Targeting Satellite Repeat RNAs in High-Grade Serous Ovarian Cancer
Abstract
Ovarian cancer is currently the fifth leading cause of all cancer deaths in women and is the most lethal of the gynecologic malignancies. High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of epithelial ovarian cancers and is most often detected at advanced stages. Despite many women entering remission after initial surgery and combination chemotherapy, the overall survival remains low, and the majority of women still die of increasingly treatment-resistant cancer. Thus, novel treatment approaches are needed to improve outcomes in HGSOC. Our laboratory has used novel RNA sequencing (RNA-Seq) methods to reveal that many human epithelial cancers, including ovarian, contain massive amounts of non-coding RNAs. One class of these non-coding RNAs, satellite repeat RNAs, are generally silenced in normal tissue and were previously thought to be inactive. However, recent work from our laboratory and others has uncovered important implications of their presence in cancer cells. In particular, these repeat RNAs have been found to behave like viruses, with the ability to convert their RNA into DNA and also to trigger immune responses. Because of these unique features, we have begun investigating whether targeting satellite repeat RNAs in cancer cells could represent a novel strategy to target certain epithelial cancers. In support of this, recent work in our laboratory has revealed that treating cancer cells with drugs that interfere with the viral life cycle (nucleoside reverse transcriptase inhibitors [NRTIs]) induces cell death in colorectal cancer (CRC). Our work in CRC has also demonstrated that NRTIs are most effective in cancers with TP53 mutations. Moreover, TP53 is known to play a key role in suppressing the production of repeat RNAs in normal cells. Since more than 95% of HGSOC cases are known to have TP53 mutations, we hypothesize that there are high levels of satellite repeat RNAs in HGSOC, making it particularly vulnerable to NRTI therapy. Accordingly, we propose to first comprehensively define the spectrum of repeat RNA expression across HGSOC by performing Total RNA-Seq in a panel of HGSOC cell lines and patient-derived xenograft (PDX) models. Given their unique expression in cancer cells, this will allow the development of specific blood-based biomarkers in ovarian cancer. In addition, these results will guide further investigations into the feasibility and efficacy of targeting repeat RNAs as a therapeutic strategy in HGSOC. To this end, we will quantify the expression of the most abundant repeat RNAs in primary ovarian tumors and correlate this with immune cell presence and location in the tumors to determine the relationship between repeat RNAs and the tumor immune response. The other major aim of this proposal is to determine whether targeting repeat RNAs by interfering with their viral-like life cycle could represent an effective means to treat HGSOC. Therefore, we will expose the HGSOC cell lines and PDX models to a panel of NRTIs and look for cancer cell death. In addition, we will perform RNA-Seq following treatment to reveal changes in repeat RNA expression. We will then further study the most effective NRTI in immunodeficient mice with human ovarian cancer tumors to determine the effect of these drugs in vivo. We will also perform correlative studies on these tumors after treatment to determine changes in repeat RNA expression in response to this therapy. Finally, we will test the effect of combining NRTI therapy with standard chemotherapeutic agents, carboplatin and paclitaxel, as well as with epigenetic drugs that are known to also affect repeat RNA expression to determine whether there are superior outcomes with combination therapy. Overall, our proposed studies will aim to (1) broaden our understanding of satellite repeat RNAs in ovarian cancer, which is undoubtedly important, given their abnormally high abundance in cancer cells; (2) provide a plat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910058
Entities
People
- Rebecca L. Porter
Organizations
- Massachusetts General Hospital
- United States Army