My goals in participating in this Academy are to complete the research studies described in this proposal, be a participant in a structured mentorship program, establish contacts and collaborations with other Academy scholars who are likely to be the future leaders in ovarian cancer research, and establish relationships with the other mentor in the program to obtain advice, guidance, and advocates for other national opportunities. All of these assets of the Academy will help launch my career as an independent investigator, enhancing the likelihood of independent funding and productive collaborations.

The career development assets at the University of Alabama at Birmingham (UAB) are outstanding. Dr. Alvarez is an internationally recognized expert in translational research and gene therapy of gynecologic cancers, and has served on several national committees with influence in this arena. The Department of Obstetrics and Gynecology is committed to my career as a physician scientist, and is protecting my research time appropriately. UAB has a top Comprehensive Cancer Center, a structured Career Development program, and holds a Clinical and Translational Service Award. Departments of nationally recognized strength that would contribute specifically to this research project include Pathology and Cell Biology, and Biomatrix Engineering and Regenerative Medicine Center (examining biology of stem cells). This support and potential for institutional collaboration will enhance the likelihood of positive research, establishing a niche as a national expert in the field, and ultimately increase chances of independent funding.

Ovarian cancer is the fifth leading cause of cancer-related death in women. This is primarily due to a lack of effective screening methods and presentation at an advanced stage of disease. While the majority of patients will have an excellent initial response to therapy, most will recur and ultimately succumb to disease. The clinical course of ovarian cancer suggests that there is a subpopulation of cells that can survive initial therapies, lie dormant and undetectable, and later cause recurrence that ultimately is resistant to therapy. In many solid tumors, there is evidence that such a population can be identified, and is capable of recapitulating the original tumor. Such "cancer stem cells" (CSC's) or "tumor initiating cells" (TIC's) are more resistant to therapy and may represent those cells that cause recurrence. Data on whether or not such a population is present in ovarian cancer is limited, and is the focus of this proposal.

Based on our preliminary data, we believe that one of the markers that has defined a stem cell subpopulation in other cancers, aldehyde dehydrogenase-1 (ALDH1), may possess stem cell properties in ovarian cancer. Furthermore, we have seen that ALDH1-positive cells are associated with resistance to chemotherapy, and that knocking out ALDH1 can make them more susceptible to treatment. Therefore, we wish to study this population further.

This proposal has four primary goals: (1) Determine if the cells with increased ALDH1 activity have tumor-initiating or cancer stem cell properties, (2) determine if ALDH1 cells within the tumor microenvironment are those that survive initial chemotherapy and may be responsible for recurrence, (3) determine if targeting ALDH1 results in decreased tumor growth and increased chemosensitivity, and (4) determine the mechanisms involved in ALDH1's role in chemoresistance.

If our findings are confirmed, a treatment plan may be devised such that the population surviving initial chemotherapy might be specifically targeted to prolong remission rates or increase cures. The method of targeting ALDH1 is a novel clinically feasible approach that is about to begin Phase I trials, and therefore could be in clinical use within 5 years if data are promising. Additional data from this proposal will be valuable in that we may be able to better define the true chemoresistant population in tumors, and find additional biologic pathways on which they depend for survival. Such information may be used to develop additional therapies and improve outcomes in this devastating disease.