Dr. Fath’s research and career development activities have focused on exploiting metabolic differences between cancer cells and normal cells to develop new therapeutic regimens that selectively kill cancer. More specifically it has been shown that tumor cell mitochondria produce greater levels of O2·- and H2O2 relative to normal cells. Compared to normal cells, cancer cells also appear to have increased labile transition metals (Fe and Cu) that participate in oxidation reactions. It has been suggested that the intracellular reactive oxygen species and redox status is a critical factor regulating stem cell self-renewal and cancer stem cell resistance to radiation. Currently Dr. Fath’s research is focused on using small molecules (pharmacological ascorbate, disulfiram and D-penicillamine) that generate reactive oxygen species in the presence of transition metal ions as a means of defeating the mechanism in which neuroendocrine tumor cells of the lung and pancreas use to evade traditional therapy. Given the translational nature of her research, she has a strong interest in moving her work from bench to bedside, and she has been involved in a number of translational projects.
Papers investigating the use of 2-deoxy-D-glucose to enhance responses of traditional chemotherapy and radiation in colon, lung and head and neck cancers both in vitro and in mouse xenograft models.
- Simons AL, Fath MA, Mattson DM, Smith BJ, Walsh SA, Graham MM, Hichwa RD, Buatti JM, Dornfeld K, and Spitz DR: Enhanced response of human head and neck cancer xenograft tumors to cisplatin combined with 2-deoxy-D-glucose correlates with increased 18F-FDG uptake as determined by PET imaging. Int J Rad Oncol Biol Phys 2007; 69:1222-1230. PMID 17967311.
- Simons AL, Parsons AD, Foster KA, Orcutt KP, Fath MA and Spitz DR: Inhibition of glutathione and thioredoxin metabolism enhances sensitivity to perifosine in head and neck cancer cells. J Oncol 2009:519563. PMID 19746172.
- Fath MA, Diers AR, Aykin-Burns N, Simons AL, Hua L, and Spitz DR: Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells. Cancer Biol Ther 2009; 8:1228-1236. PMID 19411865.
- Papers investigating the interaction of the glutathione and thioredoxin pathways and the effects of inhibiting these pathways in head and neck, lung, breast and pancreatic cancer cells and using inhibitors of the thioredoxin and glutathione pathways to enhance standard chemotherapy and radiation in cells both in vitro and in vivo.
- Fath MA, Ahmad IM, Smith CJ, Spence J, and Spitz DR: Enhancement of carboplatin-mediated lung cancer cell killing by simultaneous disruption of glutathione and thioredoxin metabolism. Clin Cancer Res 2011; 17:6206-6217. PMID 21844013.
- Simons AL, Parsons AD, Foster KA, Orcutt KP, Fath MA and Spitz DR: Inhibition of glutathione and thioredoxin metabolism enhances sensitivity to perifosine in head and neck cancer cells. J Oncol 2009:519563. PMID: 19746172.
- Hrabe JE, O'Leary BR, Fath MA, Rodman SN, Button AM, Domann FE, Spitz DR, Mezhir JJ: Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor β-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells. Redox Biol 2015 Aug 5:319-27. PMID: 26114584
- Li L, Fath MA, Scarbrough PM, Watson WH, Spitz DR. Combined inhibition of glycolysis, the pentose cycle and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer. Redox Biol 2014 Dec 10;4C:127-135 PMID 25560241
Papers investigating the effects of oxidative stress in breast and other cancer stem cells.
- Wegman-Points LJ, Teoh-Fitzgerald ML, Mao G, Zhu Y, Fath MA, Spitz DR, Domann FE. Retroviral-infection increases tumorigenic potential of MDA-MB-231 breast carcinoma cells by expanding an aldehyde dehydrogenase (ALDH1) positive stem-cell like population. Redox Biol 2014; 2:847-54. PMID:25009786
- Rodman SN III, Spence J, Ronnfeldt TJ, Zhu Y, Xiangming G, Spitz DR, and Fath MA: Enhancement of radiation response by simultaneous inhibition of thioredoxin and glutathione dependent metabolism. Radiation Res 2016; (In Press)
- Sciegienka SJ, Solst SR, Falls KC, Schoenfeld JD, Klinger AR, Ross NL, Rodman SN, Spitz DR, Fath MA. D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H(2)O(2)-mediated oxidative stress. Free Radic Biol Med. 2017 Jul;108:354-361. doi: 10.1016/j.freeradbiomed.2017.04.001. Epub 2017 Apr 5. PubMed PMID: 28389407; PubMed Central PMCID: PMC5495544
Papers investigating using ketogenic diet to enhance tradition chemotherapy and radiation in mouse models of lung, pancreatic and head and neck cancer types.
- Fath MA, Simons AL, Erickson J, Anderson ME, and Spitz DR: Enhancement of cancer therapy using ketogenic diets in Oxidative Stress in Applied Basic Research and Clinical Practice: Oxidative Stress in Cancer Biology and Therapy (Spitz, Gius, Krishnan, Dornfeld, editors) Humana Press, New York, NY pp. 47-58, 2012.
- Allen BG, Bhatia SK, Buatti JM, Brandt KE, Lindholm KE, Button AM, Szweda LI, Smith BJ, Spitz DR, Fath MA. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clin Cancer Res 2013; 19(14):3905-13. PMID: 23743570
- Allen BF, Bhatia SK, Anderson CM, Eichenberger Gilmore JM, Sibenaller ZA, Mapuskar KA, Schoenfeld JD, Buatti JM, Spitz DR, Fath MA. Ketogenic diets as adjuvant cancer therapy: History and potential mechanism. Redox Biol 2014; Aug 7, 2C:963-970 PMID: 25460731
- Zahra A, Fath MA, Opat, E, Bhatia, SK, Eichenberger-Gilmore JM, Chenard CA, Bodeker, K, Ahmann L, Vollstedt S, Brown H, Abu Hejleh T, Clamon GH, Berg DJ, Spitz DR, Buatti JM, and Allen BG Consuming a ketogenic diet while receiving radiation and chemotherapy for locally advanced lung and pancreas cancer: the University of Iowa experience of two phase I clinical trials. Radiation Res submitted