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

• 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
• 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

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.

肺癌发展/进展的主要组成部分是肿瘤抑制因子的丢失， 基因，E-钙粘蛋白和分泌的信号蛋白，SEMA 3F。我们最初发现了SEMA 3F基因， 报道，其在患者样本中的下调与晚期疾病相关。SEMA3f 在体外和体内有效抑制肿瘤细胞，并对内皮细胞具有额外的抗血管生成作用。 细胞，其中NRP作为VEGF的共受体发挥作用。最近，我们发现SEMA 3F导致 下调肿瘤细胞中活化的avp 3整联蛋白，伴有磷酸化ERK、AKT和STATS的丧失，以及 对HIF和VEGF的抑制作用。这至少部分是由于抑制了整联蛋白连接的激酶， SRC. SEMA 3F是一种大分子，目前限制了其治疗潜力。 脑信号蛋白信号传导的知识，小分子和抗体抑制剂的使用应该允许 模拟SEMA 3F效应。 E-cadherin和SEMA 3F的下调最常见的是通过沉默转录因子来实现。 抑制子，特别是ZEB 1和Snail。转录抑制因子诱导的分子变化是 负责上皮-间充质转化（EMT），这是侵袭性/转移性的基础 很多上皮癌的症状我们已经发现E-钙粘蛋白缺失与肺癌预后不良相关 患者ZEB 1不仅负责E-钙粘蛋白的丢失，而且还抑制SEMA 3F，并赋予 对EGFR抑制剂的耐药性。这项工作已经导致两个正在进行的肺癌试验厄洛替尼加 HDAC抑制剂、SAHA（伏立诺他）和厄洛替尼加塞来昔布。 我们目前的研究集中在：1）通过小分子和小分子的作用来概括SEMA 3F的作用， 2）鉴定ZEB的新靶点，以及 导致肺癌发病/进展和EGFR抑制剂耐药的蜗牛， 3)确定肺癌发展过程中EMT的时间和频率， 信号通路（包括SEMA 3F），重要的是，它在人类肺癌和癌前病变中的临床相关性 病变我们还将检验这一假设，即癌前病变与EMT更有可能 发展成癌症或更具侵袭性的肿瘤。如果得到证实，这些病变可能对以下治疗有反应： HDAC抑制剂。项目1的转化目标通过使用临床前数据来设计 正在进行的具有SPORE生物标志物支持的临床试验，以及一项新的临床试验计划， 孢子生物标志物。