A major component in the development / progression of lung cancer is loss of the tumor suppressorgenes, E-cadherin and the secreted semaphorin, SEMA3F. We originally identified the SEMA3F gene andreported that its downregulation in patient samples correlates with advanced-stage disease. SEMA3Fpotently inhibits tumor cells in vitro and in vivo, and has additional anti-angiogenic effects on endothelialcells, where NRPs function as co-receptors for VEGF. Recently, we found that SEMA3F causesdownregulation of activated avp3 integrin in tumor cells with loss of phospho-ERK, AKT and STATS, andinhibitory effects on HIF and VEGF. This results, at least in part, from inhibition of integrin-linked kinase andSRC. SEMA3F is a large molecule, which presently limits its therapeutic potential, However, based on ourknowledge of semaphorin signaling, the use of small molecule and antibody inhibitors should allowmimicking of the SEMA3F effect.Downregulation of E-cadherin and SEMA3F occurs most commonly by silencing from transcriptionalrepressers, particularly ZEB1 and Snail. The molecular changes induced by transcriptional repressers areresponsible for the epithelial-mesenchymal transition (EMT), which underlies the invasive / metastatic natureof many epithelial cancers. We've shown that E-cadherin loss correlates with poor outcome in lung cancerpatients. Not only is ZEB1 responsible for E-cadherin loss, but it also suppresses SEMA3F, and confersresistance to EGFR inhibitors. This work has resulted in two ongoing lung cancer trials of erlotinib plus theHDAC inhibitor, SAHA (Vorinostat), and erlotinib plus celecoxib.Our current studies are focused on: 1) recapitulating the effects of SEMA3F by small molecules andantibodies with the goal of developing an effective therapeutic strategy, 2) identifying new targets of ZEB andSnail that contribute to the pathogenesis / progression of lung cancer and resistance to EGFR inhibitors and,3) identifying the timing and frequency of EMT during lung cancer development, its relationship to othersignal pathways (including SEMA3F) and, importantly, its clinical relevance in human lung cancers and premalignantlesions. We will also test the hypothesis that pre-malignant lesions with EMT are more likely todevelop cancer or more aggressive tumors. If confirmed, these lesions may be responsive to treatment withHDAC inhibitors. The translational goals of Project 1 are highlighted by the use of preclinical data to designongoing clinical trials with SPORE biomarker support, and plans for a new clinical trial also supported bySPORE biomarkers.
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