Targeting FoxM1 Pathway in Ovarian Cancer

Principal Investigator: CHIEN, JEREMY
Program: OCRP
Proposal Number: OC130492
Award Number: W81XWH-14-1-0116
Funding Mechanism: Pilot Award
Partnering Awards:
Award Amount: $339,750.00


One of the central problems in ovarian cancer is the treatment failure. Although addition of paclitaxel to cisplatin has significantly extended the overall survival of patients with ovarian cancer and led to a new standard of care, 6 out of 10 women with ovarian cancer succumb to the disease within 5 years from diagnosis, whereas only 1 out of 10 women with breast cancer will die from the disease within 5 years from diagnosis. Clearly, better drugs and combinations are needed to improve the outcome of patients with ovarian cancer.

Our studies will focus on enhancing our understanding and developing drugs and combinations that target two factors that are frequently altered in the most common subtype of ovarian cancer, high-grade serous ovarian cancer. TP53 gene, which produces the gene product called "p53," is mutated in 95% of high-grade serous ovarian cancer. FoxM1 protein is overexpressed in approximately 84% of high-grade serous ovarian cancer. Overexpressed proteins are frequently targeted for cancer treatment benefits. For example, Herceptin targets Her2 protein that is frequently overexpressed in breast cancer and Gleevec targets Abl protein that is frequently overexpressed in chronic myelogenous leukemia. Therefore, our studies will fundamentally address the relationship between two proteins, p53 and FoxM1, how this relationship can be disrupted to enhance the chemotherapy and prevent resistance to chemotherapy.

The proposed research is relevant to the vision of the Department of Defense Ovarian Cancer Research Program to "eliminate ovarian cancer" and the mission "to support research to detect, diagnose, prevent, and control ovarian cancer" because our studies are focused on improving treatment options that will control ovarian cancer and ultimately eliminate it from being a deadly cancer.

In the short-term, the proposed studies will investigate the effectiveness of drugs that target FoxM1 protein and whether these drugs enhance the effect of chemotherapeutic agents, cisplatin and paclitaxel. Moreover, we will investigate to understand the relationship between p53 and FoxM1 so that weaknesses in the relationship can be exploited for better treatment benefits.

In the long-term goal, if proven that targeting FoxM pathway enhances the effect of conventional chemotherapy, we will further develop new drugs that target this pathway. The lead institution, the University of Kansas, has built a nationally recognized program in drug discovery and development. In drug discovery, University of Kansas (KU) possesses national leadership in medicinal chemistry, securing $40 million in National Institutes of Health funding through the Roadmap program. In drug delivery, KU has held a formulation development contract with the National Cancer Institute since 1976, and has formulated eight of the last 17 cancer drug products advanced by NExT, including Taxol® and Velcade® drug products. We have the expertise, capacity, and resources to further develop drugs that target FoxM1 pathway in ovarian cancer. These studies will ultimately improve treatment options for patients with ovarian cancer and enhance the survival chance of patients with ovarian cancer from this deadly disease.