Exploiting Metabolic Changes Induced by ATM Inhibitors as a Synthetic Lethal Therapeutic Strategy for Ovarian Cancer
Abstract
Scientific Rationale and Objectives: Ovarian cancer is the deadliest gynecological cancer with over 22,000 new diagnoses and 14,000 deaths in 2017 alone. While chemotherapy such as platinum has had a major impact on the management of this devastating disease, the development of chemoresistance is a major cause of the high morbidity and mortality observed in ovarian cancer patients. The statistics are grim, with over 75% of ovarian cancer patients developing chemoresistant disease. Therefore, new therapies are needed to discover a long-term cure for these women. This proposal seeks to address this critical problem in ovarian cancer. Ovarian cancer is characterized by changes in the way tumor cells use nutrients to create the building blocks needed for cell growth. This phenomenon is termed the Warburg Effect. Most normal cells do not undergo this process, suggesting that the Warburg Effect could be inhibited to selectively kill cancer cells. To date, there are no ovarian cancer therapies that specifically target The Warburg Effect. We discovered that inhibition of a protein called Ataxia Telangiectasia Mutated (ATM) further increases ovarian cancer cell dependence on the Warburg Effect. We then asked the question, "Can this increased dependence on the Warburg Effect be exploited to lead to ovarian cancer cell death?" Using an unbiased screen, we found that treatment of ovarian cancer cells with the combination of an ATM inhibitor (ATMi) and the FDA-approved lipid-lowering drug fenofibrate leads to ovarian cancer cell death. Fenofibrate has been shown to inhibit the Warburg Effect. Excitingly, neither drug alone increased cell death. This suggests that only ovarian cancer cells, and not normal cells, will be killed by this combination therapy. Given these observations, in this proposal, we will study the newly-discovered combination therapy of ATMi + fenofibrate that will kill ovarian cancer cells and spare normal cells. Thus, the objectives of the proposal are to: (1) study how the combination of ATMi and fenofibrate leads to ovarian cancer cell death; and (2) explore whether this combination is a novel therapeutic strategy for platinum-resistant ovarian cancers. Relevance to Vision and Mission of the OCRP: These studies are highly relevant to the vision and mission of the OCRP. The proposed studies will use new disease-relevant ovarian cancer models, such as cancer cells derived from patients, to study resistance of ovarian cancer. They will also investigate the role of The Warburg Effect in therapy-resistant ovarian cancers. Finally, the proposed animal studies will identify whether the newly discovered combination of ATMi + fenofibrate leads to a durable, long-term cure for therapy-resistant ovarian cancer. The ultimate goal of these studies is to eliminate ovarian cancer. Ultimate Applicability and Impact for Military Service Members, Their Families, and Other Military Beneficiaries: We anticipate that this work could ultimately benefit ovarian cancer patients who have developed resistance to platinum, the current standard ovarian cancer care. ATM inhibitors are currently in clinical trials, and fenofibrate is an FDA-approved drug. Therefore, if successful, the proposed studies could quickly lead to initiation of a Phase I clinical trial for ovarian cancer patients that have failed all previous therapies. This would lead to a new paradigm for treating platinum-resistant ovarian cancer patients. The physical and mental cost of ovarian cancer on military health is clear. A staggering number of female Service members and wives and adult daughters of active duty military will be diagnosed with ovarian cancer (~11,900 of 850,000 women). Therefore, the proposed research may have a potential significant impact on the welfare of military Service members, their Families, and other beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810103
Entities
People
- Katherine M Aird
Organizations
- Penn State Milton S. Hershey Medical Center
- United States Army