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

基本信息

批准号：
10162548
负责人：
Lisa M Barroilhet
金额：
$ 33.37万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/10162548
关键词：
Address Algorithms Antimalarials Antioxidants Apoptosis Attenuated BRCA1 gene BRCA2 gene Benign Binding Sites Biological Markers Breast Cancer Risk Factor Cancer cell line Cancerous Carcinoma Cells Chemoprevention Chemopreventive Agent Chemoresistance Clinical Trials Contraceptive Usage Control Animal Cytochromes b Cytology Data Deterioration Development Disease Dose Early Diagnosis Electron Transport Electron Transport Complex III Enterobacteria phage P1 Cre recombinase Epithelial 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 Menopause Methods Mitochondria Mus Neurologic Operative Surgical Procedures Oral Oral Contraceptives Outcome Ovarian Ovary Oxidative Phosphorylation Oxidative Stress Participant Patient Triage Patients Penetrance Pharmaceutical Preparations Pharmacology Phosphorylation Placebo Control Premature Menopause Prevention Proteins Randomized Clinical Trials Resistance Resources Risk Risk Reduction Role SOD2 gene 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 base 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 inhibitor/antagonist innovation interest lead candidate lifetime risk mouse model multidisciplinary novel pre-clinical preclinical development premature prevent prospective reproductive resistance mechanism response screening success transcriptome tumor

项目摘要

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).

即使在高风险人群中，使用筛查算法对卵巢癌的早期检测也无效。携带种系突变的患者（例如BRCA）的选择有限，可以降低卵巢癌风险，缺乏去除卵巢和输卵管。对于防止新颖的方法有至关重要的需求卵巢癌没有手术更年期的负面影响。抑制OXPHOS（例如Atovaquone）的药物具有有效的化学预防剂。 Atovaquone是一种线粒体复合物III抑制剂。我们实验室支持的初步数据Atovaquone's 通过干扰线粒体电子传输有效阻断OXPHOS的能力。 Atovaquone目前是 FDA批准用于治疗疟疾，是一种耐受良好的口服药物。它减慢了卵巢体外和体内癌症生长，并增加与p53相关的凋亡。假设：我们假设Atovaquone将阻止氧化磷酸化，增加氧化应激，，并可能激活p53介导的凋亡，防止前体病变发展到卵巢在基因工程的小鼠模型中进行癌症。 AIM 1。检查Atovaquone在延迟OVGP1小鼠中卵巢癌发作中的作用模型。 OVGP1 BPRN基因工程的小鼠模型基于输卵管转化和模仿人类高级浆液性癌发育。该鼠标模型将用于确定是否 Atovaquone延迟了易感这种疾病的小鼠卵巢癌的发作。其他研究将调查卵巢和输卵管中可以用作的短期转录组变化在我们提出的临时临床试验窗口窗口中，其他探索性生物标志物。目标2。完成机会临床试验窗口，检查阿托夸酮对正常的影响接受计划的妇科手术的患者的输卵管和卵巢上皮。有资格的患者将是原定去除至少一个输卵管以进行良性适应症的女性。输卵管的基线细胞学采样将使用办公室宫腔镜检查。收集细胞可用于转录组分析。受试者将暴露于Atovaquone 25-35天之前操作。 MDA表达是抑制OXPHOS的标志物，将在Atovaquone暴露后测量确认其提出的作用机理。 p53和p53磷酸化的IHC表达将是执行。可以添加鼠标工作中的其他生物标志物。目标3。研究阿托瓦夸酮治疗的潜在障碍。 NRF-2化学抗性机制将探索与氧化磷酸化有关的。制定克服策略至关重要 NRF-2调节基因诱导的抗氧化机制，包括超氧化物歧化酶（MNSOD），过氧化氢酶和血氧酶-1（HO-1）。