Therapeutic Targeting Using Tumor-Specific Peptides Inhibits Long Noncoding RNA HOTAIR Oncogenic Activity in High-Grade Serous Ovarian Cancer
Abstract
Ovarian epithelial cancer is a persistent cancer that frequently does not go away with treatment. Recurrent ovarian cancer is cancer that has come back after it has been treated. Evidence strongly suggests that a reason 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 conclusively demonstrated that chemotherapy decreases tumor growth but also contributes to enriching the population of ovarian cancer stem cells in the tumors that remained, indicating that ovarian cancer stem cells could be one cause of tumor relapse after therapy. Further using the innovative animal model we developed, we published that a next-generation "epigenetic" therapy inhibited the outgrowth of ovarian cancer stem cells and delayed tumor recurrence. However, not all ovarian cancer stem cells 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 the epigenome, that is the chemical modifications to the genome that direct the activity of the genome over time, we can exploit epigenetic vulnerabilities of ovarian cancer stem cells and achieve long-term remission or by eliminating ovarian cancer stem cells possibly develop a cure. For this grant, we provide convincing published and preliminary data, experience in ovarian cancer stem cell biology and epigenetic targeting, a long-standing interest in treatment resistance, and highly impactful and translational specific aims. We reported that the long non-coding RNA (lncRNAs; functional transcripts >200 nucleotides) named "HOTAIR," which is frequently overexpressed, promotes metastasis and is predictive of decreased survival in ovarian and other cancers, plays a key role in altering the epigenome, turning off genes that help to control ovarian cancer cells. We demonstrated a strong association between HOTAIR expression and chemoresistant high-grade serous ovarian cancer, making HOTAIR a potential therapeutic target. We developed a targeting strategy for oncogenic HOTAIR that re-sensitizes ovarian cancer cells to chemotherapy. Our data further show that ovarian cancer stem cells from patient tumors and high-grade serous cell lines express higher levels of HOTAIR compared to non-cancer stem cells, indicating that targeting HOTAIR may reduce the ovarian cancer stem cell population. We propose a basic laboratory investigation plus animal validation study for targeting the oncogenic lncRNA HOTAIR as a novel therapeutic approach to targeting ovarian cancer stem cells and reversing drug resistance (Aim 1). The approach we are taking with HOTAIR could prove synergistic to existing therapies, which will be examined in Aim 2. Our exploratory deep sequencing analysis in Aim 3 may allow us to identify genes and pathways regulated by HOTAIR and important to ovarian cancer stem cells survival that can be targeted in ovarian cancer stem cells. In summary, although ovarian cancer is a chemoresponsive tumor with very high initial response rates to standard platinum/paclitaxel therapy, most women eventually develop recurrence, which rapidly evolves into chemoresistant disease. Recurrent ovarian cancer is essentially incurable. We anticipate that this research will impact the design of future clinical investigations in ovarian cancer, as successful completion of these studies will provide the rationale for using epigenetic regulators to eliminate ovarian cancer cells surviving after standard chemotherapy, addressing the Fiscal Year 2016 Area of Encouragement of treatment resi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710076
Entities
People
- Kenneth P Nephew
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army