Project 2: Targeting MYC in Colorectal Cancer

Vanderbilt University Medical Center, Nashville TN

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT: Project 2 MYC oncoprotein transcription factors are overexpressed in a majority of malignancies and contribute to ~100,000 cancer-related deaths each year in the USA. There is a clear unmet need for targeted therapies to treat MYC-driven cancers, especially in colorectal cancer (CRC), where dysregulation of Wnt/β-catenin signaling leads to pathophysiological activation of the canonical c-MYC protein. MYC itself, however, is widely viewed as undruggable, meaning that innovative new strategies are needed to pharmacologically thwart MYC function in CRC. Together with the Fesik laboratory, we pioneered and reduced to practice the idea that MYC can be targeted through WDR5, a co-factor that it uses to drive enhanced protein synthesis in cancer cells. Supported by the NCI Experimental Therapeutics (NExT) Program, we developed a potent and orally bioavailable inhibitor of the "WIN" site of WDR5, characterized its mechanism of action, and showed that it is active against hematologic malignancies in vivo. A clinical candidate WIN site inhibitor (WINi) was recently declared and is making its way to IND enabling and a phase I clinical trial. Supported by this GI SPORE, we have laid the foundation for the application of WINi for the treatment of CRC. In the last cycle, we exposed the mechanism of action of WINi in CRC, showed single agent activity against CRC in vivo, and identified genetic modifiers of response as well as potential drug combinations that can increase WIN site inhibitor activity. In this renewal, we will gather essential new information to support the clinical implementation of WINi for the treatment of CRC. Cutting edge genetic, genomic, and proteomic approaches, together with sophisticated tissue culture models, will be deployed to identify and validate patient selection criteria, predict pathways of resistance, identify and validate surrogate biomarkers, and prioritize mechanism-driven drug synergies. The resulting biological insight and output will be used to support a phase II clinical trial to determine the efficacy of WIN site inhibition in CRC patients. Backed by the superb resources and infrastructure of the Vanderbilt GI SPORE, an experienced and capable team, and a highly-vetted clinical candidate WINi, this project is poised to complete the first-in-class trial of a new therapy for patients with metastatic CRC for which there are currently very limited treatment options. Results of these studies will also lay the foundation for the clinical application of these agents against other solid tumor types.