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

重新利用阿托伐醌预防卵巢癌：成功抑制氧化磷酸化的一个例子

• 批准号: 10658885
• 负责人: Lisa M Barroilhet
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658885
• 关键词: Address; Algorithms; Antimalarials; Antioxidants; Apoptosis; BRCA1 gene; BRCA2 gene; Benign; Binding Sites; Biological Markers; Breast Cancer Risk Factor; Cancer cell line; Cancerous; Carcinoma; Chemoprevention; Chemopreventive Agent; Chemoresistance; Clinical Trials; Collecting Cell; Contraceptive Usage; Control Animal; Credentialing; Cytochromes b; Cytology; Data; Deterioration; Development; Disease; Dose; Early Diagnosis; Electron Transport; Electron Transport Complex III; Eligibility Determination; Enterobacteria phage P1 Cre recombinase; Epithelium; Evaluation; Excision; Exposure to; FDA approved; Future; Genes; Genetically Engineered Mouse; Germ-Line Mutation; Goals; Growth; Gynecologic; Gynecologic Surgical Procedures; Health; High Risk Woman; Human; Hysteroscopy; In Vitro; Laboratories; Lesion; Malaria; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Measures; Mediating; Methods; Mitochondria; Mus; Neurologic; Operative Surgical Procedures; Oral; Oral Contraceptives; Outcome; Ovarian; Ovary; Oxidative Phosphorylation; Oxidative Stress; Participant; Patient Triage; Patients; Penetrance; Pharmaceutical Preparations; Phosphorylation; Placebo Control; Premature Menopause; Prevention; Prevention approach; Prevention strategy; Proteins; Resistance; Resources; Risk; Risk Reduction; Role; Sampling; Schedule; Screening for Ovarian Cancer; Serous; Signal Transduction; Specimen; Structure; Superoxide Dismutase; Surrogate Endpoint; Survival Rate; System; TP53 gene; Tamoxifen; Testing; Time; Tissues; Tube; Tumor Suppressor Genes; Ubiquinone; Variant; Woman; Work; Xenograft procedure; aerobic glycolysis; atovaquone; biomarker evaluation; bone health; cancer cell; cancer risk; cardiovascular health; catalase; cohort; comparative; cytotoxicity; early phase clinical trial; efficacy evaluation; efficacy study; exposed human population; high risk; high risk population; human disease; in vivo; inducible Cre; inhibitor; innovation; interest; lead candidate; lifetime risk; mouse model; multidisciplinary; novel; pharmacologic; pre-clinical; preclinical development; premature; prevent; prospective; randomized, clinical trials; reproductive; resistance mechanism; response; screening; success; surgical menopause; transcriptome; tumor

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).

使用筛查算法早期发现卵巢癌是无效的，即使在高危人群中也是如此。 携带生殖系突变（如BRCA）的患者降低卵巢癌风险的选择有限， 除非切除卵巢和输卵管迫切需要新的方法来预防 卵巢癌而没有手术绝经的负面后果。 抑制OXPHOS的药物，如阿托伐醌，具有作为有效的化学预防剂的潜力。 Atovaquone是一种线粒体复合物III抑制剂。我们实验室的初步数据支持阿托伐醌 通过干扰线粒体电子传递有效阻断OXPHOS的能力。Atovaquone目前 FDA批准用于治疗疟疾，是一种耐受性良好的口服药物。它能减缓卵巢功能 体外和体内的癌生长，并增加p53相关的凋亡。 假设：我们假设阿托伐醌会阻断氧化磷酸化，增加氧化应激， 并潜在地激活p53介导的细胞凋亡，防止前体病变进展到卵巢 癌症在基因工程小鼠模型。 目标1。检查阿托伐醌在延缓OVGP 1小鼠卵巢癌发病中的作用 模型OVGP 1 BPRN基因工程小鼠模型基于输卵管转化， 模仿人类高级别浆液性癌的发展。该小鼠模型将用于确定 阿托伐醌在易患卵巢癌的小鼠中延迟卵巢癌的发病。其他研究 将研究在卵巢和输卵管中观察到的短期转录组变化， 在我们提出的机会之窗临床试验中增加探索性生物标志物。 目标二。完成一项机会之窗临床试验，检查阿托伐醌对正常 计划进行妇科手术的患者的输卵管和卵巢上皮。资格 患者将是因良性适应症而计划接受至少一个输卵管切除术的女性。 将使用诊室宫腔镜进行输卵管基线细胞学采样。收集的细胞 可用于转录组分析。受试者将暴露于阿托伐醌25-35天， 有效地在阿托伐醌暴露后测量MDA表达，其是对OXPHOS的抑制的标志物 以确认其拟议的作用机制。p53和p53磷酸化的免疫组化表达将是 执行。可以添加来自我们的小鼠工作的其他生物标志物。 目标3.调查阿托伐醌治疗的潜在障碍。Nrf-2耐药机制 与氧化磷酸化有关的研究。必须制定战略， Nrf-2调控基因诱导的抗氧化机制，包括超氧化物歧化酶（MnSOD）， 过氧化氢酶和血红素加氧酶-1（HO-1）。