Growth Factor Inhibitors for Lung Cancer Therapy and Prevention

该项目的总体目标是开发和改进治疗和化学预防策略 通过抑制一个或多个自分泌/旁分泌生长因子信号通路而导致肺癌。 自分泌/旁分泌生长环在人肺的发生发展中起重要作用 癌症。尽管概念证明和令人兴奋的临床前数据，只有EGFR TKIs被批准用于肺 癌症治疗和关于使用生物标记物进行选择的其他前瞻性研究是必要的。我们的 以往的研究主要集中在神经肽和EGFR信号通路上。我们开发并评估了 FISH法检测EGFR基因拷贝数对患者选择EGFR TKI的预测作用 与EGFR外显子19的缺失一样，是一个很好的预测标记。表皮生长因子受体蛋白的表达 免疫组化法不如FISH法检测EGFR基因拷贝数有效，但可能具有增值作用。一个可预测的蛋白质组学 上皮性标志物的概况和表达也在评估中。我们开发了一种新型的缓激肽2 受体(BK2R)拮抗剂，称为CU201，在临床前模型中定义了其活性，其药代动力学 在小鼠和猴子中的概况，以及在小鼠和猴子中的毒理学，为临床试验做准备。我们 也证明了成纤维细胞生长因子环在肺癌中的重要性，并表明FGFR抑制剂抑制 表达配体和受体的肺癌细胞生长及其与EGFR-TKI的协同作用 表达TGFa和/或EGFR。还开发了IGFS和IGFR的生物标志物。在即将到来的 Grant Cycle我们计划单独和联合测试EGFR、FGFR、IGF-1R和BK2R的抑制剂 一组肺癌细胞系，将表征每种配体和受体的表达。单元格 品系还将通过Affymetrix阵列确定它们的全局基因表达，以搜索其他 候选预测标记物。我们相信，计划中的临床前和临床试验将使我们能够 识别和验证在选择生长因子抑制剂方面将有用的生物标志物 肺癌患者的联合用药。我们的具体目标是：1)确定缓激肽、EGF、FGFs的作用， 生长因子和IGFS在肺癌自分泌/旁分泌生长中的表达 一组肺癌细胞系上的受体及其配体；测定这些细胞系的敏感性 对生长因子抑制剂的敏感性及其与配体/受体的关系 表情。2)确定生长因子受体及其配体的表达和对 通过测试合理选择的单独抑制剂来预测体外和体内的联合作用 已确定的肺癌细胞系中的组合。3)确定FGFR、IGF-1R、IGF-2R和BK2R 受体频率分析肺癌患者的表达和活性与预后的关系 人肺癌组织芯片中各受体和配体的表达我们还将 探讨不同受体/配体组合对预后的影响，不同受体/配体之间的关系 表达与其他临床特征(性别、吸烟状况、组织学等)的关系 在信号通路之间。4)进行CU201治疗晚期实体瘤的I期临床试验 药代动力学和药代动力学评价。5)评估从我们的临床前阶段选择的生物标记物 在EGFR、FGFR、BK2R和IGF-1R抑制剂临床试验的患者选择中的有效性研究， 单独的和组合的。

The overall goal of this project is to develop and improve therapeutic and chemoprevention strategies for lung cancer through inhibition of one or more autocrine / paracrine growth factor signal pathways. Autocrine / paracrine growth loops play a major role in the pathogenesis and progression of human lung cancer. Despite proof of concept and exciting preclinical data, only EGFR TKIs are approved for lung cancer therapy and additional prospective studies on the use of biomarkers for selection are needed. Our prior studies have focused on neuropeptide and EGFR signal pathways. We developed and evaluated predictive biomarkers for patient selection for EGFR TKIs showing that EGFR gene copy number by FISH is an excellent predictive marker as are deletions in exon 19 of the EGFR. EGFR protein expression by IHC is not as effective as EGFR gene copy number by FISH but may add value. A predictive proteomic profile and expression of epithelial markers are also under evaluation. We developed a novel bradykinin 2 receptor (BK2R) antagonist, termed CU201, defined its activity in preclinical models, its pharmacokinetic profile in mice and monkeys, and its toxicology in mice and monkeys in preparation for a clinical trial. We also demonstrated the importance of FGF loops in lung cancer and showed that FGFR inhibitors inhibit the growth of lung cancer cell lines expressing ligand and receptor and synergize with EGFR TKIs in cell lines expressing TGFa and/or EGFR. Biomarkers for IGFs and IGFRs were also developed. In the upcoming grant cycle we plan to test inhibitors of EGFR,FGFR, IGF-1R and BK2R alone and in combination in a panel of lung cancer cell lines that will be characterized for expression of each ligand and receptor. The cell lines will also have their global gene expression determined by Affymetrix arrays to search for other candidate predictive markers. We believe that the planned preclinical and clinical trials will allow us to identify and validate biomarkers that will be useful in selection of growth factor inhibitors alone and in combination for lung cancer patients. Our specific Aims are: 1) Define the role of bradykinin, EGF, FGFs, and IGFs in autocrine / paracrine growth of lung cancer by determining the expression of growth factor receptors and their ligands on a panel of lung cancer cell lines; determining the sensitivity of these cell lines to growth factor inhibitors and determining the relationship between sensitivity and ligand/receptor expression. 2) Determine whether expression of growth factor receptors, their ligands and sensitivity to individual inhibitors predicts combination effects in vitro and in vivo by testing rationally selected combinations in defined lung cancer cell lines. 3) Determine if FGFR, IGF-1R, IGF-2R, and BK2R expression and activity correlate with prognosis in lung cancer patients by analysis of frequency of receptor / ligand expression of each receptor and ligand in human lung cancer tissue microarrays. We will also examine the relationship of various receptor / ligand combinations on prognosis, the relationship between expression and other clinical features (gender, smoking status, histology, etc.), and the relationship between signal pathways. 4) Conduct a phase I clinical trial of CU201 in advanced solid tumors with pharmacokinetic and pharmacodyanmic assessments. 5) Evaluate biomarkers selected from our preclinical studies for their utility in patient selection for clinical trials of EGFR, FGFR, BK2R, and IGF-1R inhibitors, alone and in combination.