MYCinTOPshape
Financiado
Mechanism and targeting of topoisomerase regulatory interactions to arrest MYC-d...
Mechanism and targeting of topoisomerase regulatory interactions to arrest MYC-driven tumors
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...
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 clinic. Development of tumour-specific TOP inhibitors will require a better knowledge of the mechanisms of TOPs. This research program aims to define how TOP are regulated during transcription and replication and develop drugs that target these regulatory mechanisms for anticancer treatment.
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. 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 to current TOP drugs.
By using new genomic tools to analyse 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. 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. 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.
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Duración del proyecto: 65 meses
Fecha Inicio: 2023-12-07
Fecha Fin: 2029-05-31
Fecha Fin: 2029-05-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-12-07
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2022-COG:
ERC CONSOLIDATOR GRANTS
Cerrada
hace 2 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
KAROLINSKA INSTITUTET
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5