My primary career goal is to become an independent and successful ovarian cancer research faculty. With the help of this grant, I can realize this goal in the next 5 years. I aim to develop physiologically relevant in vitro three-dimensional (3D) models of ovarian cancers for the efficient screening of novel ovarian cancer therapeutics. The current in vitro 2D models used for culturing ovarian cancer cells and their preclinical testing are inadequate, as they do not reflect ovarian cancer physiology. I am proposing a high-throughput 384 hanging drop array platform to generate and maintain spheroids from human patient derived ovarian cancer and ovarian cancer stem cells (OvCSC). OvCSC represent a small proportion of cancer cells that are believed to be responsible for resistance to chemotherapy regimens, and ultimately the cause of cancer recurrence. To address the non-physiologic nature of 2D culture to predict therapeutic responses of CSC, I am creating a 3D long-term spheroid array platform. This model can be tested with both patient total cancer cells and OvCSCs. This model will be utilized to evaluate the efficacy of patient-derived OvCSCs against new chemotherapy regimens and to accurately predict response of these therapeutics in mouse model of human ovarian cancers.

I have a successful record of productive research in biomedical engineering and tissue engineering. I would like to apply this training and research experience in developing 3D platforms to ovarian cancer, a deadly disease for which we have made limited therapeutic progress. I would like to focus on the study of ovarian cancer given the extreme challenge of the disease, and the physiologic relevance of our model to ovarian cancer; since cancer cells can be found growing in tumor spheres of the ascites of ovarian cancer patients. In order to achieve my goal of becoming an independent ovarian cancer researcher, I have established a mentoring team comprised of Drs. Ronald Buckanovich, Shuichi Takayama, Daniel Hayes, and Max Wicha. I have also identified key short- and long-term goals that will serve as important milestones for my progress towards an independent tenure track faculty position.

This project will allow me the opportunity to expand my knowledge of ovarian cancer biology and will greatly enhance my personal experience and practical skills by working with human primary ovarian cancer tissue. Further, this work will also provide critical hands-on experience with murine models of ovarian cancer, which are essential for confirming in vivo therapeutic responses. Finally, collaborations within the Ovarian Cancer Academy will allow us to expand our study platform to other areas of ovarian cancer biology.

To fortify my knowledge in gynecologic oncology, I will enroll in courses at the University of Michigan, apply for AACR translation biology conference Translational Cancer Research for Basic Scientists, and attend workshops and conferences relevant to my proposed research plan. I will also present my work at national scientific meetings that cater to research in ovarian cancers and/or biomedical engineering. Together, Drs. Buckanovich and Takayama will evaluate my progress with respect to achievements needed to obtain and succeed as an independent ovarian cancer researcher. With this career development plan in place, I am confident that I will launch a long and sustained career as an independent ovarian cancer researcher.

This proposal forges a critical collaboration between a biomedical engineer and an established ovarian cancer researcher to develop a high-throughput 3D in vitro model for long-term growth of primary patient tumor-derived spheroids. The platform to be developed in this proposal has a wide potential for use in the study of ovarian cancer stem cells, basic biology, physiology, and ultimately therapeutic development. I anticipate future research projects in the ovarian cancer realm in my lab that will utilize the platform described in this proposal. The results of our proposed research have a great potential for creating individualized therapy catering to the unique needs of each ovarian cancer patient. The ultimate goal of our work is a clinical trial directly assessing the ability of our platform to predict patient response to therapy, with the hope of ultimately being able to individualize ovarian cancer therapy. Since we will be screening drug combinations that target OvCSC specifically, we will also reduce the risk of cancer relapse. Additionally, using targeted drugs that are effective for a particular patient, will remove the potential side effects of ineffective drugs. Therefore, with targeted and individualized therapies against patient OvCSC, we will work towards eliminating ovarian cancers.