Papillary serous ovarian cancer is among the five most lethal cancers affecting women in the U.S. While ovarian cancers initially respond well to chemotherapy involving platinum and taxol-based agents, most cancers eventually recur as platinum-resistant disease that is no longer amenable to currently available chemotherapeutic drugs. Therefore, ovarian cancer progression and acquired drug resistance are intricately linked processes, and many of the genes that promote cancer growth have also been implicated in drug resistance. Understanding the molecular mechanisms involved in acquired drug resistance is paramount to the design of novel therapies that target the genes maintaining drug resistance. Here, we propose to study tumor evolution under the selection pressure of chemotherapy in a mouse model of ovarian cancer. Human ovarian cancers will be propagated in mice and exposed to conventional chemotherapy or targeted therapy. The goal is to select for cancer cells that become resistant to the given chemotherapeutic agent. Using molecular profiling techniques, we will then compare the resulting tumors from different treatment groups to each other and to the original specimen, in order to identify genetic events that occurred during the drug selection process. Specific genes that become activated during tumor evolution will be characterized in the context of drug resistance and tumor progression. Finally, we will assess if the activation of novel drug resistance genes correlates with clinical parameters, such as survival. Taken together, we hope that these studies will contribute to the molecular understanding of ovarian cancer and help translate this knowledge into clinical applications.
This grant was made possible in part through a generous donation from OCRF Board member Susie Fragnoli.