Prostate cancer (CaP) is the most common cancer affecting men, accounting for more than 27,000 American deaths with additional suffering due to spread from primary sites to other organs such as bone, liver, and lungs before the end of life (cancer metastasis). Kinase dysregulation is an important and common biological event in CaP. Since the introduction of drugs such as imatinib (Gleevec), kinases have been seen as tractable pharmacologic targets. To date, kinase inhibitors have not demonstrated impressive efficacy in CaP, but it is not clear whether this represents investigation of less relevant targets or deficiencies in their clinical evaluation. We have identified Fyn, a member of the Src family (SFK), as dysregulated during CaP progression. Our studies have shown that reduction of Fyn in CaP cells causes reorganization of the cellular cytoskeleton, reduced or reversed the directional response to well-known chemical attractants in laboratory models without diminishing the speed of cellular movement, and diminished tumor growth and spread in mouse models. Our studies of human tissue and cellular models also have given us insight into the biochemical pathways through which these signals are transmitted, namely: HGF/MET upstream and FAK/paxillin/PAK downstream. These findings raise the hypothesis that Fyn pathway upregulation augments directional cellular motility thereby increasing CaP metastatic capacity and making it a relevant therapeutic target.

I propose to test this assertion with the following three related but separate projects:

Project 1: Quantify the impact of Fyn modulation on aspects cancer cell movements in non-animal laboratory models. These studies will use standard CaP laboratory models to determine if changing Fyn expression in prostate cancer cells will alter the ability of various cells with manipulated Fyn expression to determine direction and/or impact their ability to move through tissue barriers -- both key steps to metastasis. Simultaneously, we will study the biochemical effects of Fyn alterations on the biochemical signals we have found to be related to Fyn.

Impact: These studies will refine our understanding of the biology and biochemistry of Fyn. This information would be needed to understand if and how to combine Fyn-directed therapy with other treatments, and when best to use Fyn-targeted drugs.

Project 2: To test the impact of Fyn modulation on the ability of cancer cells to spread into the circulation AND move into tissues away from a primary tumor using a mouse model. We have started to develop models related to this project, but need to refine the current models to tease apart the steps of dissemination (spread) and invasion. By collaborating with experts in CaP mouse modeling of cancer behavior, we have devised a series of experiments that will either (1) fix the amount of primary tumor present, allowing us to see how much cancer escapes into the circulation, and (2) fix the amount of cancer in the circulation, and see if changing Fyn will impact how many different sites will be affected by spread.

Impact: These studies will be used to define endpoints for use in clinical studies of Fyn inhibitors.

Project 3: Determine alterations of FYN pathway members in human CaP and correlate them with demographic, pathological and clinical outcome parameters. These studies will examine various changes in Fyn which may exist in men with CaP. We have already found changes in the genetic code of Fyn in patient samples, but a larger sample is needed to understand how changes in Fyn relate to human disease. These changes will be re-studied in our laboratory models to see how they affect the information we have gained from projects 1 and 2.

Impact: These studies will provide initial data that may help to identify men who will best benefit from Fyn-directed therapies.

The preclinical data we have generated already provides strong evidence for Fyn playing an important role in CaP metastasis. Given the availability of agents active against Fyn (though non-specifically), there is an urgent need to understand how to optimize Fyn-targeted therapeutics. The work herein will validate a novel venue of Fyn-targeted anti-metastatic therapy and may help to identify those patients at risk from Fyn-driven prostate cancers who then should be directed toward therapies effective against Fyn overactivity. Our current understanding of targeted therapies suggests that there are certain groups of patients that may have greater benefit than others based on genetic alterations. As a physician-scientist, I recognize this and am working toward translating these findings to benefit patients. This work represents the next step in this evolution toward personalized molecular medicine and will complement a NCI/CTEP-approved clinical trial that my group will be launching shortly.