Molecular Mechanisms of Blockage of ErbB receptors

描述（由申请人提供）：目前在癌症治疗中使用egfr靶向方法的基本原理已经确立，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EGFR靶向药物是否对缺失突变体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，它增强了致瘤性，通常与侵袭性肿瘤表型相关。EGFR-TKIs在实体瘤的靶向治疗中仍然是一个显著的进步。最近发现的药物反应预测非小细胞肺癌患者使用吉非替尼（易瑞沙）治疗时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遗传缺陷，使恶性细胞更有可能对特定治疗产生反应。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，吉非替尼在胶质瘤患者中没有引起临床反应，尽管这类患者中EGFR基因扩增和重排的频率很高。对TKIs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激活突变、EGFR配体水平和其他可能形成异源二聚体并允许持续信号放大的ErbB家族成员的表达。此外，我们已经在乳腺癌中检测到野生型EGFR与EGFRvIII的共表达，以及ErbB-2与EGFRvIII的共表达。评估EGFRvIII表达对这些EGFR-TKIs应答的影响是很重要的。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)：评价EGFR靶向治疗对表达EGFR及其变异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，有助于优化现有药物和促进新药物的开发。

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.