The Integrin-Regulated Kinase PYK-2: A Therapeutic Target for Prostate Cancer

Abstract : A prostate cancer cell's growth differentiation and survival are guided by its interactions with the surrounding extracellular matrix (ECM). A number of promising therapeutic targets for androgen-independent and metastatic prostate cancers are contained within the signaling cascades downstream of the ECM-binding Integrin molecules. My research focuses on one component of these cascades, the phosphotyrosine kinase PYK-2, whose expression levels and activity I aim to manipulate in cell culture and within tumors in mice, using constitutively-active and dominant-negative PYK-2 constructs under the control of tetracycline-inducible promoters. Such regulation of PYK-2 may provide a means of pushing cells forward or backward in cancerous progression. By monitoring changes in the behaviors of cells expressing PYK-2 mutant variants, in the presence and absence of integrin-stimulating and blocking factors, we are simultaneously studying the downstream role of PYK-2 in regulating cell behaviors, and the upstream role of integrins in regulating PYK-2. Finally, we will introduce the PYK- 2-construct-expressing cells into adult mice, that we treat with tetracycline at different times during tumor development, castrate or leave whole, and monitor for tumor progression and necrosis. An extremely valuable tool in these studies will be the lineage- related LNCaP cell lines, developed in our laboratory, each of which represents a stage in prostate cancer cell progression, from marginally-tumorigenic and androgen-sensitive, to highly-metastatic and androgen- insensitive. If intentional PYK-2 modulation proves sufficient to control LNCaP model cell proliferative, migratory or apoptotic behaviors, our laboratory is uniquely equipped to develop the approach into a clinical therapy, by delivering the genes in an adenoviral vector, first to LNCaP tumors in mice, and eventually to men.