Quantitative Analysis of ErbB-Targeted-Drug Efficacy

描述（由申请人提供）：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，因此它们已成为癌症治疗的靶标，旨在通过抑制配体结合，受体二聚化和激酶活性来干扰其信号传导。虽然第一代这些药物显示出希望，但我们才刚刚开始了解它们如何起作用的细节（例如，受体运输的改变）以及在何种情况下（例如，ErbB表达谱）特定药物（或其组合）可能最有效。为了加强这种理解，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中断ErbB介导的信号传导的能力，以及这些抑制剂对ErbB运输（内化、再循环、降解）的影响。利用测量的参数，我们将开发一个ErbB运输和信号模型，以预测哪种治疗方法对给定的ErbB特征最有效。最终，这项工作预示着如何更好地设计ErbB靶向药物，以及如何根据ErbB表达最好地治疗个体。

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.