Despite advances in our understanding of the underlying genomic landscape of high- grade serous ovarian carcinoma (HGSC), few new targeted treatments have entered clinical care with significant survival benefit. Super-enhancers (SEs) are epigenetic features previously understudied in HGSC that are targetable with a variety of drugs. In cancer, SEs regulate expression of oncogenes such as MYC, but the specific set of oncogenes regulated by SEs depends on the cancer type, and these have not been previously defined in HGSC. Preliminary data suggests that SEs underlie the oncogenic functions of ovarian cancer, as SE-targeting drugs such as triptolide and bromodomain inhibitors are effective in ovarian cancer models in vitro and a rare ovarian cancer subtype in vivo. The work proposed here will lead to new understandings of how SEs influence HGSC growth and therapy response, and how HGSC might be better treated with new therapeutic strategies targeting SEs, ultimately improving outcomes for patients with HGSC. Hypothesis: Based both on the proven role of SEs in the pathogenesis of other cancers through unique regulation of oncogenes and also on data showing sensitivity of HGSC to SE-targeting drugs, this proposal tests the hypothesis that SE dysregulation plays a central role in HGSC tumorigenesis and treatment response.
Specific Aims :
Aim 1 : Map HGSC SEs contributing to oncogenic phenotypes.
Aim 2 : Determine dynamic SE modification following standard-of-care treatment.
Aim 3 : Evaluate the efficacy of SE-targeting drugs in HGSC. Study Design: To identify HGSC-specific SEs, six serous HGSC cell lines and twenty tumors will be examined by RNA-Seq and ChIP-Seq for H3K27 acetylation. SEs will be identified both bioinformatically and through functional characterization for roles in cell proliferation and response to chemotherapy using the CRISPR interference system. In the independent phase of this award, the dynamics of SEs will be assessed in response to platinum treatment and SE-targeting drugs will be tested as single agents and for synergy in combination with platinum-based chemotherapies in HGSC cell lines, patient-derived xenograft organoid models, and animal xenograft models of HGSC. Career Development: Towards the goal of becoming an independent investigator studying novel therapies for ovarian cancer treatment, this proposal has also assembled a career development plan. This includes K99 phase mentorship by leaders in genomics (Dr. Jeffrey Trent, mentor) and ovarian cancer (Dr. Lorna Rodriguez, co-mentor) and an advisory team that includes experts in bioinformatics, super-enhancers, and ovarian cancer. As an institute, TGen provides all the scientific support, facilities, and equipment necessary to complete this project. TGen has a structured plan for responsible conduct of research training and other professional development. Additional coursework in bioinformatics analysis of ChIP-Seq and RNA-Seq data is built into the plan, as well as attendance at relevant national meetings, and participation and/or lead the writing of a number of manuscripts and grants.
The identification of super-enhancers in ovarian cancer that contribute to growth and therapeutic response will be instrumental in diagnostic, prognostic, and therapeutic decision making. Not only will this work identify ovarian cancer-specific super-enhancers, but it will also determine how they are modified in response to standard-of-care chemotherapies, as well as identify new drugs to target them directly. By better understanding the location and functional role of these master transcriptional hubs in ovarian cancer, we can more specifically treat each ovarian cancer patient to achieve the best possible outcome.
