Quantitative Analysis of ErbB-Targeted-Drug Efficacy

由于ErbB受体酪氨酸激酶（ErbB 1/EGFR， ErbB 2/HER 2/neu、ErbBS和ErbB 4）已经成为设计用于治疗癌症的癌症治疗剂的靶标。 它们通过抑制配体结合、受体二聚化和激酶活性来进行信号传导。而第一 这些药物的一代显示出希望，我们才刚刚开始了解它们如何工作的细节 (e.g.,受体运输的改变）以及在何种情况下（即，ErbB表达谱） 药剂（或其组合）可能是最有效的。为了加深这种理解，我们提出了一个 实验和建模方法。使用具有已知ErbB谱的细胞系，我们将测量 各种抑制剂中断ErbB介导的信号传导和这些抑制剂对ErbB的影响 贩运（内化、回收、退化）。使用测量的参数，我们将开发一个ErbB 运输和信号传导模型，以能够预测哪种治疗剂对给定的 ErbB配置文件。最终，这项工作预示着对如何更好地设计ErbB靶向 药物以及如何基于ErbB表达用可用疗法最好地治疗个体。

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 interferewith 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.