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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：
7932247
负责人：
MENASHE BARELI
金额：
$ 28.89万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7932247
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 Clinical Clinical Trials Clinical Trials Design Cyclin D1 Cytostatics DNA biosynthesis Data Dependency Disease Disease Progression Disorder by Site Down-Regulation 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 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 Play Positioning Attribute Prevalence Primary Neoplasm Production Program Description Property Proteins Receptor Inhibition Receptor Signaling Recombinants Regulation Relative (related person)Reproduction spores Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Role Sequence Analysis Signal Transduction Signal Transduction Pathway Site Small Interfering RNA Solid Neoplasm Specimen Staining method Stains Stimulus TP53 gene Testing Therapeutic 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 Urogenital Cancer Urothelial Cell Vascular Endothelial Growth Factors Work Xenograft Model Xenograft procedure angiogenesis autocrine base bladder transitional cell carcinoma cancer cell cancer therapy cell growth chemotherapy clinically relevant cytokine cytotoxic data management design flexibility human TNF protein humanized antibody in vivo inhibitor/antagonist interest kinase inhibitor meetings neoplastic cell overexpression 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表达，临床相关的EGFR拮抗剂在体内抑制肿瘤异种移植物的生长。然而，EGFR 在其他疾病部位进行的临床试验中，抑制剂未显示出一致的活性，抑制了临床进一步积极开发它们的热情。研究在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，这表明更好地了解生物学机制， EGFR抑制剂对肿瘤细胞的作用将有助于识别将产生反应的肿瘤（生物学或临床）接受治疗在第一轮SPORE资助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）阻断了8/20人膀胱癌细胞系的细胞周期进程，我们已经确定了似乎介导这些效应的分子机制。虽然没有细胞 75个原发性肿瘤中没有一个含有激活EGFR激酶结构域突变，初步数据表明超过50%的原发性肿瘤表达EGFR的截短形式（EGFRvIII），配体非依赖性信号传导并促进其他模型系统中的肿瘤生长。因此，总体目标本项目的目的是确定与膀胱中EGFR依赖性生长相关的生物学特性，并开发可用于在组织活检中监测它们的药效学标志物在治疗过程中获得。为此，我们提出了四个具体目标。(1)定义分子机制 EGFR抑制剂在尿路上皮癌细胞中的抗增殖作用的基础。(2)确定尿路上皮癌中EGFR-vIII表达的功能意义。(3)定义主机的角色在对EGFR导向治疗的反应中观察到的血管生成抑制反应。(4)评价 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临床试验旨在测试西妥昔单抗对原发性肿瘤药效学标志物的影响。因此，在本发明中，我们处于一个独特的位置，可以直接测试我们在临床前研究中产生的假设的有效性。研究，并利用它们设计更有效的，基于EGFR的治疗策略。