Iron, Ferroptosis and Ovarian Cancer

铁、铁死亡和卵巢癌

• 批准号: 10371385
• 负责人: Suzy V Torti
• 金额: $ 1.55万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371385
• 关键词: Antineoplastic Agents; Budgets; Cancer Etiology; Cancer Patient; Cell Death; Cells; Cessation of life; Epithelial ovarian cancer; Fostering; Funding; Goals; Grant; Growth; Homeostasis; Image; Imaging Techniques; Investigation; Iron; Knowledge; Laboratories; Lateral; Lead; Lipids; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Mediating; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Predisposition; Prognosis; Research; Resolution; Risk; Role; Signal Pathway; Signal Transduction; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrometry, Mass, Secondary Ion; Stage at Diagnosis; Study Section; Testing; Treatment Failure; Work; advanced disease; cancer cell; experimental study; improved; innovation; insight; novel; novel strategies; ovarian neoplasm; oxidation; oxidized lipid; palliative; response; successful intervention; tumor; tumor microenvironment

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.

概括 卵巢癌导致与美国任何其他妇科癌症相比，导致死亡更多。令人沮丧的进展 在过去的30年中，患有晚期疾病的患者几乎没有改变。需要新的方法。 在我的R01赠款中，标题为“铁，铁毒性和卵巢癌”，我们探索了铁在铁肉食中的作用，这是一种 铁介导的细胞死亡形式可能代表了靶向卵巢癌的新方法。虽然铁是 铁肉食的中心，对铁实际承认这种敏感性的认识知之甚少。在这笔赠款中，我们测试了 铁在铁凋亡中扮演关键，新颖和以前未描述的作用的假设，而新的目标 在我们最近发现的铁铁病途径中，可能会导致卵巢癌的成功干预。 我们用两个广泛的物体解决了这个问题：1）更好地了解铁在铁凋亡中的作用； 2） 确定可以通过促进促侵蚀性来增强促氧诱导剂活性的特定靶标 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的。这些特定的目标和预算以实现这些目标 已由研究部分批准，并在第三个百分点中给予了优先评分。然而， 出于行政原因，预算随后降低了50％以上，因此很难 进行提案中描述的实验。特别是，AIM 2和3C中描述的实验是 由于资金有限而有未能完成的风险。在AIM 2中，我们使用最先进的高方面分辨率 次级离子质谱（Nanosims）成像和MALDI-MSI，以探测 铁毒性死亡信号，与氧化的脂质的氧化脂质共定位，这些脂质的氧化脂质。在AIM 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影响的药物的反应 通过将这些相同的成像技术应用于肿瘤，铁凋亡。这些实验的结果至关重要 为了这项研究的主要目的：对铁在卵巢癌中的作用的精确理解 与铁毒性影响者。这种补充剂将使我们能够按照最初提出的实验进行这些实验。 我们认为，这项工作最终可能有助于改善卵巢癌患者的治疗选择。