Faye Johnson M.D., Ph.D.

This grant is being fully funded by the Caine Halter Fund for Lung Cancer Research, through the Uniting Against Lung Cancer Grant Program.

Lay Description

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.

Scientific Abstract

Better systemic therapy is needed for the treatment of non-small cell lung cancer (NSCLC). One promising target is the receptor tyrosine kinase EphA2. EphA2 depletion inhibits tumor growth, angiogenesis, and metastasis in several epithelial cancers. However, the roles of EphA2 in NSCLC are unknown. Our preliminary work supports a role for EphA2 in NSCLC progression. EphA2 expression in NSCLC correlates with decreased survival in patients. Depletion of EphA2 in NSCLC also leads to decreased migration and proliferation in vitro. Our hypothesis is that EphA2 mediates NSCLC progression by affecting NSCLC migration, proliferation, and angiogenesis. However, others have demonstrated negative feedback loops in which EphA2 can attenuate the activation of ERK1/2 by epidermal growth factor receptor (EGFR) or PI3K/AKT by Ras. It is essential to define these feedback loops as this could completely alter the biological effects of EphA2-targeted therapy. Our overall goal 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. We will utilize EphA2-specific siRNA and confirm our findings in vivo with the following specific aims: To measure the effect of EphA2 depletion on NSCLC proliferation, survival, and angiogenesis in vivo; to determine if EphA2 mediates a feedback loop downstream of EGFR in NSCLC cells; and to investigate the effects of the combination of EGFR inhibition and EphA2 depletion on cytotoxicity, proliferation, survival, and angiogenesis in vivo. This research will result in a much better understanding of the role of the EphA2 signaling pathway in NSCLC and will determine whether EphA2 is a valuable therapeutic target in the treatment 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 three years.