Dr. Melissa Fath is currently 100% supported by the program project grant entitled ?Exploiting Redox Metabolism Using Pharmacological Ascorbate (P-AscH?) for Cancer Therapy? (P01 CA217797). The theme of this P01 is exploiting cancer cell redox metabolism using pharmacological ascorbate (P-AscH-; high dose intravenous vitamin C) for improving cancer therapy. The P01 is composed of 3 major research projects and 3 core facilities. The proposal is highly integrated and focused on preclinical, translational and clinical studies relevant to the use of P-AscH? in cancer therapy and Dr. Fath's research will impact all three of the research projects and two of the cores. This R50 application proposes 100 % salary support for Dr. Fath to support all the projects and two cores in the P01 research program as well as any new research initiatives funded by NCI that may arise from that work. The Unit Director of the current proposal, Dr. Douglas Spitz, is part of the multi- PI leadership team as well as the principle investigator on Project 2, ?Exploiting Labile Iron Pools for Improving NSCLC Therapy Using Pharmacological Ascorbate?. Specifically Project 2 in the P01 will test the hypothesis that P-AscH? selectively sensitizes non-small cell lung cancers to radiation and chemotherapy by selectively increasing cancer cell steady-state levels of H2O2 as a result of specific disruptions in redox-active iron metabolism mediated by endogenous levels of O2.-/H2O2 . The Free Radical and Radiation Biology Program (FRRBP) in the Department of Radiation Oncology at the University of Iowa is an ideal scientific environment for this proposed research because of its historic roots in radiation biology as well as the free radical theory of cancer in association with a strong Radiation Oncology Department. Dr. Spitz is the division director of FRRBP and Dr. Fath is an associate research scientist that has been an active collaborative member for over 10 years. Dr. Fath has considerable expertise in testing the involvement of free radicals, thiol oxidation, redox sensitive signaling pathways, and oxidative damage end-points in many studies exploiting manipulations of redox metabolism to repurpose drugs for cancer therapy. Her background and training in Clinical Pharmacy, Medicinal & Natural Products Chemistry, and Free Radical Cancer Biology make her ideally suited to work in this highly collaborative and integrated group doing both in vitro and in vivo translational research as well as supporting clinical trials. Dr. Fath will focus on the redox biology of O2- and H2O2 as well as the involvement of Fe metabolism in the differential effects of that mediate P-AscH- induced radio-chemotherapy sensitization. She will quantify radio-chemo- sensitization, measure steady-state H2O2, study and manipulate labile iron pools using both pharmacological and genetic approaches, and assess oxidative stress, and DNA damage endpoints in cancer treatment models. In addition, Dr. Fath will be responsible for measuring biomarkers of oxidative stress in the clinical trials and determining if they correlate to clinical responses. It is clear that Dr. Fath's experience and expertise is invaluable to P01 CA217797 and she is well-qualified as a candidate for the P50 award mechanism.
Intravenous dosing of pharmacological levels of ascorbate has recently remerged as a redox active agent that enhances lung, glioblastoma, and pancreatic cancer cell responses to radiation and chemotherapy without increasing toxicity to normal cells. As pharmacological ascorbate advances through clinical trials it is important that we thoroughly understand the mechanisms involving metabolic oxidative stress and redox active metal ions that account for the selective sensitization of cancer cells to radio-chemo-therapy. Dr. Fath's research and expertise will help build the knowledge base in an active NCI P01 grant in order to identify novel mechanisms that can be exploited to capitalize on the use of pharmacological ascorbate in cancer therapy.