| Better therapies are needed for patients with non-small cell lung cancer (NSCLC). One promising target for therapy is a protein called EphA2 that is expressed on the surface of NSCLC tumor cells. In other cancers, reducing the level of EphA2 results in smaller, less invasive cancers, but the roles of EphA2 in NSCLC are unknown. Our data support a role for EphA2 in NSCLC progression. Patients with NSCLC whose tumors have high levels of EphA2 have shorter survival. Depletion of EphA2 leads to a decrease in the migration and proliferation of NSCLC cells in tissue culture. Our hypothesis is that EphA2 mediates NSCLC progression by affecting NSCLC migration, proliferation (cell growth), and angiogenesis (blood vessel formation). However, others have demonstrated negative feedback loops in which EphA2 can attenuate the activation of growth stimulatory signals (e.g. MAPK or AKT). It is essential to understand if these negative feedback loops exist in NSCLC as this could completely alter the clinical utility of EphA2-targeted therapy. Our overall goal with this project is to determine the potential clinical value of EphA2 depletion in NSCLC and to investigate the pathways downstream of EphA2 that may influence its biological effects. At the end of this project, we will know whether EphA2-targeting agents are appropriate for the therapy of NSCLC. We may also know which other pathways to target in order to enhance the therapeutic efficacy of EphA2. Given that novel EphA2 targeting agents are in development, this work could lead to direct clinical application within the next 3 years.
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