Iron, Ferroptosis and Ovarian Cancer

总结

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.