Analysis of Tumorigenic Signaling Pathways with PROTACS

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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.