Identification of Correlated Genetic and Epigenetic Alterations Driving Chemoresistance
Abstract
High-grade serous ovarian cancer is an aggressive disease with a poor prognosis, as it diagnosed late when tumors acquire numerous genetic changes and become increasingly chemoresistant. Platinum-based inhibitors have been especially effective in individuals that harbor mutations of the BRCA1 and BRCA1 genes. However, a vast majority of patients eventually develop resistance to these agents, necessitating secondary therapies. Recently, promising data from Phase I and Phase II clinical trials have propelled the approval of a new class of compounds, PARP inhibitors (Olaparib), as first-line therapy as well as for recurrent or relapsed disease by the Food and Drug Administration. These results have also prompted a series of Phase III trials where PARP inhibitors are being tested in combination with platinum-based compounds and with anti-angiogenesis inhibitors. However, although encouraging, it is widely anticipated that a subset of patients may develop resistance to cisplatin and PARP inhibitor treatments. Hence, it is extremely important to gain a better understanding of the resistance pathways that would help to develop tailored therapies that would target these pathways. Our proposal aims to identify the molecular signatures of resistance to cisplatin and PARP inhibition by using a novel approach that tests the link between two classes of molecular alterations. We will investigate the correlation between patterns of genetic and epigenetic alterations in the genome that arise during acquisition of resistance. One of the most well-studied epigenetic alterations is DNA methylation, which involves the addition of a methyl group to cytosine residue, one of the four bases in the DNA, in the context of CG dinucleotides (CpG). Hypermethylation often leads to gene silencing while hypomethylation results in gene activation. Both genetic and epigenetic alterations are acquired during cancer progression and development of therapy resistance. Epigenetic changes have been classically thought to be changes that are not encoded by the genetic sequence. However, multiple studies have recently demonstrated that genetic sequence (methylation determining region) does play a role in regulating DNA methylation. Hence, we hypothesize that since ovarian cancer and chemoresistance are driven primarily by DNA copy number alterations, these changes may overlap methylation determining regions and produce a cascading effect on DNA methylation. Therefore, in the proposed study, we will test our hypothesis using an in-house cohort of samples from women treated with cisplatin and/or PARP inhibitors. Further, will use emerging genome editing approaches to make deletions in genomic DNA and observe the effects on correlated DNA methylation and on conferring resistance to platinum/PARP sensitive cells. This approach has not been utilized in ovarian cancer before and will provide novel insights into the "driving mechanisms" underlying resistance that can inform the Phase III clinical trials underway. In addition, since global inhibitors of methylation have shown promise in resensitizing tumors to chemotherapy, our results will help in tailoring more targeted methylation inhibitors with reduced side effects. In the short term, we will develop correlated genetic-epigenetic signatures associated with resistance. This study will set the stage to test different inhibitors to the pathways of resistance identified in the proposed study that can be used to treat women carrying BRCA mutations that have failed chemotherapy and/or treatment with PARP inhibitors. In the long term, it will open up a new area of investigation aimed at investigating further, the biological mechanisms by which genetic sequences affect methylation in conferring chemoresistance. The proposed study may help provide insights into the genetic basis for whole genome hypo- or hypermethylation. Our study therefore supports the overall mission of the Ovarian Cancer Researc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610687
Entities
People
- Sunita R Setlur
Organizations
- United States Army