future design of phase III trials.
StatusFinished
Effective start/end date2/14/141/31/19

Funding

  • National Institutes of Health: $323,700.00
  • National Institutes of Health: $323,700.00
  • National Institutes of Health: $323,701.00

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Carboplatin
Epigenomics
Ovarian Neoplasms
Platinum
Transferases
Neoplasms
DNA Methylation
Computational Biology
DNA
Gene Regulatory Networks
Methylation
Genes
Phase II Clinical Trials
Biopsy
SGI-110
Therapeutics
Randomized Controlled Trials
Clinical Trials

ASJC

  • Medicine(all)