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

• 批准号: 8135639
• 负责人: MENASHE BARELI
• 金额: $ 28.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/8135639
• 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; 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

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 临床上相关的EGFR拮抗剂在体内抑制肿瘤移植瘤的生长。然而，EGFR 在其他疾病地点进行的临床试验中，抑制剂没有显示出一致的活性，这已经 抑制了临床上进一步积极发展它们的热情。在以下时间内进行的研究 非小细胞肺癌的背景表明，临床反应与激活有关 EGFR酪氨酸激酶结构域内的突变，表明更好地理解生物 EGFR抑制剂对肿瘤细胞的作用将有助于识别有反应的肿瘤(生物学或临床) 去接受治疗。在第一轮孢子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，并且 我们已经确定了似乎调节这些效应的分子机制。尽管没有一个细胞 初步数据显示，75株原发肿瘤中没有一株含有激活的EGFR激动域突变 提示超过50%的原发肿瘤表达截短形式的EGFR(EGFRv11)，它介导 不依赖配体的信号转导，并在其他模型系统中促进肿瘤生长。因此，总的目标是 这个项目的目的是定义与膀胱中EGFR依赖的生长相关的生物学特性。 并开发药效标记物，可用于在组织活检中监测它们 在治疗过程中收获的。为此，我们提出了4个具体目标。(1)明确分子机制 EGFR抑制剂在尿路上皮癌细胞中的抗增殖作用。(2)确定 尿路上皮癌组织中EGFR-V11表达的功能意义(3)明确主持人的角色 在血管生成抑制中观察到的对EGFR指导治疗的反应。(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 西妥昔单抗对原发肿瘤药效学标志物影响的临床试验。因此， 我们处于一个独特的位置，可以直接测试我们在临床前阶段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。