Synthetic Regulators of Tyrosine Protein Kinases

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DESCRIPTION (provided by applicant): Conventional strategies for identifying the biochemical basis of tumorigenesis and metastasis rely upon the search for up- (or down-) regulated genes and proteins. Although this approach has lead to life-saving discoveries, many areas of cancer diagnosis, treatment, and prognosis remain intractable. For example, the vast majority of men diagnosed with prostate cancer, a typically slow growing disease, will eventually die from some other disorder. For these patients, treatment is unnecessary and often worse than the disease. However, a significant fraction of prostate cancer patients will find themselves dealing with the difficult-to-cure metastatic form of the disease: nearly 30,000 American men die from prostate cancer every year. The absence of clear-cut biochemical markers precludes a satisfactory treatment protocol at the time of diagnosis. Indeed, conventional biomarkers may simply not exist given the complexity and heterogeneity of prostate cancer. Is it possible to identify and image subcellular structures that are barometers of metastatic disease in general and the deadly androgen-independent form of prostate cancer in particular? Recently, metastatic potential has been linked to the formation of invadopodia, protease-active protrusions displayed by metastatic cancer cell lines and by patient-derived tumor cells. Invadopodia promote the breakdown of the extracellular matrix in a machete-like fashion, a behavior required for subsequent invasion of surrounding tissue. The protein tyrosine kinase Src is both sufficient and necessary for invadopodia formation and function. However, Src kinase activity within invadopodia has not been explicitly assessed nor has its localized activity been determined as a function of global Src content. The latter lies at the heart of a recently formulated hypothesis concerning the biochemical basis of metastatic potential: local-excitation, global-inhibition of signaling pathways that promote cell invasion. In short, cancer aggressiveness may be a consequence of high signaling activity in spatially focused regions of the intracellular environment. A new breed of imaging reagents, with properties that display a high degree of spatial (and temporal) resolution, will be prepared to address this unexpected change in direction of cancer research. PUBLIC HEALTH RELEVANCE: The reagents to be developed in this study may ultimately make it feasible to rapidly determine metastatic potential at the time of cancer diagnosis.