A major component in the development / progression of lung cancer is loss of the tumor suppressor genes, E-cadherin and the secreted semaphorin, SEMA3F. We originally identified the SEMA3F gene and reported that its downregulation in patient samples correlates with advanced-stage disease. SEMA3F potently inhibits tumor cells in vitro and in vivo, and has additional anti-angiogenic effects on endothelial cells, where NRPs function as co-receptors for VEGF. Recently, we found that SEMA3F causes downregulation of activated avp3 integrin in tumor cells with loss of phospho-ERK, AKT and STATS, and inhibitory effects on HIF and VEGF. This results, at least in part, from inhibition of integrin-linked kinase and SRC. SEMA3F is a large molecule, which presently limits its therapeutic potential, However, based on our knowledge of semaphorin signaling, the use of small molecule and antibody inhibitors should allow mimicking of the SEMA3F effect. Downregulation of E-cadherin and SEMA3F occurs most commonly by silencing from transcriptional repressers, particularly ZEB1 and Snail. The molecular changes induced by transcriptional repressers are responsible for the epithelial-mesenchymal transition (EMT), which underlies the invasive / metastatic nature of many epithelial cancers. We've shown that E-cadherin loss correlates with poor outcome in lung cancer patients. Not only is ZEB1 responsible for E-cadherin loss, but it also suppresses SEMA3F, and confers resistance to EGFR inhibitors. This work has resulted in two ongoing lung cancer trials of erlotinib plus the HDAC inhibitor, SAHA (Vorinostat), and erlotinib plus celecoxib. Our current studies are focused on: 1) recapitulating the effects of SEMA3F by small molecules and antibodies with the goal of developing an effective therapeutic strategy, 2) identifying new targets of ZEB and Snail 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 other signal pathways (including SEMA3F) and, importantly, its clinical relevance in human lung cancers and premalignant lesions. We will also test the hypothesis that pre-malignant lesions with EMT are more likely to develop cancer or more aggressive tumors. If confirmed, these lesions may be responsive to treatment with HDAC inhibitors. The translational goals of Project 1 are highlighted by the use of preclinical data to design ongoing clinical trials with SPORE biomarker support, and plans for a new clinical trial also supported by SPORE biomarkers.
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