DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Investigation of Human Prostate Cancer Progression and Treatment Response Using a Novel Genetically Engineered Culture Model

Principal Investigator: TOIVANEN, ROXANNE
Institution Receiving Award: COLUMBIA UNIVERSITY
Program: PCRP
Proposal Number: PC131821
Award Number: W81XWH-14-1-0276
Funding Mechanism: Postdoctoral Training Award
Partnering Awards:
Award Amount: $124,200.00


PUBLIC ABSTRACT

My Prostate Cancer Research Program Postdoctoral Training Award application outlines a comprehensive training plan for my early career in prostate cancer research. I am a passionate prostate cancer researcher with a primary career goal of establishing my own independent laboratory at an academic institution in order to study prostate cancer progression to discover more effective therapies for this disease.

My mentor, Dr. Michael Shen, is a leader in the prostate research field and has extensive experience with training young independent researchers. Under his direction, I will learn the latest methodologies to study cancer biology as well as intellectual skills that will be essential for running a successful prostate cancer research laboratory. Furthermore, this training will take place at the Herbert Irving Comprehensive Cancer Center of Columbia University Medical Center, an intellectually stimulating and collaborative medical research facility. Here, I will be immersed in an environment of world-renowned cancer biologists, where I will undertake further training from research collaborators Drs. Andrea Califano and Ketan Badani and will actively participate in meetings, journal clubs, seminars, and conferences.

As described in my proposal, I will conduct a highly innovative study that has the ultimate goal of improving outcomes for patients suffering from prostate cancer. I will develop and test a novel experimental model of prostate cancer that will enable scientists to more accurately screen for more effective therapies. Current experimental models of prostate cancer are limited in their number and their ability to accurately mimic the disease, and consequently candidate prostate cancer therapies lag in their progression to clinical trials. In particular, prostate tumors vary in their aggressiveness and response to individual therapies, but current experimental model systems do not recapitulate this tumor diversity. To establish an experimental model system that can overcome these issues, I will pursue two main objectives:

(1) Establish a prostate cancer "organoid" culture model derived from human patient tissues, which is genetically engineered to recapitulate the diverse biology of prostate tumors. Previously, it has been difficult to establish patient prostate cancer cells in two-dimensional culture, but my mentor, Dr. Shen, has recently devised a method to reliably culture prostate cancer cells using a three-dimensional method called organoid culture. In this study, I will establish organoid cultures from prostate cancer patients and then engineer these organoid lines to create the precise genetic alterations that often correlate with poor outcomes.

(2) Evaluate the response of organoid cultures to a panel of prostate cancer therapies. Establishing a culture model that accurately mimics prostate cancer diversity will provide a valuable resource to determine which therapies are most beneficial against tumors with specific genetic alterations. Therefore, both engineered and non-engineered organoid lines will undergo treatment with a panel of prostate cancer drugs to evaluate the effectiveness of each treatment on a particular patient or genetic alteration.

In summary, this proposal will establish an innovative experimental prostate cancer model to study disease progression and treatment response. The findings of this study will be ultimately beneficial for patients that require treatment for prostate cancer, particularly those who fail first-line therapies. Currently, patients diagnosed with prostate cancer are subjected to treatments that are the standard of care for all patients. My study is novel because it will provide a predictive model of which therapies should be the most successful for each patient, according to their tumor characteristics. In principle, these findings should have significant clinical applications, since they would provide a foundation for the use of precision medicine, where patient treatment regimens are tailored to their biological profile, thereby improving the likelihood of treatment success. Ultimately, completion of the proposed study should lead to the development of clinical trials to determine whether the predicted treatment regimens based on organoid cultures can correlate with patient treatment outcomes. Therefore, my proposed research has the potential to directly affect prostate cancer patient outcomes by identifying optimal treatment regimes that can extend patient lives.