Quantitative Analysis of ErbB-Targeted-Drug Efficacy

描述(申请人提供)：由于ErbB受体酪氨酸激酶(ErbB1/EGFR、ErbB2/HER2/neu、ErbBS和ErbB4)的异常活性与人类癌症有关，已成为癌症治疗的靶点，旨在通过抑制配体结合、受体二聚化和激酶活性来干扰它们的信号转导。虽然这些药物的第一代显示出希望，但我们才刚刚开始了解它们如何发挥作用的细节(例如，受体贩运的变化)以及特定药物(或其组合)在什么情况下(即ErbB表达谱)可能最有效。为了加强这一理解，我们提出了一种实验和建模方法。利用已知ErbB谱的细胞系，我们将测量各种抑制剂阻断ErbB介导的信号传递的能力，以及这些抑制剂对ErbB转运(内化、循环、降解)的影响。使用测量的参数，我们将开发一个ErbB交易和信号传递模型，以预测对于给定的ErbB简档，哪种疗法将最有效。最终，这项工作预示着加强对如何更好地设计ErbB靶向药物以及如何根据ErbB的表达最好地使用可用的治疗方法来治疗个体的理解。

DESCRIPTION (provided by applicant): Because their aberrant activity is implicated in human cancer, ErbB receptor tyrosine kinases (ErbB1/EGFR, ErbB2/HER2/neu, ErbBS, and ErbB4) have become targets of cancer therapeutics designed to interfere with their signaling by inhibiting ligand binding, receptor dimerization, and kinase activity. While the first generation of these drugs shows promise, we are just beginning to appreciate the details of how they work (e.g., alterations to receptor trafficking) and in which contexts (i.e., ErbB expression profiles) particular agents (or combinations thereof) may be most effective. To enhance this understanding, we propose an experimental and modeling approach. Using cell lines with known ErbB profiles, we will measure the ability of various inhibitors to interrupt ErbB-mediated signaling and the effects of those inhibitors on ErbB trafficking (internalization, recycling, degradation). Using measured parameters, we will develop an ErbB trafficking and signaling model to enable prediction of which therapeutics will be most effective for a given ErbB profile. Ultimately, this work portends enhanced understanding of how to better design ErbB-targeted agents and how to best treat individuals with available therapies based on their ErbB expression.