Targeting EZH2-HOTAIR to Block Platinum-Induced Ovarian Cancer Stem Cell Enrichment and Reduce Recurrence
Abstract
Although most ovarian tumors initially respond to chemotherapy, the cancer typically returns because the tumors become resistant to the standard drugs. It is a persistent cancer that frequently does not go away with treatment. 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 not just by genetic changes, but also by 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, 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. Abnormal epigenetic changes are seen in the majority of human cancers, including high-grade serous ovarian cancer (HGSOC). About 75% of women diagnosed with advanced HGSOC experience chemo-resistant relapse after first-line chemotherapy and have a 5-year survival rate of only 26%. Epigenetic changes are recognized as important drivers of HGSOC development, growth, and resistance to therapy. In this regard, we have shown that epigenetic therapies have the potential to resensitize platinum-resistant ovarian tumors to platinum. Evidence strongly suggests that a reason ovarian cancer patients are not cured by current treatments is because a small “pool of malignant cells” responsible for maintaining the disease has not been eliminated and are able to survive current treatments and continue to feed tumor growth. These cells can self-renew (copy themselves) extensively and also produce more mature cells (non-cancer stem cells that make up the “bulk” of the tumor) that do not divide and so do not contribute to tumor growth. We have demonstrated that, while chemotherapy decreases tumor growth, platinum can also contribute to enriching the population of ovarian cancer stem cells (OCSCs) in the tumors that remained, indicating that OCSCs could be one cause of tumor relapse after therapy. Further, using the innovative animal model we developed, we published that epigenetic therapy inhibited the outgrowth of OCSCs and delayed tumor recurrence. However, not all OCSCs were eliminated, suggesting further improvements on this treatment paradigm are possible. Nonetheless, our findings are significant because they suggest that, by targeting factors that influence epigenetic changes, we can exploit epigenetic vulnerabilities of OCSCs and achieve long-term remission, or by eliminating OCSCs and possibly develop a cure. Over 80% of patients with HGSOC have recurrent disease after chemotherapy. OCSCs resist effects of traditional anticancer strategies and can reconstitute recurrent tumors, which become chemotherapy-resistant. OCSC maintenance requires reprogramming of the epigenome. Epigenetic drugs can be used as differentiation therapy in CSCs and result in conversion of CSCs to more differentiated cancer cells that are susceptible to conventional chemotherapy. Recent work by our group and others demonstrated that platinum treatments can enrich for OCSCs and connected this enrichment to epigenetic changes. Specifically, we demonstrated that two key epi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110284
Entities
People
- Kenneth P Nephew
Organizations
- Indiana University
- United States Army