The overall goal of this research proposal is to gain a deeper level of understanding of the signaling pathways and mechanisms that govern the development of platinum resistance in ovarian cancer. A deeper level of understanding for how platinum resistance develops is necessary in the field of ovarian cancer research as this is a common occurrence in patients with ovarian cancer and it prevents clinical effectiveness. To date, efforts at preventing the acquisition of platinum resistance have been limited due to lack of knowledge on the mechanism for how it develops;while efforts to reverse platinum resistance after it has already developed have only shown partial response rates. This research project is to serve as a 5 year career development plan for Dr. Samudio-Ruiz to transition from post doctoral fellow to research assistant professor with the long term goal of becoming tenure track faculty. Specific training in additional techniques related to molecular biology and epigenetics will prepare Dr. Samudio-Ruiz for a successful career in biomedical research with particular focus on cancer and epigenetics research. Additional training in clinical and translational research will allow Dr. Samudio-Ruiz to disseminate information gathered from basic biomedical research to clinical applications;thus, potentially advancing the efforts of ovarian cancer treatment in the clinic. This significantly coincides with the National Cancer Institute's goal of supporting research that could lead to the advancement of cancer treatment. The location for this work is the University of New Mexico (UNM) which is known for its commitment to cancer research, specifically women's cancer research, as a whole as it is the state's only National Cancer Institute-designated cancer center and the Official Cancer Center of the State of New Mexico. UNM offers a supportive environment where investigators can take advantage of several shared resources through the UNM Cancer Research and Treatment Center (CRTC) which Dr. Samudio-Ruiz will take full advantage of. The proposed research will evaluate epigenetic mechanisms, specifically DNA methylation, and its role in the development of platinum resistance in ovarian cancer. Particular focus will be paid to the Epidermal Growth Factor Receptor (EGFR) as Dr. Samudio-Ruiz recently found a link between EGFR and DNA methylation and that work was just accepted for publication. The overall research design is to generate an in vitro model of platinum resistance to evaluate changes in DNA methylation associated with the development of platinum resistance and determine if inhibition of the EGFR can prevent development of resistance. Data generated from the in vitro model will also be confirmed in human tissue samples both before and after the development of platinum resistance;thus setting up future experiments that can be taken to in vivo and eventually clinical models.
A significant number of women diagnosed with ovarian cancer will have poor outcomes due to the fact that a large majority of them will acquire platinum resistance following primary treatment with platinum based chemotherapeutic agents. Considerable efforts are currently being made in the attempt to reverse platinum resistance, but not enough efforts are being made to understand the development of resistance so that we can prevent it from occurring in the first place. The proposed research intends to evaluate the mechanism behind the development of platinum resistance with the long term intent of targeting that mechanism in clinical trials so that the development of platinum resistance is eliminated in ovarian cancer patients.