The eDyNAmiC team is supported through the Cancer Grand Challenges initiative. Learn more here

Our Research

Visualizing cytosolic DNA in cancer cells

Aims

Our proposed Aims are aspirational, integrated, and ambitious.

  • Aim 1: To identify the mechanisms involved in generation, function, and maintenance of ecDNA.
  • Aim 2: To determine the role of ecDNA in tumor evolution: understanding and predicting how ecDNA drives cancer heterogeneity, progression, and drug resistance
  • Aim 3: To identify targetable vulnerabilities of ecDNA-driven cancers that could be exploited for treatment

Team eDyNAmiC is poised to remove existing barriers and transform the field of cancer research. We will do this by: 

  • Building a pioneering team;
  • Discovering mechanisms of formation, maintenance, function, evolution, immunology, and genetic and tissue contexts of ecDNA;
  • Innovating to detect ecDNA in cancer patients and create new blood-based diagnostics for early detection and treatment monitoring;
  • Creating a suite of first-in-class chemical probes as starting points for a transformative new class of medicines to treat ecDNA-driven cancers;
  • Advocating for patients whose cancers are driven by ecDNA, and their families, through education and support;
  • Sharing a suite of tools, data, and models with the broader scientific community to accelerate progress.

Work Packages

WP1 uses powerful genetic approaches to understand how ecDNA forms and how it functions. We have succeeded in using genetic approaches to make ecDNA-driven tumors in mice, opening a new opportunity for understanding its fundamental biology, including its interaction with the immune system, and probing therapeutic vulnerabilities.

WP2 focuses on understanding the unique and powerful ways by which the circular structure of ecDNA and the interactions between ecDNA particles in the nucleus of cancer cells change how genes are regulated to promote tumour growth and to drive resistance.

WP3 applies a powerful toolkit of mutational signatures to investigate the factors leading to ecDNA formation, and subsequently, to understand what mutational processes contribute to both ecDNA and tumour evolution during progression, treatment resistance, and metastasis.

WP4 maximizes learning from patients, leveraging the powerful, CRUK-funded TRACERx and PEACE datasets, as well as the Genomics England Cohort, the Hartwig cohort, and other datasets. We are learning about when and where ecDNA forms; how it changes over time, over space, and with treatment; and about the level and composition of ecDNAs, including how they resist treatment and suppress the immune response.

WP5 focuses on understanding the evolutionary dynamics of ecDNA in human cancers. Our goal is to uncover the core principles guiding ecDNA evolution in aggressive cancers, encompassing aspects like random inheritance, ecDNA generation and reintegration, mutagenesis, selection forces, copy number variation, spatial distribution, and treatment-driven changes. WP5 is unique in that it integrates computational and mathematical models of somatic evolution with clinical and experimental data.

WP6 focuses on understanding the ecDNA sensing mechanism through innate immunity, aiming to develop immune-targeting approaches to treat ecDNA-driven cancers. Understanding how ecDNA flies under the radar of detection, and how to turn defenses back on, will be critical for understanding ecDNA biology and developing immunologically-informed treatments.

WP7 focuses on the discovery and optimization of chemical probes for ecDNA-relevant proteins. As our understanding of the mechanisms governing ecDNA formation, stability, and turnover deepens, certain proteins linked to these processes have become focal points for chemical probe and drug development. WP7 leverages innovative chemical proteomic and covalent chemistry methods to accelerate the discovery of ligands for historically undruggable proteins.

Research News

eDyNAmiC
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