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

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $307,768

## Abstract

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).

## Key facts

- **NIH application ID:** 9970928
- **Project number:** 1R01CA238423-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Lisa M Barroilhet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,768
- **Award type:** 1
- **Project period:** 2020-05-11 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970928

## Citation

> US National Institutes of Health, RePORTER application 9970928, Repurposing Atovaquone for Preventing Ovarian Cancer: An Example of Successful Inhibition of Oxidative Phosphorylation (1R01CA238423-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970928. Licensed CC0.

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