): This proposal is designed to provide training in molecular oncology, allowing the applicant to strengthen his investigative skills and develop into an independent clinician investigator in oncology. A comprehensive academic program, to be conducted at the University of Virginia Health Sciences Center, under the guidance of J. Thomas Parsons, Ph.D., has been developed, integrating a didactic program and a focused, mentored research plan. Local invasion and metastases signify solid tumor disease progression, treatment failure and portend the organism's death. Integrins modulate many normal cellular processes that are perturbed in tumors and associated with progression. A role for integrins has been implicated in the multi-step process of tumor progression. Focal adhesion kinase (FAK), a protein tyrosine kinase, is central to integrin-mediated signaling; a correlation between FAK and malignant potential also has been reported. The long-term goal of this research is to investigate the molecular mechanisms by which integrin-mediated signals influence tumor progression. Completion of this plan will provide the applicant a solid investigative foundation. This research plan focuses on integrin signaling in tumor progression and the role of the FAK in this signaling cascade. As a model, human prostate epithelial cell lines (several sharing a common cell lineage) with diverse t u morigenic, androgen-responsive, and metastatic potentials, provide a powerful experimental system to explore the role of integrin signaling in tumor progression. Two objectives of the proposed studies are: 1) To test whether FAK activity correlates with malignant potential and determine if such changes result from altered FAK expression, structure, or function; 2) To test whether regulation of FAK activity can modify a cell's in vivo malignant potential. To investigate these objectives, the applicant proposes studies with the following Specific Aims: 1) Determine the role of focal adhesion signaling in tumor progression, focusing on FAK, as it is a central regulator of integrin-mediated signals. Molecular mechanisms regulating FAK's role in tumor progression will be explored. The functional consequences of altered FAK function on integrin signaling will be characterized, providing insight into mechanisms by which altered integrin signaling might contribute to tumor p r o gression. The clinical relevance of FAK will be determined by immunohistochemical analysis of FAK expression in archival specimens of human prostate cancer. 2) Using gene transfer techniques, the applicant will directly evaluate the role of integrin signaling in tumor progression by altering FAK activity in cells with various malignant potentials and evaluating the consequences of these alterations in a biologic model.
| Rovin, Joshua D; Frierson Jr, Henry F; Ledinh, Wayne et al. (2002) Expression of focal adhesion kinase in normal and pathologic human prostate tissues. Prostate 53:124-32 |
