Targeting Topoisomerase Regulation of Oncogenic Growth

Cancer is a leading cause of death. Inhibitors of topoisomerases (TOPs) are mainstays of anti-cancer therapy. While they have proven effective, the toxicity of current TOP drugs in non-cancer cells limits their use. Development of tumor-specific TOP inhibitors will require better knowledge of TOP biology.

This proposal aims to define how TOPs are regulated and to target these regulatory mechanisms with drugs.TOPs promote transcription by cleaving-resealing DNA strands, removing supercoiling produced during elongation. In my work published in Cell, I discovered that the activity of TOPs is regulated.

In my study currently in revision at Cell, I show that the oncoprotein MYC nucleates TOPs into a complex and stimulates their activity to promote fast cellular grow.

Therefore, targeting the interactions that stimulate the activity of TOPs above their basal level will halt oncogenic overexpression while preserving physiological TOP activity, avoiding the DNA damage associated with current TOP drugs .

By using molecular and genomic approaches as well as drug screens I will define how MYC regulates TOP activity and discover novel drugs targeting the interaction with TOPs. I will apply translational approaches to test drugs targeting TOP regulation in tumor models. Based on my compelling data and strong collaborations, I predict this project to be highly feasible.

My work will identify novel ways to target TOPs that can be put forward in clinical trials for the benefit of society.