Ovarian cancer is the fifth-most lethal cancer and deadliest of any gynecological cancer in the United States. The most common treatment for ovarian cancer is the removal of tumors, followed by platinum-based chemotherapy. Unfortunately, even when the treatment is successful, most patients relapse and experience resistance to chemotherapy. Thus, resistance is the major contributing factor to the 35% 5-year cancer survival rate. To combat this lethal disease, we must discover how to increase the sensitivity of cancer cells to platinum-based chemotherapy.
An ideal anti-cancer agent will target a pathway that is altered in cancer, produce selective cytotoxic response in cancer cells, induce immunogenic cell death, and enhance tumor immunity. We believe that targeting the FoxM1 gene with thiostrepton could produce this ideal anti-cancer agent. FoxM1 is demonstrated to have a role in DNA repair, cell proliferation and chemotherapy resistance, has increased expression in 84% of malignant tumors, and it may contribute to cancer progression, but it has not been fully investigated as a drug target for ovarian cancer. Therefore, this study aims to 1) define how FoxM1 inhibitors impact cancer cell immunity and 2) determine the effect of FoxM1 inhibitors on carboplatin sensitivity.
The first goal of this proposal will assess how inhibiting FoxM1 will impact the immunity of cancer cells, which is a new and promising area of research. By altering the immune response, cancer cells can become more sensitive to chemotherapy. The FoxM1 inhibitor thiostrepton has demonstrated the ability to affect genes involved in cancer cell immunity but these results need to be validated in a mouse model. To confirm the effect and to evaluate the immunotherapeutic potential of thiostrepton, mice seeded with tumors will be treated with thiostrepton and the immune profile will be evaluated and compared to control-treated mice.
The second proposal goal will address the need to enhance cancer cell sensitivity to carboplatin by identifying the changes in DNA repair and cell death processes induced by the FoxM1 inhibitors in order to gain insight into their mechanism of action. We will test this with two groups of mice, one being treated with thiostrepton before tumor formation and the other group will receive treatment, thiostrepton alone and in combination with chemotherapy, after the tumors have been established. These two experiments will determine mechanism and effectiveness of thiostrepton to alter cancer onset, progression and regression.
Collectively, the studies proposed will define the newly uncovered FoxM1 pathway in ovarian cancer by characterizing the role of FoxM1 in the immune response of cancer cells and determining the mechanism by which FoxM1 inhibitors enhance carboplatin sensitivity in preclinical and cancer cell lines.
This grant was made possible by a generous donation from Newk’s Cares, and Ovarian Cycle Jackson, Mississippi.
Jill Madden, Ph.D. is a postdoctoral fellow in the lab of Dr. Jeremy Chien at the University of Kansas Medical Center, Department of Cancer Biology. Dr. Madden earned her Bachelor of Science degree in Genetics at Iowa State University where she continued her education to earn a Ph.D. in Genetics with a minor in Toxicology. Under the mentorship of Dr. Aileen Keating, her Ph.D. dissertation focused on determining the mechanism of ovarian follicle death induced by the chemotherapy drug cyclophosphamide, specifically evaluating the role of xenobiotic metabolism and autophagy. Currently, Dr. Madden is investigating the therapeutic potential of targeting the TP53-FoxM1 axis in ovarian cancer and the molecular mechanisms by which FoxM1 inhibitors enhance sensitivity to carboplatin in ovarian cancer. Dr. Madden was also a recipient of the 2015 University of Kansas BIRCWH (Building Interdisciplinary Research Careers in Women’s Health) K12 Postdoctoral Fellowship Award.