Molecular Mechanisms of Blockage of ErbB receptors

ErbB 受体阻断的分子机制

• 批准号: 7076876
• 负责人: Careen K Tang
• 金额: $ 23.95万
• 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/7076876
• 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牢固确立，并且大量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一个问题：EGFR 靶向药物是否对缺失突变体 EGFRvIII 具有活性。这种突变形式在包括乳腺癌在内的多种癌症中表达，它增强了致瘤性，并且通常与侵袭性肿瘤表型相关。 EGFR-TKIs 仍然是实体瘤靶向治疗的显着进步。最近发现的一种药物反应可以预测接受吉非替尼（易瑞沙）治疗的非小细胞肺癌患者表皮生长因子受体基因的激活突变，开创了综合诊断和治疗的新时代——新的抗癌药物正在利用特定的基因缺陷，使恶性细胞更有可能对特定的治疗产生反应。尽管结果令人鼓舞，但并非所有过度表达 EGFR 或具有 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，吉非替尼尚未在神经胶质瘤患者中引起临床反应，尽管此类患者中 EGFR 基因扩增和重排的频率很高。对 TKI 的反应与 EGFR 表达不相关。肿瘤细胞对 EGFR 抑制的敏感性可能受到其他因素的影响，例如 EGFR 的激活突变、EGFR 配体的水平以及可能形成异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，我们在乳腺癌中检测到野生型 EGFR 与 EGFRvIII 共表达，以及 ErbB-2 与 EGFRvIII 共表达。评估 EGFRvIII 表达对这些 EGFR-TKI 反应的影响非常重要。为了实现这一目标，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依赖于 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)：评估EGFR靶向疗法对表达EGFR及其变异体的异种移植模型系统的治疗效果和药理作用。我们相信这些研究将提供有价值的信息，可能有助于优化现有药物并促进新药的开发。