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Team

eDyNAmiC

Challenge

Extrachromosomal DNA: Understand the biology of ecDNA generation and action, and develop approaches to target these mechanisms in cancer.

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Paul Mischel MD

Paul Mischel MD, Team Lead

Professor of Pathology

eDyNAmiC

INSTITUTIONS

13

LOCATIONS

UK, US, Germany

FUNDED BY

Cancer Research UK, National Cancer Institute

SPECIALISMS

cancer biology, genetics, chemistry, evolutionary biology, computer science, maths and clinical research

Cancer’s surprising circular genome: developing new ways to treat some of the most challenging forms of cancer

Funded by:

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funders

The eDyNAmiC team seeks to be a model of collaborative science to gain new insights into extrachromosomal DNA, translating them into new treatments for people with some of the hardest-to-treat types of cancer.

Tumour evolution, driven by genetic diversity, poses a major clinical problem by enabling tumours to resist treatment. A major driver of tumour evolution is extrachromosomal DNA (ecDNA), small circular DNA particles that cells to rapidly change their genomes and can drive adaptive evolution in diverse organisms. Although ecDNA was first observed in cancer in 1965, we are only now appreciating its presence in around a third of cancers and the extent to which it drives tumour evolution, promoting aggressive tumour behaviour and poorer patient survival. 

Many questions about ecDNA remain unanswered. How does it form and function? How does it evade the immune system? Can we find its vulnerabilities and target them to benefit patients? This Cancer Grand Challenge invited teams to foster bold collaborations and innovative solutions to interrogate this fundamental aspect of cancer biology and potentially launch a new field of cancer therapeutics. 

The Cancer Grand Challenges eDyNAmiC team aims to foster bold collaborations and innovative solutions to interrogate this fundamental aspect of cancer biology and potentially launch a new field of cancer therapeutics. 

Tackling the Extrachromosomal DNA Challenge

The team’s three overarching aims, uniting seven areas of research, are each aspirational but grounded in substantial preliminary data and leveraging the team members’ unique expertise.

  1. Identify the mechanisms of ecDNA generation, function and maintenance 

Using model systems and human samples, the team aims to understand the mechanisms of ecDNA generation, function and maintenance, including underlying mutational signatures. Among many goals, they hope to better understand ecDNA hubs – precursor structures that may provide novel therapeutic targets. 

  1. Decipher ecDNA’s roles in tumour evolution driving cancer heterogeneity, progression and drug resistance 

Using multi-regional tumour sequencing, single-cell omics, live-cell imaging and computational modelling, the team hopes to understand how ecDNA subverts conventional evolution and enables tumour cells to grow, evade the immune system and resist treatments. This information could help identify patients with ecDNA-driven cancers and lead to new blood-based diagnostics for early detection and therapeutic monitoring. 

  1. Identify targetable vulnerabilities of ecDNA-driven cancers 

By unravelling ecDNA’s potential to trigger the immune system and relating it to features such as chromatin structure, the team hopes to enable ecDNA-targeting immunotherapies. The team will explore the vulnerabilities of ecDNA-containing cells and attempt to target them with first-in-class chemical probes, to provide a starting point for new therapeutics targeting ecDNA-driven cancers. 

Many of the Cancer Grand Challenges eDyNAmiC team members are pioneers in the ecDNA field. Together, they hope to bring new perspectives and technologies to the ecDNA challenge, and ultimately find new ways to target highly aggressive cancers by attacking their unstable genomes and drugging currently undruggable targets.

Their ambitious approach could transform understanding of this fundamental aspect of cancer biology and provide new insights into diagnosis, monitoring and treatment of patients in whom current therapies fail. 

Paul Mischel MD

Paul Mischel MD, Team Lead

Professor of Pathology

We want to bring new hope to patients and have assembled an aspirational, ambitious programme, which could happen only under the auspices of Cancer Grand Challenges.
Paul Mischel MD
Dr Howard Chang
Dr Michelle Monje
Dr Jef Boeke
Dr Benjamin Cravatt
Harmit Malik headshot
Dr Zhijian (James) Chen
Dr Roel G.W.Verhaak
Dr Vineet Bafna
Dr Anton Henssen
Dr Benjamin Werner
Dr Weini Huang
Dr Mariam Jamal-Hanjani
Professor Serena Nik-Zainal
David Arons headshot
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