Biology and Therapeutic Targeting of the Epidermal Growth Factor Receptor in Blad

Blad 表皮生长因子受体的生物学和治疗靶向

基本信息

批准号：
7729507
负责人：
MENASHE BARELI
金额：
$ 22.25万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729507
关键词：
1-Phosphatidylinositol 3-Kinase Aftercare Angiogenesis Inhibition Angiogenic Factor Antibodies Antineoplastic Agents Apoptosis Apoptotic Binding Sites Biochemical Biological Biological Assay Biological Models Biological Response Modifier Therapy Biology Biometry Biopsy Biopsy Specimen Bladder Bladder Neoplasm Blood Vessels CDK2 gene Cancer cell line Cell Cycle Progression Cell Line Cell Proliferation Cells Cetuximab Chemicals Class Clinical Clinical Trials Clinical Trials Design Cyclin D1 Cytostatics DNA biosynthesis DNA chemical synthesis Data Dependency Disease Disease Progression Disorder by Site Down-Regulation End Point Endothelial Cells Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Erbitux Evolution Freedom Funding Gefitinib Glioma Goals Growth Harvest Heterogeneity Human Hyperplasia IL8 gene Image Immune response Immunoblotting Immunofluorescence Immunologic Invasive Knockout Mice Laboratories Ligands Link Liver Malignant Epithelial Cell Malignant Glioma Malignant neoplasm of urinary bladder Mediating Messenger RNA Methods Modeling Molecular Molecular Weight Monitor Monoclonal Antibody C225 Mus Mutation Neoadjuvant Therapy Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Patients Pericytes Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phosphotransferases Platelet-Derived Growth Factor Pliability Positioning Attribute Prevalence Primary Neoplasm Production Program Description Property Protein Overexpression Proteins Rate Receptor Inhibition Receptor Signaling Recombinants Regulation Relative (related person)Reproduction spores Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Role Role playing therapy Sequence Analysis Signal Transduction Signal Transduction Pathway Site Small Interfering RNA Solid Neoplasm Specimen Staining method Stains Stimulus TP53 gene Testing Therapeutic Thinking Time Tissue Microarray Tissues Toxic effect Transgenic Mice Transgenic Organisms Transitional Cell Carcinoma Tumor Angiogenesis Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumor-Derived Tyrosine Kinase Domain United States Food and Drug Administration Up-Regulation Urothelial Cell Vascular Endothelial Growth Factors Work Xenograft Model Xenograft procedure ZD1839 (IRESSA)angiogenesis autocrine base bladder transitional cell carcinoma cancer cell cancer therapy cell growth chemotherapy clinically relevant cytokine cytotoxic data management design human TNF protein in vivo inhibitor/antagonist interest kinase inhibitor neoplastic cell p27 Cell Cycle Protein p27 Enzyme Inhibitor polypeptide pre-clinical preclinical study receptor receptor expression response small molecule therapeutic target translational study tumor tumor growth tumor progression tumor xenograft

项目摘要

The epidermal growth factor receptor (EGFR) is overexpressed during bladder cancer progression, and clinically relevant EGFR antagonists inhibit the growth of tumor xenografts in vivo. However, EGFR inhibitors not displayed consistent activity in clinical trials performed in other disease sites, which has dampened clinical enthusiasm for aggressively developing them further. Studies performed within the context of non-small cell lung cancer demonstrated that clinical responses were linked to activating mutations within the EGFR tyrosine kinase domain, suggesting that a better understanding of the biological effects of EGFR inhibitors on tumor cells will help to identify tumors that will respond (biologically or clinically) to therapy. In preliminary studies conducted during the first cycle of SPORE funding, we found that EGFR inhibitors (gefitinib or cetuximab) blocked cell cycle progression in 8/20 human bladder cancer cell lines, and we have identified molecular mechanisms that appear to mediate these effects. Although none of the cell lines nor any of 75 primary tumors contained activating EGFR kinase domain mutations, preliminary data suggests that over 50% of primary tumors express a truncated form of the EGFR (EGFRvlll) that mediates ligand-independent signaling and promotes tumor growth in other model systems. Therefore, the overall goal of this project is to define the biological properties associated with EGFR-dependent growth in bladder cancer cells and to develop pharmacodynamic markers that can be used to monitor them in tissue biopsies harvested during therapy. To this end, we propose 4 Specific Aims. (1) Define the molecular mechanisms underlying the antiproliferative effects of EGFR inhibitors in urothelial carcinoma cells. (2) Determine the functional significance of EGFR-vlll expression in urothelial carcinoma. (3) Define the role of the host response in the angiogenesis inhibition observed in response to EGFR-directed therapy. (4) Evaluate the activity of combined therapy with EGFR inhibitors and TRAIL. An important component of this project is a clinical trial designed to test the effects of cetuximab on pharmacodynamic markers in primary tumors. Thus, we are in a unique position to directly test the validity of the hypotheses we have generated in our preclinical studies and to exploit them in the design of more effective, EGR-based therapeutic strategies.

表皮生长因子受体 (EGFR) 在膀胱癌进展过程中过度表达，并且临床相关的 EGFR 拮抗剂可抑制体内肿瘤异种移植物的生长。然而，EGFR 抑制剂在其他疾病部位进行的临床试验中并未表现出一致的活性，这已挫伤了进一步积极开发它们的临床热情。在以下范围内进行的研究非小细胞肺癌的背景表明，临床反应与激活 EGFR 酪氨酸激酶结构域内的突变，表明更好地了解生物学 EGFR 抑制剂对肿瘤细胞的影响将有助于识别有反应的肿瘤（生物学或临床）来治疗。在 SPORE 资助的第一轮期间进行的初步研究中，我们发现 EGFR 抑制剂（吉非替尼或西妥昔单抗）阻断 8/20 人膀胱癌细胞系的细胞周期进程，以及我们已经确定了似乎介导这些效应的分子机制。虽然没有一个细胞初步数据显示，75 个原发性肿瘤细胞系或任何一个都含有激活 EGFR 激酶结构域突变表明超过 50% 的原发性肿瘤表达截短形式的 EGFR (EGFRvIII)，其介导配体独立信号传导并促进其他模型系统中的肿瘤生长。因此，总体目标该项目的目的是定义与膀胱中 EGFR 依赖性生长相关的生物学特性癌细胞并开发可用于在组织活检中监测它们的药效学标记物治疗期间收获。为此，我们提出4个具体目标。 (1) 明确分子机制 EGFR 抑制剂对尿路上皮癌细胞的抗增殖作用。 (2) 确定 EGFR-vlll 表达在尿路上皮癌中的功能意义。 (3)定义主持人角色 EGFR靶向治疗中观察到的血管生成抑制反应。 (4) 评估 EGFR 抑制剂和 TRAIL 联合治疗的活性。该项目的一个重要组成部分是旨在测试西妥昔单抗对原发性肿瘤药效学标志物影响的临床试验。因此，我们处于独特的地位，可以直接测试我们在临床前产生的假设的有效性研究并利用它们来设计更有效的、基于 EGR 的治疗策略。