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SEMA3F and ZEB1 in Lung Cancer: Therapy and Target Gene Discovery

SEMA3F 和 ZEB1 在肺癌中的应用：治疗和靶基因发现

基本信息

批准号：
7448818
负责人：
HARRY A. DRABKIN
金额：
$ 26.5万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7448818
关键词：
3p21.3 Affect Antibodies Binding Biological Markers Cancer Patient Cancer cell line Cell Line Clinical Trials Dasatinib Data Development Disease Down-Regulation E-Cadherin E-Cadherin Staining Method EPHA2 gene EPHB2 gene Endothelial Cells Engineering Ephrin-B3 Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Erlotinib Family Frequencies Gefitinib Gene Targeting Genes Goals Growth Factor Hand Histone Deacetylase Human In Vitro Integrins Invasive Knowledge Lesion Malignant Neoplasms Malignant neoplasm of lung Mesenchymal Molecular Nature Neoplasm Metastasis Neuropilin-1 Neuropilins Outcome Pathogenesis Pathway interactions Patients Premalignant Preparation Proteins Proto-Oncogene Proteins c-akt Recurrence Reporting Reproduction spores Resistance Sampling Signal Pathway Signal Transduction Snails Staging Testing Tetanus Helper Peptide Therapeutic Therapeutic Agents Time Tissue Banks Tumor Suppressor Genes VAV3 gene Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vorinostat Work Xenograft Model antibody inhibitor base cancer therapy celecoxib clinically relevant design gene discovery in vivo inhibitor/antagonist integrin-linked kinase mutant neoplastic neoplastic cell plexin pre-clinical receptor research study small hairpin RNA small molecule tumor vector control

项目摘要

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.

肺癌发生/发展的一个主要因素是肿瘤抑制因子的丧失