Identification of Synthetic Lethal Targets for MYC-Driven Cancers

MYC is one of the most commonly activated oncogenes in human cancer. However, MYC as a transcription factor has been difficult to directly target with a therapeutic.

Our general hypothesis is that synthetic lethal targets for MYC high tumors will be an effective approach for treating human cancer.

To answer this, we are going to interrogate genes that are vital for MYC-high cancer cells while redundant for non-cancerous cells. After which their specific mechanisms are going to be elucidated. To reach these goals, we have performed a CRISPR based screen in a MYC-driven murine hepatocellular carcinoma (HCC).

There, we have identified essential genes in the context of both high and low MYC expression levels. From these, we identified a novel pathway with over 20 gene members that are involved in RNA transport. Our specific hypothesis is that nuclear to cytoplasmic transport performs an essential function in MYC high tumors.

To determine which genes that only is vital for tumor cells, we will individually knock out the genes in cancer and normal cells.

To this end, we will determine which of the 20 genes we found in nuclear to cytoplasmic transport are the best therapeutic targets, and identify the mechanism of how their inhibition elicits tumor regression. This project is planned to run over three years, the work will be done by Dr. Carl Herdenberg with the mentorship of Professor Dean Felsher.