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：
10813900
负责人：
Lisa M Barroilhet
金额：
$ 7.1万
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/10813900
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

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).

即使在高危人群中，使用筛查算法早期检测卵巢癌也是无效的。携带生殖系突变（例如 BRCA）的患者降低卵巢癌风险的选择有限，没有切除卵巢和输卵管。迫切需要新的方法来预防卵巢癌没有手术绝经的负面后果。抑制 OXPHOS 的药物，例如阿托伐醌，具有作为有效化学预防剂的潜力。 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来有效阻断 OXPHOS 的能力。目前阿托伐醌 FDA 批准用于治疗疟疾，是一种耐受性良好的口服药物。它会减慢卵巢功能癌症在体外和体内的生长并增加 p53 相关的细胞凋亡。假设：我们假设阿托伐醌会阻断氧化磷酸化，增加氧化应激，并可能激活 p53 介导的细胞凋亡，防止前体病变进展至卵巢基因工程小鼠模型中的癌症。目标 1. 检查阿托伐醌在延缓 OVGP1 小鼠卵巢癌发病方面的作用模型。 OVGP1 BPRN基因工程小鼠模型基于输卵管转化和模仿人类高级别浆液性癌的发展。该小鼠模型将用于确定是否阿托伐醌可延缓易患卵巢癌的小鼠的发病。额外的研究将研究卵巢和输卵管中观察到的短期转录组变化，这可以作为我们提议的机会之窗临床试验中的其他探索性生物标志物。目标 2. 完成机会之窗临床试验，检查阿托伐醌对正常人的影响接受计划的妇科手术的患者的输卵管和卵巢上皮。有资格的患者将是计划因良性症状而切除至少一根输卵管的女性。将使用办公室宫腔镜检查对输卵管进行基线细胞学取样。收集的细胞可用于转录组分析。受试者将在实验前接触阿托伐醌 25-35 天。可操作地。 MDA 表达是 OXPHOS 抑制的标志物，将在阿托伐醌暴露后进行测量确认其拟议的行动机制。 p53 和 p53 磷酸化的 IHC 表达将为执行。可能会添加来自我们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 化疗耐药机制将探讨与氧化磷酸化相关的因素。制定克服困难的战略至关重要 Nrf-2 调节基因诱导的抗氧化机制，包括超氧化物歧化酶 (MnSOD)、过氧化氢酶和血氧合酶-1 (HO-1)。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers.

阿托伐醌：一种在妇科癌症中研究的氧化磷酸化抑制剂。

DOI：
发表时间：
2022-05-05
期刊：
影响因子：
5.2
作者：
Kapur, Arvinder;Mehta, Pooja;Simmons, Aaron D;Ericksen, Spencer S;Mehta, Geeta;Palecek, Sean P;Felder, Mildred;Stenerson, Zach;Nayak, Amruta;Dominguez, Jose Maria Ayuso;Patankar, Manish;Barroilhet, Lisa M
通讯作者：
Barroilhet, Lisa M