WDR5 WIN Site Inhibition in Colorectal Cancer

项目总结

PROJECT SUMMARY Colorectal cancer is the third most common cancer in the United States. It accounts for over 50,000 deaths annually, the third highest cause of cancer related mortality in America. While improved screening methods and adherence have reduced the overall incidence of colon cancer in the US population as a whole, the incidence has increased in patients less than 50 years of age by 2% annually since the mid-1990s. Thus, new drug development is needed. This project investigates the mechanism and therapeutic potential of an indirect method of targeting MYC in colon cancer using small molecule inhibitors directed against MYC’s newly discovered cofactor WDR5. MYC is an oncogenic transcription factor overexpressed in the majority of human cancers, including colon cancer. As a transcription factor, MYC controls the expression of genes important for cancer cell growth and survival, but no pharmacologic method to inhibit MYC has been developed. WDR5 recruits MYC to a subset of its target genes. Recently developed WDR5 inhibitors block the ability of WDR5 to recruit MYC to its target genes. In so doing, WDR5 inhibitors serve as a novel means to inhibit a fundamental portion of oncogenic MYC transcriptional activity. Preliminary data reveal WDR5 inhibitors may represent a novel therapeutic strategy in colon cancer, yet little is known about the activity of these drugs in colon cancer cells. The proposed research includes a detailed mechanistic study of WDR5 inhibition in colon cancer, establishes molecular markers of sensitivity and resistance, and examines the breadth of WDR5 inhibitor activity as well as novel drug-drug combinatorial therapies in pre-clinical colon cancer models. Aim 1 of this project uses a combination of genomic, transcriptional, and proteomic approaches to fully characterize the molecular mechanism of WDR5 inhibitors in colon cancer cells and identify candidate pharmacodynamic biomarkers. Aim 2 will identify factors that govern sensitivity and resistance to WDR5 inhibitors, helping to forecast mechanisms of resistance as well as detect molecular pathways that can be targeted pharmacologically to improve response to WDR5 inhibition. Novel drug- drug combinations will be tested in cultured colon cancer cells and in a molecularly diverse panel of patient derived organoids, known for accurately predicting in vivo drug sensitivity. Results from these experiments may identify a subset of patients that could benefit from treatment with WDR5 inhibitors. Collectively these studies will lead to a robust understanding of the mechanism of WDR5 inhibitors and their utility as therapeutic agents in colon cancer. The results will provide practical pre-clinical evidence for possible patient selection criteria, pharmacodynamic biomarkers and novel combinatorial therapies that will be foundational to any future clinical trials of WDR5 inhibitors in colon cancer.