Repurposing Atovaquone for Preventing Ovarian Cancer: An Example of Successful Inhibition of Oxidative Phosphorylation

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Early detection of ovarian cancer using screening algorithms is ineffective, even in high-risk populations. Patients who carry germline mutations, such as BRCA, have limited options to lower their ovarian cancer risk, short of removing their ovaries and fallopian tubes. There is a critical need for novel methods to prevent ovarian cancer without the negative consequences of surgical menopause. Drugs that inhibit OXPHOS, such as atovaquone, have potential as effective chemoprevention agents. Atovaquone is a mitochondrial complex III inhibitor. Preliminary data from our laboratory support atovaquone's ability to effectively block OXPHOS by interfering with mitochondrial electron transport. Atovaquone is currently FDA approved for the treatment of malaria, and is a well-tolerated, orally available medication. It slows ovarian cancer growth in vitro and in vivo and increases p53-related apoptosis. Hypothesis: We hypothesize that atovaquone will block oxidative phosphorylation, increase oxidative stress, and potentially activate p53-mediated apoptosis, preventing precursor lesions from progressing to ovarian cancer in a genetically engineered mouse model. Aim 1. Examine the role of atovaquone in delaying the onset of ovarian cancer in an OVGP1 mouse model. The OVGP1 BPRN genetically engineered mouse model is based on fallopian tube transformation and mimics human high-grade serous carcinoma development. This mouse model will be used to determine if atovaquone delays the onset of ovarian cancer in mice predisposed to develop this disease. Additional studies will investigate short-term transcriptome changes seen in the ovary and fallopian tube that could serve as additional exploratory biomarkers in our proposed window-of-opportunity clinical trial. Aim 2. Complete a window of opportunity clinical trial examining the effects of atovaquone on normal fallopian tube and ovarian epithelium in patients undergoing planned gynecologic surgery. Eligible patients will be women scheduled to undergo removal of at least one fallopian tube for benign indications. Baseline cytology sampling of the fallopian tube will be performed using office hysteroscopy. Cells collected can be used for transcriptome analysis. The subjects will be exposed to atovaquone for 25-35 days pre- operatively. MDA expression, a marker of inhibition to OXPHOS, will be measured after atovaquone exposure to confirm its proposed mechanism of action. IHC expression for p53 and p53 phosphorylation will be performed. Additional biomarkers from our mouse work may be added. Aim 3. Investigate potential barriers to atovaquone therapy. The Nrf-2 chemoresistance mechanisms pertinent to oxidative phosphorylation will be explored. It is critical to develop strategies to overcome the antioxidant mechanisms induced by Nrf-2 regulated genes, including superoxide dismutase (MnSOD), catalase, and hemoxygenase-1 (HO-1).