Understanding how MYC drives transcriptional amplification via regulation of DNA topology

Inhibitors of Topoisomerases (TOPs, TOP1, TOP2) are mainstays of anticancer therapy. While they have proven effective, the toxicity of current TOP drugs in non-cancer cells, limits their use. Development of tumour-specific TOP inhibitors will require a better knowledge of TOPs. This project will define how TOP are regulated and target these regulatory mechanisms with drugs.

TOPs promote transcription and replication by cleaving/resealing DNA strands, removing supercoils generated during polymerase elongation. In my works published in Cell and Mol Cell, I discovered that the activity of TOPs is regulated.

The oncoprotein MYC joins TOP1 and TOP2 in a topoisome complex and stimulates their activities to boost cell proliferation.

Targeting the mechanism of the topoisome instead of the single TOPs might selectively halt MYC while preserving physiological TOP activity, avoiding DNA damage associated to current TOP drugs.By using genomics, biochemical and microscopy approaches, as well as drug screens, I will define the mechanism of MYC-driven cellular proliferation via regulation of the topoisome and develop drugs blocking the topoisome to arrest tumor growth.

This project is feasible based on compelling preliminary data and collaborations.

The work will identify novel drugs to target TOPs that can be put forward in clinical trials for the benefit of the society. This new way of targeting TOPs to affect MYC is a beyond the state-of-the-art approach to the field of cancer biology.