Analysis of Tumorigenic Signaling Pathways with PROTACS

描述（由申请人提供）：确定特定癌症治疗过程的关键部分是鉴定导致恶性生长的特定活化信号通路。事实上，特定癌症的治疗可能取决于激活的信号传导途径;例如，HER 2/neu阳性与阴性乳腺癌的治疗方法不同。Abl酪氨酸激酶抑制剂Gleevec的开发是这种个性化医疗方法的最佳例证，它彻底改变了CML的治疗。随着越来越多的药物靶向特定的信号通路的开发，它将是重要的，以确定这些致癌信号通路激活在一个给定的肿瘤活检。为此，我们的长期目标是开发一个小分子库，用作评估原发性癌组织样本的诊断工具。我们最近开发了一种称为PROteolysis Targeting Chimera molecules（PROTAC）的新技术，可以选择性地敲除体内特定的蛋白质。这些细胞可渗透的异双功能分子利用细胞自身的泛素/蛋白酶体蛋白降解途径来选择性地破坏我们选择的靶蛋白。我们建议调整这项技术，以便肿瘤持续生长所需的蛋白质仅在具有特定激活的酪氨酸激酶途径的细胞中降解。通过这种方式，将有可能鉴定出在特定肿瘤细胞中上调的那些信号通路，以及其生长所需的那些信号通路。为了实现新的肿瘤诊断技术开发的目标，在随后的R33应用中，我们建议开发一组可用于识别激活的癌细胞信号通路的PROTAC。将对该面板进行测试，以用作确定最佳药物治疗过程的诊断工具。

DESCRIPTION (provided by applicant): A key part of determining the course of treatment for a specific cancer is the identification of the specific activated signaling pathways, which are causing the malignant growth. In fact the treatment for a given cancer can be dependent upon the activated signaling pathway; for example HER2/neu positive vs. negative breast cancers are treated differently. This personalized medicine approach is best exemplified by the development of the Abl tyrosine kinase inhibitor Gleevec, which has revolutionized the treatment of CML. As more drugs targeting specific signaling pathways are developed, it will be important to identify those oncogenic signaling pathways activated in a given tumor biopsy. Towards this end, our long-term goal is the development of a library of small molecules to be used as diagnostic tools for assessing primary cancerous tissue samples. We have recently developed a new technology known as PROteolysis TArgeting Chimera molecules (PROTACs) that can selectively knock down a specific protein in vivo. These cell permeable hetero- bifunctional molecules utilize the cells own ubiquitin/proteasome protein degradation pathway to selectively destroy a target protein of our choosing. We propose to adapt this technology so that proteins required for continued tumor growth are degraded only in those cells with a particular activated tyrosine kinase pathway. In this way, it will be possible to identify those signaling pathways upregulated in a particular tumor cell and which are required for its growth. Towards the goal of novel tumor diagnostic technology development, in the subsequent R33 application, we propose to develop a panel of PROTACs that can be used in identifying the activated cancerous cell signaling pathways. This panel will be tested for use as a diagnostic tool for determining the best course of drug treatment.