Targeting High Mobility Group Box Protein 3 to Sensitize Chemoresistant Human Ovarian Cancer Cells to Cisplatin In Vivo
Abstract
Rationale and Objective of the Proposed Work: Ovarian cancer is the leading cause of death from gynecological cancer and the fifth most common cause of cancer-related death in women in the United States. This high mortality is in large part due to lack of improvements in chemotherapy for ovarian cancer patients. First-line chemotherapy includes DNA-damaging drugs, such as cisplatin or carboplatin. Unfortunately, even with the best treatment strategies currently available, the 5-year survival rate is only ~48%, and the cancer recurrence rate is devastatingly high at ~70%. Drug resistance contributes to cancer recurrence and poor patient survival. If tumor cells can repair and remove anticancer drug-DNA lesions, then cancer drug resistance can develop. Thus, improved treatment strategies are sorely needed; this is the goal of our proposed pilot project. There is a critical need to identify novel drug targets to treat patients who have stopped responding to chemotherapy (i.e., chemoresistant patients). Our goal is to study the effects of inhibiting a novel target, the High Mobility Group Box 3 (HMGB3) protein in animal models of human cancer to sensitize chemoresistant ovarian tumors to the chemotherapeutic drug, cisplatin. We propose to screen drug libraries to find inhibitors of HMGB3 function in chemoresistance to test in animal models for their ability to sensitize (or reverse) chemoresistance in human tumors for future drug development. We found that HMGB3 participates in the repair of chemotherapeutic drug-induced DNA lesions; thus, by depleting this protein, we can restore killing of formerly drug-resistant human ovarian cancer cells. The role of HMGB3 in the responsiveness of ovarian cancer patients to chemotherapy is of clinical relevance and may provide a novel therapeutic target for the treatment of ovarian cancer. The Critical Problem in Ovarian Cancer Addressed in the Proposed Research: A critical problem in ovarian cancer is the development of recurrent and chemoresistant forms of ovarian cancer that are considered incurable and will eventually lead to the death of these patients. Current treatment regimens need to be improved to better manage the response of the recurrent and chemoresistant forms of ovarian cancer to chemotherapy. We will address this issue in our proposed research by utilizing an animal model of human ovarian cancer where HMGB3 can be targeted selectively in chemosensitive and chemoresistant human ovarian tumors and the responses to therapy can be evaluated by measuring the growth of the tumors. In addition, the HMGB3 inhibitors identified through the screening of ~80,000 compounds may lead to the development of drugs that can be used to treat chemoresistance and recurrence in these ovarian cancer patients. New Paradigms, Insights, Technologies, or Applications in Ovarian Cancer: Our results can be considered paradigm-shifting because they challenge the earlier view that HMGB proteins inhibit the repair of drug-DNA lesions. Instead, we found that HMGB proteins facilitate the repair of cisplatin-DNA adducts, contributing to drug resistance in ovarian cancer patients. Further, we found a novel role for HMGB3 in sensitizing cisplatin-resistant ovarian cancer cells to chemotherapy by transcriptional regulation of DNA damage response genes. The hypothesis to be tested is unique and may provide new target/drug for the treatment of ovarian cancer patients. Relevance to the Vision and Mission of the OCRP: Relevant to the vision and mission of the OCRP, results from our proposed research will help develop and validate animal models to better understand the treatment, response, chemoresistance, and recurrence of ovarian cancer. Thus, the results will guide our attempt to increase long-term survivorship and improve quality of life throughout the continuum of ovarian cancer care. Which Individuals Will This Study Help and How Will It Help Them? This study addresses a critica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110392
Entities
People
- Karen M Vasquez
Organizations
- United States Army
- University of Texas at Austin