Mechanism and targeting of topoisomerase regulatory interactions to arrest MYC-driven tumors

Inhibitors of DNA topoisomerases (TOPs, TOP1 and 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 the mechanisms of TOP.

This proposal will define how TOP are regulated and will target these regulatory mechanisms with drugs.My works published in Cell and Molecular Cell have shown that the DNA cleavage-religation activity of TOPs is regulated.

The oncoprotein MYC joins TOP1 and TOP2 in a “topoisome” complex and stimulates their activities to remove the supercoiling produced during transcription and replication, thus boosting cellular proliferation.

Therefore, targeting the mechanism of the topoisome instead of the single TOPs, will selectively halt MYC oncogenic function while preserving physiological TOP activity, avoiding the generation of DNA damage associated to current TOP drugs.By using new genomic tools to study TOPs, biochemical and microscopy approaches, as well as drug screens, I will define the mechanism of MYC-driven transcriptional amplification via topoisome assembly and develop drugs blocking topoisome activity to arrest tumour growth.

This proposal is highly feasible based on my background, compelling preliminary data, and strong collaborations with KI and NIH. My work will identify novel ways to target TOPs that can be put forward in clinical trials for the benefit of society.