Blood-Based DNA Methylation Biomarkers of Acquired Platinum Resistance in Women with Ovarian Cancer
Abstract
Rationale: Although most ovarian tumors initially respond to chemotherapy, the cancer typically returns because the tumors become resistant to the standard drugs. Unfortunately, few treatments are available for patients with recurrent and resistant disease, which is essentially incurable. We have shown that progression of ovarian tumors to the state of platinum resistance is caused by, not just genetic changes, but also chemical modifications that affect how the genetic code is read in the tumor cells. These are called epigenetic changes (in the context of the Greek prefix epi [“over”], implying features that are “on top of” DNA). If the genetic code is a musical score, then epigenetics represents the various ways in which it may or may not be played. Although the actual notes on the sheet music do not change, alterations in tempo, instrument, volume, and other parts of the piece change what the listener hears. In this analogy, epigenetic modifications do not change the DNA sequence, which is virtually identical in all cells in a person’s body. Rather, epigenetic changes regulate how the DNA is expressed and control how the DNA is used by switching particular genes “on” or “off” to determine cell function. Unlike cancer-associated genetic events, epigenetic modifications are potentially reversible, and the field of epigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect. In the majority of human cancers, including ovarian cancer (OC), there are errors in the genome and the epigenome, and these errors can contribute to cancer development, growth, and treatment resistance. We study an epigenetic therapy that can render platinum-resistant, high-grade, serous OC (HGSOC) cells sensitive to chemotherapy. The hypomethylating agent (HMA) specifically removes the epigenetic mark named DNA methylation from the DNA of tumor cells. By removing methyl groups, HMA is believed to stop cancer cell growth and to sensitize them to chemotherapy. We have successfully completed two clinical trials using HMAs as sensitizers to traditional chemotherapy in women with recurrent, platinum-resistant HGSOC and demonstrated significant clinical activity of combining an HMA with carboplatin. Many, but not all, patients derived benefit from this treatment. We reasoned that new markers that can identify patients likely to respond will improve the efficacy of the epigenetic therapy. Toward this goal, we identified molecular changes in ovarian tumors biopsied before and after treatment. This clearly demonstrated that the HMA was active in tumor cells. However, we recognize that obtaining tumor biopsies for selecting patients is difficult. Therefore, we propose to develop blood-based biomarkers that can predict platinum resistance in OC and could be used to select patients likely to respond to this epigenetic therapy. Our approach will be minimally invasive, analyzing patients’ peripheral mononuclear blood cells (PBMCs) as a surrogate for tumor biopsies. The objective of this proposal is to identify DNA methylation changes associated with platinum resistance and markers that can identify patients most likely to benefit from epigenetic treatment strategies. To accomplish this goal, we propose to examine changes in PBMCs collected from women treated on a completed clinical trial (NCT01696032), which we led and for whom clinical specimens and outcomes are already available. The ultimate goal is to develop new strategies for selecting patients that will respond to HMA treatment. We propose to analyze PBMs collected when patients entered the trial (baseline). We will compare the changes to PBMCs collected from patients with platinum-sensitive tumors; patients treated with platinum and progressed, but the tumors are still sensitive to the drug; and PBMCs from cancer-free women. By identifying specific changes in DNA methylation in PBMCs from patients that responded to the HMA (vs. patients th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110281
Entities
People
- Kenneth P Nephew
Organizations
- Indiana University
- United States Army