Analysis of the Tandem Duplicator Phenotype as a New Driver and Biomarker of BRCA1-Linked Ovarian Cancer
Abstract
Rationale: Ovarian cancer remains a major public health threat. To improve ovarian cancer treatment success, we need better tools to distinguish between different drivers of ovarian cancer and to determine their distinct genetic causes. This will allow us to find the best ways to deploy treatments that already exist or to develop new effective therapies. Ovarian cancers lacking BRCA1 are often responsive to PARP inhibitors or cisplatin. In this regard, it would be advantageous to be able to positively identify BRCA1 mutant ovarian cancers, including those cancers in which BRCA1 is functionally inactivated, even if not mutated. We have developed a remarkable new biomarker of BRCA1 inactivation. In a recent study, we analyzed the whole genomes of >3,000 cancers using computational methods and identified a distinct genetic "fingerprint" in breast and ovarian cancer, called the "tandem duplicator phenotype" (TDP). This fingerprint is characterized by massive rearrangements of cancer genes collectively driving cancer growth. Our analysis also found, based on the genetic makeup of TDP cancers, that a novel combination of chemotherapies -- distinct from what is used now in the clinic -- would be highly effective in shrinking TDP triple-negative breast cancer tumors. We also found that not all TDP tumors are the same. We now have strong preliminary data identifying susceptibility of TDP tumors to specific therapies are already Food and Drug Administration (FDA)-approved or in development. Thus, we have the tools to unpack this complexity in a way that creates unprecedented opportunities for better classifying, treating, and curing ovarian cancer. Aims, Deliverables, and Goals: The ultimate goal of our proposal is to bring a more precise approach for classifying and treating ovarian tumors to the clinic that is based on identifiable molecular mechanisms. We will do this by identifying comprehensively the BRCA1-interacting genes that regulate TD formation (Aim 1), and to determine relationships between TDP driver genes and drug sensitivity (Aim 2). Our proposal uses a range of molecular and cell biological tools, many of which have been pioneered or perfected in the Scully laboratory, for the investigation of ovarian cancer. Here, they come together as an integrated platform that we expect to deliver (1) a better mechanistic understanding of the formation of TDP in ovarian cancer and (2) novel treatment regimens that exploits specific gene interactions in regulating TD formation. With this project, we hope to bring greater insight into the cause of ovarian cancer and to develop new tools to optimize therapeutic combinations and ultimately achieve cures. Ultimate Applicability of the Research: We are using the power of genomics to derive a more precise classification of ovarian cancer that can direct more effective therapies through a mechanistic understanding of the disease. This work will directly benefit patients because it will uncover novel treatment regimens tailored to specific TDP subtypes that, for FDA-approved chemotherapies and their combinations, could be ready for immediate testing in a clinical setting. It could also identify and validate novel targets that could be pursued for pharmaceutical development. Both outcomes would have immense clinical relevance to and direct impact on women diagnosed with ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710179
Entities
People
- Ralph Scully
Organizations
- Beth Israel Deaconess Medical Center
- United States Army