Target Validation and Inhibition of RHNO1 Function in Ovarian Cancer
Abstract
Rationale and Objective: DNA replication stress (RS) is a defect in the process that duplicates DNA. RS occurs at high levels in cancer cells and low levels in normal cells and makes cancer cells dependent on the cellular RS response. The RS response protects cancer cells from DNA damage and increases cancer cell survival. Thus, drugs that inhibit the RS response can be effective treatments for cancer in that they kill cancer cells but spare the normal cells of the body. Investigating new ways to inhibit the RS response in cancer cells is thus backed by a strong rationale. RHNO1 is a protein that plays a role in the cellular response to RS. We showed that RHNO1 is greatly increased in high-grade serous ovarian cancer (HGSC) compared to normal tissues and is present in the vast majority of HGSC cases (~85%). In addition, we showed that RHNO1 promotes both the RS response and HGSC cell survival. The first objective of the proposed study is to determine whether RHNO1 promotes HGSC tumor growth in vivo, using mice. The second objective of the proposed study is to develop drugs that prevent RHNO1 from activating the cellular RS response. Such drugs have high potential as new therapeutics for the treatment of HGSC patients. Critical Problem in Ovarian Cancer: HGSC is the most common and deadly subtype of ovarian cancer, leading to the deaths of ~15,000 women per year in the United States. A major clinical problem in HGSC is that, after completion of the initial therapy, many women experience disease recurrence, and a large proportion of the relapsed patients ultimately die from HGSC. This sobering fact emphasizes the critical need for improved therapies to treat women with recurrent HGSC. The proposed study directly addresses this critical problem by working to validate a new therapeutic target and by developing new drugs to treat HGSC. This is further supported by the fact that RHNO1 is overexpressed in chemoresistant, recurrent HGSC and that RHNO1 helps to mediate chemoresistance. Thus, drugs that target RHNO1 are anticipated to be helpful to patients with recurrent HGSC. New Paradigms, Insights, Technologies, and Applications in Ovarian Cancer: This study will provide new insight into the mechanisms of HGSC by investigating a newly discovered contributor to the disease, the oncoprotein RHNO1. In addition, this study will investigate new treatments for HGSC by developing drugs to inhibit the function of RHNO1 in the cellular RS response, which will target cancer cells and spare normal cells. FY22 OCRP Area of Emphasis: Develop novel therapeutic strategies for treatment and prevention. Individuals Helped: The study has the potential to help most women with HGSC because RHNO1 overexpression is common in HGSC, occurring in ~85% of HGSC cases. In addition, increased RS is a defining characteristic of most HGSC cases. Impact on the Health And Well-Being of Service Members, Veterans, Their Family Members, and All Women Impacted by Ovarian Cancer: By providing information about the biological causes of HGSC and developing novel treatment approaches for HGSC, this study has the potential to benefit military Service Members, their families, and all other women who are diagnosed with HGSC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310238
Entities
People
- Adam R Karpf
Organizations
- United States Army
- University of Nebraska Medical Center