Molecular Mechanisms of Blockage of ErbB receptors

ErbB 受体阻断的分子机制

• 批准号: 6986388
• 负责人: Careen K Tang
• 金额: $ 24.52万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986388
• 关键词: antineoplastics; athymic mouse; breast neoplasms; cell line; drug screening /evaluation; epidermal growth factor; gene mutation; genetic susceptibility; growth factor receptors; kinase inhibitor; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; pharmacogenetics; pharmacokinetics; protein tyrosine kinase; protooncogene; xenotransplantation

DESCRIPTION (provided by applicant): The rationale for using EGFR-targeted approaches in cancer treatment is now firmly established, and numerous clinical trials are in progress. Improved understanding of EGFR's role in cancer has raised the question of whether EGFR-targeted agents are active against the deletion mutant EGFRvIII. This mutant form is expressed in several types of cancer, including breast cancer, in which it enhances tumorigenicity and is often associated with an aggressive tumor phenotype. EGFR-TKIs remain a remarkable advance in targeted therapy for solid tumors. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene of patients with non-small cell lung cancer treated with gefitinib (Iressa) has inaugurated a new era of integrated diagnostics and therapeutics --- new anticancer drugs are taking advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatments. Despite the encouraging results, not all tumors that overexpress EGFR or with EGFR mutant (EGFRvIII) respond to these treatments. In a phase II trial, gefitinib has not elicited clinical responses in patients with gliomas, despite the high frequency of amplification and rearrangement of the EGFR gene in such patients. The response to TKIs was not correlated with EGFR expression. The sensitivity of tumor cells to EGFR inhibition is likely to be influenced by other factors such as activating mutations in EGFR, levels of EGFR ligands, and expression of other ErbB family members that may form heterodimers and allow continued signal amplification. Furthermore, we have detected co-expression of wild-type EGFR with EGFRvIII, as well as co-expression of ErbB-2 with EGFRvIII, in breast cancer. It is important to evaluate the impact of EGFRvIII expression on responses to these EGFR-TKIs. To achieve this goal, we propose the following Specific Aims. 1): To assess whether sensitivity and resistance to tyrosine kinase inhibitors are dependent upon the expression levels and activities of EGFR and its variants as well as other members of the EGFR family of receptors. 2): To evaluate the therapeutic efficacy and pharmacologic effect of EGFR-targeted therapies on xenograft model systems expressing EGFR and its variants. We believe that these studies will provide valuable information, which may help optimize the current available drugs and promote the development of novel agents.

描述（由申请人提供）：在癌症治疗中使用EGFR靶向方法的基本原理现已确立，许多临床试验正在进行中。对EGFR在癌症中的作用的进一步了解提出了EGFR靶向药物是否对缺失突变型EGFRvIII有活性的问题。这种突变形式在几种类型的癌症中表达，包括乳腺癌，其中它增强了致瘤性，并且通常与侵袭性肿瘤表型相关。EGFR-TKI仍然是实体瘤靶向治疗的显著进展。最近发现的药物反应预测的表皮生长因子受体基因的激活突变的非小细胞肺癌患者与吉非替尼（易瑞沙）治疗开辟了一个新的时代的综合诊断和治疗-新的抗癌药物正在利用特定的遗传缺陷，使恶性细胞更有可能响应特定的治疗。尽管结果令人鼓舞，但并非所有过表达EGFR或EGFR突变体（EGFRvIII）的肿瘤都对这些治疗有反应。在一项II期试验中，吉非替尼在神经胶质瘤患者中没有引起临床反应，尽管在这些患者中EGFR基因的扩增和重排频率很高。对TKI的反应与EGFR表达无关。肿瘤细胞对EGFR抑制的敏感性可能受到其他因素的影响，如EGFR中的激活突变、EGFR配体水平以及可能形成异源二聚体并允许持续信号放大的其他ErbB家族成员的表达。此外，我们已经检测到野生型EGFR与EGFRvIII的共表达，以及ErbB-2与EGFRvIII在乳腺癌中的共表达。评价EGFRvIII表达对这些EGFR-TKI应答的影响非常重要。为实现这一目标，我们提出以下具体目标。1）、评估对酪氨酸激酶抑制剂的敏感性和耐药性是否取决于EGFR及其变体以及EGFR受体家族其他成员的表达水平和活性。2）、评价EGFR靶向治疗对表达EGFR及其变体的异种移植模型系统的疗效和药理学作用。我们相信，这些研究将提供有价值的信息，这可能有助于优化目前可用的药物，并促进新药物的开发。