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

即使在高危人群中，使用筛查算法进行卵巢癌的早期检测也是无效的。 携带生殖系突变的患者，如BRCA，降低卵巢癌风险的选择有限， 没有切除他们的卵巢和输卵管。迫切需要新的方法来预防 卵巢癌无手术绝经的负面后果。 抑制OXPHOS的药物，如阿托瓦酮，有可能成为有效的化学预防药物。 阿托瓦酮是一种线粒体复合体III抑制剂。来自我们实验室的初步数据支持阿托瓦酮 通过干扰线粒体电子传递有效阻断OXPHOS的能力。阿托瓦酮目前 FDA批准用于治疗疟疾，是一种耐受性良好的口服药物。它会减缓卵巢的速度 肿瘤在体外和体内的生长并增加与P53相关的细胞凋亡。 假设：我们假设阿托瓦酮会阻止氧化磷酸化，增加氧化应激， 并潜在地激活P53介导的细胞凋亡，防止前驱病变进展到卵巢 基因工程小鼠模型中的癌症。 目的1.研究阿托瓦酮在延缓OVGP1小鼠卵巢癌发病中的作用 模特。OVGP1 BPRN基因工程小鼠模型是基于输卵管转化和 模仿人类高级别浆液性癌的发展。这个老鼠模型将被用来确定 阿托瓦酮可延缓易患卵巢癌小鼠卵巢癌的发病。其他研究 将研究卵巢和输卵管中的短期转录组变化，这可能是 在我们提议的机会之窗临床试验中增加了探索性生物标志物。 目的2.完成一次机会窗临床试验，检查阿托瓦酮对正常人的影响 妇科计划手术患者的输卵管和卵巢上皮。合资格 患者将是计划切除至少一条输卵管的良性指征的女性。 输卵管的基线细胞学采样将使用办公室宫腔镜检进行。收集的单元格 可用于转录组分析。受试者将在试验前25-35天内接触阿托瓦酮。 从操作上讲。阿托瓦酮对OXPHOS抑制的标志物--丙二醛的表达将在阿托瓦酮作用后被检测 以确认其拟议的行动机制。P53和P53磷酸化的IHC表达将是 已执行。可能会添加来自我们鼠标工作的其他生物标记物。 目的3.研究阿托瓦酮治疗的潜在障碍。NRF-2耐药机制的研究进展 与氧化磷酸化有关的内容将会被探讨。至关重要的是制定战略来克服 NRF-2调控基因诱导的抗氧化机制，包括超氧化物歧化酶(MnSOD)， 过氧化氢酶和血氧合酶-1(HO-1)。

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).