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

肺癌发生/发展的一个主要因素是肿瘤抑制基因的缺失。 基因，E-钙粘蛋白和分泌的信号素，SEMA3F。我们最初发现了SEMA3F基因和 据报道，它在患者样本中的下调与晚期疾病有关。SEMA3F 在体内外有效抑制肿瘤细胞，并对血管内皮细胞有额外的抗血管生成作用 在这些细胞中，核糖核蛋白是血管内皮生长因子的辅助受体。最近，我们发现SEMA3F导致 在磷酸化ERK、AKT和STATS缺失的情况下下调肿瘤细胞中激活的avp3整合素，以及 对缺氧诱导因子和血管内皮生长因子的抑制作用。这至少部分是由于整合素连接的激酶和 SRC。SEMA3F是一个大分子，目前限制了它的治疗潜力，然而，基于我们的 了解信号素信号，小分子和抗体抑制剂的使用应该允许 模仿SEMA3F效应。 E-钙粘蛋白和SEMA3F的下调最常见的方式是通过沉默转录 抑制剂，特别是ZEB1和蜗牛。转录抑制因子引起的分子变化是 负责上皮-间充质转化(EMT)，这是侵袭/转移性质的基础 在许多上皮性癌症中。我们已经证明E-钙粘素缺失与肺癌的不良预后相关 病人。ZEB1不仅对E-钙粘附素的丢失负责，而且还抑制SEMA3F，并赋予 对EGFR抑制剂的耐药性。这项工作已经导致了两项正在进行的埃洛替尼加 HDAC抑制剂、SAHA(Vorinostat)和Erlotinib加Celecoxib。 我们目前的研究集中在：1)总结了SEMA3F的小分子和 抗体，目的是开发有效的治疗策略，2)识别Zeb和 与肺癌的发生/发展和对EGFR抑制剂的耐药性有关的蜗牛， 3)确定肺癌发展过程中EMT的时机和频率，以及它与其他 信号通路(包括SEMA3F)及其在肺癌和癌前病变中的临床意义 损伤。我们还将检验这样一种假设，即有EMT的癌前病变更有可能 罹患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的翻译目标通过使用临床前数据来设计 正在进行的临床试验和孢子生物标记物的支持，以及计划进行的新的临床试验也得到了 孢子生物标志物。

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.