Iron, Ferroptosis and Ovarian Cancer

总结 在美国，卵巢癌导致的死亡人数比任何其他妇科癌症都多。的悲观预测 在过去的30年里，晚期疾病患者的情况几乎没有变化。需要采取新的办法。 在我的R 01资助项目中，题为“铁、铁凋亡和卵巢癌”，我们探讨了铁在铁凋亡中的作用， 铁介导的细胞死亡形式，这可能是一种新的方式来靶向卵巢癌。虽然铁是 对于铁凋亡的核心，人们对铁如何实际赋予这种易感性知之甚少。在这份补助金中，我们测试了 假设铁在铁凋亡中起着关键的、新颖的和以前未描述的作用， 我们最近发现的铁凋亡途径可能会导致卵巢癌的成功干预。 我们的研究有两个主要目的：1）更好地了解铁在铁细胞凋亡中的作用; 确定通过促进促铁凋亡而增强铁凋亡诱导剂活性的特定靶点， 在卵巢癌本身和卵巢癌微环境中的途径。 我们的具体目标是针对这些目标。这些具体目标和实现这些目标的预算 获得了研究科的批准，并且补助金获得了第三百分位数的优先分数。然而，在这方面， 由于行政原因，预算随后被削减了50%以上， 进行提案中所述的实验。特别地，在目标2和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，我们使用最先进的高横向分辨率 二次离子质谱（NanoSIMS）成像和MALDI-MSI来探测肿瘤的起源位点。 铁凋亡死亡信号，与代表铁凋亡的氧化脂质共定位铁。目标3：评估 卵巢肿瘤微环境中的细胞如何改变卵巢癌对药物的反应， 通过将这些相同的成像技术应用于肿瘤。这些实验的结果至关重要 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。 用铁凋亡诱导剂这一补充将使我们能够按照最初的建议进行这些实验。 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.