DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Integrative Functional Genomics and Proteomics to Uncover Mechanisms of Resistance to Chemotherapy in Ovarian Cancer

Principal Investigator: CHIEN, JEREMY
Institution Receiving Award: KANSAS, UNIVERSITY OF, MEDICAL CENTER, KANSAS CITY
Program: OCRP
Proposal Number: OC093413
Award Number: W81XWH-10-1-0386
Funding Mechanism: Ovarian Cancer Academy┬┐Early-Career Investigator/Designated Mentor
Partnering Awards:
Award Amount: $1,095,316.15


PUBLIC ABSTRACT

The main cause of death associated with ovarian cancer is the treatment failure of advanced disease as a consequent of the acquired resistance to chemotherapy. Although the majority of ovarian cancer patients initially respond to chemotherapy, the majority will eventually experience relapse and become refractory to the standard treatment of carboplatin and paclitaxel. Multiple factors are thought to contribute to the resistance of tumor cells to chemotherapy; however, particular genes and biological pathways associated with resistance to chemotherapy in ovarian cancer are poorly understood.

My long-term career goal is to identify altered genes and biological pathways that contribute to the resistance of ovarian cancer cells to chemotherapy. I plan to accomplish this goal by combining various technologies that allow us to identify altered gene expression and protein function in a high-throughput manner. First, we will identify altered gene expression in ovarian tumor cells, tumor-associated stroma, and immune cells. These genomic studies will allow us to identify important genes and biological pathways that are associated with resistance to chemotherapy in ovarian cancer and will allow us to test the significant contributions of these alterations in association with cancer cell resistance to chemotherapy. We expect that knowledge gained from these studies will ultimately allow us to identify patients who will benefit from standard chemotherapy or targeted therapies, and will provide the foundation for individualizing medicine to each ovarian cancer patient.

In my second approach, I will identify factors that enhance chemotherapy-induced cell death. Considering that most chemotherapeutic agents produce the desired therapeutic effect by inducing cell death programs in cancer cells, it is important to understand the factors that enhance cancer cell death. Cancer cell death is mediated by proteases that degrade cellular proteins and bring about the demise of cancer cells. Therefore, in my second approach, I will identify some of the proteases that are activated during chemotherapy-induced cell death. We will use a recently developed activity-based protein profiling technique to identify serine proteases that are involved in chemotherapy-induced cell death. We expect that knowledge gained from these studies will allow us to identify vulnerable targets in cancer cells that, when targeted, will lead to enhanced sensitivity of cancer cells to chemotherapy. Ultimately, the results from our studies will contribute to a better understanding of biological pathways associated with chemotherapy-induced cell death and are expected to provide us with novel targets to enhance chemotherapy.