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

Introduction

Inhibitors of DNA topoisomerases (TOPs, TOP1, TOP2) are mainstays of anticancer therapy. While they have proven effective, the toxicity of current TOP drugs, caused by DNA damage-induced apoptosis of non-cancer cells, limits their use in the clinic. Development of tumour-specific TOP inhibitors will require a better knowledge of the mechanisms of TOPs. This research program aims to define how TOPs are regulated during transcription and replication and develop drugs that target these regulatory mechanisms for anticancer treatment.

Mechanism of TOPs

TOPs promote transcription and replication by removing DNA supercoiling generated during polymerase elongation. In my works published in Cell and Molecular Cell, I have discovered that the activity of TOPs in the cell 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.

Proposed Approach

Therefore, I propose that 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 with current TOP drugs.

Methodology

By using new genomic tools to analyze DNA topology, advanced biochemical and microscopy approaches, as well as drug screens, I will define the mechanism of MYC-driven transcriptional/replicational acceleration via topoisome assembly, and develop drugs blocking topoisome activity to arrest tumour growth.

Feasibility and Impact

I predict this proposal is feasible based on my excellent background, compelling preliminary data, and strong collaborations with scientists at KI and National Institutes of Health. The work will identify novel strategies to target TOPs that can be put forward in clinical trials for the benefit of society.

Conclusion

This new way of targeting TOPs to affect MYC activity constitutes a beyond the state-of-the-art and ground-breaking approach to the field of cancer biology.