Iron, Ferroptosis and Ovarian Cancer

摘要 在美国，卵巢癌是导致死亡人数最多的妇科癌症。令人沮丧的预后 在过去的30年里，晚期疾病患者的变化仍然很小。需要新的方法。 在我的R01拨款中，题为“铁、铁性下垂和卵巢癌”，我们探讨了铁在铁性下垂中的作用，以及 铁介导的细胞死亡形式，可能代表了一种新的靶向卵巢癌的方式。虽然铁是 铁下垂的核心是铁，人们对铁实际上是如何赋予这种易感性的知之甚少。在这笔赠款中，我们测试了 假设铁在铁下垂中扮演着关键的、新颖的和以前未描述的角色，以及新的靶点 在我们最近发现的铁下垂途径中，可能会导致对卵巢癌的成功干预。 我们处理这个问题有两个广泛的目标：1)更好地了解铁在铁性下垂中的作用；2) 确定通过培养前铁下垂来增强铁下垂诱导剂活性的特定靶点 卵巢癌自身和卵巢癌微环境中的信号转导通路。 我们的具体目标就是针对这些目标。这些具体目标和实现这些目标的预算 经研究科批准，赠款被给予第三个百分位数的优先分数。然而， 由于行政原因，预算后来削减了50%以上，使其非常难以 进行提案中描述的实验。特别是，目标2和目标3C中描述的实验是 由于资金有限，有可能无法完成。在目标2中，我们使用了最先进的高横向分辨率 二次离子质谱仪(NanoSIMS)成像和MALDI-MSI探测原产地 铁下垂的死亡信号，铁与氧化的脂类共同定位，这是铁下垂的典型特征。在目标3中，我们评估 卵巢肿瘤微环境中的细胞如何改变卵巢癌对诱导化疗药物的反应 通过将这些同样的成像技术应用于肿瘤来治疗铁性下垂。这些实验的结果是至关重要的 这项研究的主要目标是：准确了解铁在卵巢癌治疗中的作用 使用铁性下垂诱导剂。这份补充材料将允许我们按照最初的提议进行这些实验。 我们相信，这项工作最终可能有助于改善卵巢癌患者的治疗选择。

Summary Ovarian cancer causes more deaths than any other gynecologic cancer in the US. The dismal prognosis of patients with advanced disease remains little changed in the past 30 years. New approaches are needed. In my R01 grant, entitled “Iron, Ferroptosis and Ovarian Cancer” we explore the role of iron in ferroptosis, an iron-mediated form of cell death which may represent a new way to target ovarian cancer. Although iron is central to ferroptosis, little is known about how iron actually confers this susceptibility. In this grant, we test the hypothesis that iron plays critical, novel, and previously undescribed roles in ferroptosis, and that new targets in the ferroptosis pathway that we recently discovered might lead to successful interventions in ovarian cancer. We approach this problem with two broad objectives: 1) to better understand the role of iron in ferroptosis; 2) to identify specific targets that will enhance the activity of ferroptosis inducers by fostering pro-ferroptotic pathways both in ovarian cancers themselves and in the ovarian cancer microenvironment. Our Specific Aims are directed at these goals. These Specific Aims and the budget to achieve these Aims were approved by the Study Section and the grant was given a priority score in the 3rd percentile. However, for administrative reasons, the budget was subsequently reduced over 50%, making it exceedingly difficult to carry out the experiments described in the proposal. In particular, experiments described in Aim 2 and 3C are at risk of not being completed due to limited funding. In Aim 2, we use state-of-the-art high-lateral resolution secondary ion mass spectrometry (NanoSIMS) imaging and MALDI-MSI to probe the sites of origin of the ferroptotic death signal, co-localizing iron with the oxidized lipids that typify ferroptosis. In Aim 3, we assess how cells in the ovarian tumor microenvironment modify the response of ovarian cancers to drugs that induce ferroptosis by applying these same imaging techniques to tumors. Results from these experiments are critical to the major objective of this research: a precise understanding of the role of iron in ovarian cancers treated with ferroptosis inducers. This supplement will allow us to carry out these experiments as originally proposed. We believe this work may ultimately contribute to improved treatment options for ovarian cancer patients.