Growth Factor Inhibitors for Lung Cancer Therapy and Prevention

用于肺癌治疗和预防的生长因子抑制剂

• 批准号: 7448821
• 负责人: PAUL A. BUNN
• 金额: $ 19.41万
• 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/7448821
• 关键词: Affect; Biological Markers; Bradykinin; Bradykinin Receptor; CU201; Cancer Patient; Cancer cell line; Cell Line; Chemoprevention; Clinical; Clinical Trials; Data; Development; Drug Combinations; Drug Kinetics; E-Cadherin; EGF gene; EGFR gene; Environment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Erlotinib; Evaluation; Exhibits; Exons; FGF2 gene; FGFR1 gene; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptors; Frequencies; Gender; Gene Dosage; Gene Expression; Goals; Grant; Growth; Growth Factor; Growth Factor Receptors; Histology; Human; IGF Type 2 Receptor; Immunohistochemistry; In Vitro; Individual; Ligands; Lung; Malignant neoplasm of lung; Methods; Modeling; Molecular Profiling; Monkeys; Mus; Neoplasm Metastasis; Neuropeptides; Nude Rats; Numbers; Paraffin Embedding; Pathogenesis; Pathway interactions; Patient Selection; Patients; Pharmacodynamics; Phase I Clinical Trials; Play; Pre-Clinical Model; Preparation; Prevention; Primary Neoplasm; Prospective Studies; Protein Tyrosine Kinase; Proteomics; Resistance; Role; Selection Criteria; Signal Pathway; Smoking Status; Solid Neoplasm; Somatomedins; Testing; Therapeutic; Tissue Microarray; Toxic effect; Toxicology; Tumor Tissue; Tyrosine Kinase Inhibitor; autocrine; base; cancer cell; cancer therapy; concept; improved; in vivo; inhibitor/antagonist; mouse model; novel; outcome forecast; paracrine; pre-clinical; preclinical study; protein expression; receptor; receptor expression; subcutaneous; tumor; tumor growth

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.

该项目的总体目标是开发和改善治疗和化学预防策略 肺癌通过抑制一种或多种自分泌 /旁分泌生长因子信号途径。 自分泌 /旁分泌生长环在人肺的发病机理和进展中起主要作用 癌症。尽管概念证明和令人兴奋的临床前数据，但仅批准EGFR TKI 癌症疗法和有关使用生物标志物进行选择的其他前瞻性研究。我们的 先前的研究集中在神经肽和EGFR信号途径上。我们开发和评估了 EGFR TKI的患者选择的预测生物标志物显示EGFR基因拷贝数是鱼 是EGFR的外显子19中的缺失，是出色的预测标记。 EGFR蛋白表达 IHC不如FISH的EGFR基因拷贝数有效，但可能会增加价值。预测性蛋白质组学 上皮标记的曲线和表达也在评估中。我们开发了一个新颖的Bradykinin 2 被称为CU201的受体（BK2R）拮抗剂在临床前模型中定义了其活性 小鼠和猴子的特征及其在小鼠和猴子中的毒理学为临床试验做准备。我们 还证明了FGF环在肺癌中的重要性，并表明FGFR抑制剂抑制了 表达配体和受体的肺癌细胞系的生长在细胞系中与EGFR TKIS协同 表达TGFA和/或EGFR。还开发了IGF和IGFR的生物标志物。在即将到来的 我们计划单独测试EGFR，FGFR，IGF-1R和BK2R的抑制剂，并在A组合测试 肺癌细胞系的面板将以表达每个配体和受体的表达为特征。细胞 线还将通过Affymetrix阵列确定其全局基因表达来搜索其他 候选预测标记。我们认为，计划的临床前和临床试验将使我们能够 识别和验证生物标志物，这些标志物可用于选择单独的生长因子抑制剂和 肺癌患者的组合。我们的具体目的是：1）定义Bradykinin，EGF，FGFS的作用， 通过确定生长因子的表达，肺癌的自分泌 /旁分泌生长中的IGF 受体及其配体在一组肺癌细胞系上；确定这些细胞系的灵敏度 生长因子抑制剂并确定灵敏度与配体/受体之间的关系 表达。 2）确定生长因子受体的表达，其配体和对 个体抑制剂通过合理选择的测试在体外和体内预测组合效应 定义的肺癌细胞系组合。 3）确定FGFR，IGF-1R，IGF-2R和BK2R是否是否 通过分析受体的频率，表达和活性与肺癌患者的预后相关 /每个受体和配体在人肺癌组织微阵列中的配体表达。我们也会 检查各种受体 /配体组合对预后的关系， 表达和其他临床特征（性别，吸烟状况，组织学等）和关系 在信号途径之间。 4）在晚期实体瘤中进行C201的I期临床试验 药代动力学和药物疗法评估。 5）评估从我们的临床前选择的生物标志物 研究其在患者选择EGFR，FGFR，BK2R和IGF-1R抑制剂的临床试验方面的效用， 单独和结合。