Non-small cell lung cancer (NSCLC) is a devastating illness that will affect approximately 172,570 people in[unreadable] the United States in 2005 and for whom 5 year survival remains dismal at approximately 15%. The[unreadable] mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in promoting cell cycle[unreadable] progression and cell proliferation, and is frequently up-regulated in many cancers including NSCLC.[unreadable] Rapamycin and its analogues, such as RAD001, are highly specific inhibitors of mTOR and are now in phase[unreadable] I - II oncology clinical trials. Akt, a survival protein frequently activated due to ras mutations and[unreadable] overexpression of growth factor receptors in human NSCLC, positively regulates mTOR signaling via[unreadable] tuberous sclerosis complex 2(TSC2), whereas LKB1, a tumor suppressor gene, mutates with high frequency[unreadable] in NSCLC, negatively regulates mTOR signaling. Thus, both Akt activation and LKB1 mutation may impact[unreadable] cell sensitivity or response to mTOR inhibitors. In this proposal, we attempt to determine the prognostic[unreadable] values of key proteins (p-Akt, p-mTOR, p-70S6K, p-4E-BP1, p-S6) in the mTOR axis in non-small cell lung[unreadable] cancer by obtaining tissue from the NATCH (Nee-Adjuvant Jrial of Chemotherapy Hope) and integrating[unreadable] these biomarkers together with others obtained from Projects 2-5 into a molecular prognostic model for[unreadable] operable NSCLC. We will then cross validate that model in tissue samples from patients treated surgically for[unreadable] NSCLC at the Emory-Winship Cancer Institute Programs. Having confirmed the importance of these[unreadable] biomarkers in human lung cancer tissue, we will then use these proteins as biomarkers in a series of novel[unreadable] translational clinical trials evaluating the mTOR inhibitor as preoperative biochemical therapy in resectable[unreadable] NSCLC and subsequently in combination therapy with docetaxel in metastatic disease. By accomplishing[unreadable] these aims, we can test our hypothesis that aberrant activation of mTOR signaling due to frequent Akt[unreadable] activation and LKB1 mutations in NSCLC impacts patient prognosis and serves as opportune target for[unreadable] effective treatment of NSCLC using mTOR inhibitors and their combinations with chemotherapy.
NIH ExPorter
NIH ExPorter