My career goal is to be a physician-scientist who is a leading mind in the development and use of new cancer drugs known as signal transduction inhibitors (STIs) in the treatment of advanced prostate cancer (CaP). This goal requires that I be a physician with expertise in the design, execution, and interpretation of clinical studies in CaP and a scientist with a firm command of CaP biology particularly in the area of molecular signaling. I plan to head a research team focused upon clinical studies with STIs in CaP. I intend to establish a translational laboratory similar to my mentor, Dr. Ravi Salgia, focused on the study of molecular signaling in CaP with a particular emphasis on understanding the aspects of biology that can be manipulated with drugs in the treatment of advanced CaP. The mentors and collaborators I have assembled are committed to helping me achieve this goal by providing me with their respective skills, insights, and support.

The project I am proposing will provide me with rigorous scientific training that will complement my clinical practice, which is focused upon men with advanced CaP. I have become concerned that many clinical trials with new drugs use standards to judge response to treatments that do not properly capture the benefit that patients may experience. This results from a lack of insight into the biology on the part of the clinicians designing these trials. What I need to overcome this barrier is a rigorous hands-on experience with a new molecular target, in this case Fyn, in the lab and in clinical samples. The program I have designed with my mentors reflects their years of experience and success in their respective areas of success in molecular signaling, clinical research, and translational research. This program of training and investigation will certainly lead to additional funding and success for my efforts in prostate cancer research in the near future.

Objectives and Rationale: The goal of this project is to ultimately test the idea that Fyn is an important regulator of CaP progression. I will use a clinical tool known as a tissue microarray (TMA) to relate the presence of Fyn in human tumors to different clinical outcomes. TMAs are special research tools that have hundreds of patient samples placed on a single slide allowing pathologists to make ready comparisons between samples as they are all on one slide. The TMA I am using has more than 80 patient samples and is linked with important clinical outcomes (e.g., survival from the time of diagnosis) that I will relate to the amount of Fyn I detected in each sample. This will help me to see if Fyn is predictive of bad clinical outcomes. I will also be looking at tissue that I collect during two clinical studies I am conducting at the University of Chicago with drugs that target Fyn to see if expression of this target predicts response to treatment. Simultaneously, I will be doing further studies in the laboratory to determine how Fyn expression affects the rate at which CaP cells grow and their ability to move, steps crucial to the development of metastatic disease, the point at which we tell men they cannot be cured of prostate cancer. My initial efforts have shown that in the available databases, the gene encoding Fyn is often overexpressed in tumors that have gained the ability to spread and in the tumors that no longer respond to our typical first-line hormonal therapies. These findings led me to suspect that Fyn was very important in CaP progression. My initial lab work and studies with drugs that inhibit Fyn show that attacking this molecular target has some impact on the way these cells grow and divide, though the way this happens is still unclear. My laboratory is now setting out to answer these questions in preparation for launching a focused clinical study in CaP.

Applicability of Research: This project is geared toward developing therapy for men with advanced CaP who cannot or have not benefited from surgery or radiation therapy alone. Since drugs like dasatinib are already available it is possible to conduct a clinical study in CaP. However, without appropriate information specific to CaP, the clinical trial design and endpoints may not be appropriate. Based on my findings, this trial may be centered upon men who are high risk after surgery to prevent metastases, men who have just started hormone therapy, to perpetuate the benefits without continued castration, or men with cancers that no longer yield to hormone and/or chemotherapies. The time to consumer-related outcomes should be within 5 years as these agents are being brought into clinical studies now.

Impact on Other Studies: Data from these experiments may be used to help re-examine data from the ongoing clinical studies to determine if patients were having benefits we were unable to measure by shedding insight on how to look for benefits. Furthermore, my research may open the question as to whether or not we have enrolled the right patients on these studies if predictive markers are discovered during the course of this investigation. The drugs being introduced are not Fyn-specific, but if Fyn is as important as our preliminary findings suggest, it may be this target which needs to be monitored instead of others that have been proposed.