Extrachromosomal DNA: Understand the biology of ecDNA generation and action, and develop approaches to target these mechanisms in cancer.
Paul Mischel MD, Team Lead
Professor of Pathology
UK, US, Germany
Cancer Research UK, National Cancer Institute
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
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.
- 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.
- 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.
- 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, 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 is a physician scientist trained in pathology and cancer biology. His lab has made a series of seminal discoveries that have identified a central role for ecDNA (extrachromosomal DNA) in cancer development, progression, accelerated tumor evolution and drug resistance. These findings have provided a new understanding of the fundamental mechanisms of oncogene amplification and the spatial organization of altered tumor genomes, launching a new area of cancer research that links circular architecture with tumor pathogenesis.
Paul’s lab has also uncovered actionable metabolic co-dependencies that are downstream consequences of oncogene amplification, including in the highly lethal brain cancer glioblastoma, that are poised for therapeutic exploitation. These include a central role for altered biochemical mechanisms that regulate oncogene copy number and function. These discoveries have resulted in new understandings of some of the fundamental processes by which oncogene amplification drives cancer progression and drug resistance in the changing environments within which tumors develop.
Paul is an Elected Fellow and Past-President of the American Society for Clinical Investigation. He is also an Elected Fellow of the American Association of Physicians, and The American Association for the Advancement of Science.
Dr Howard Chang seeks to understand the role in disease played by a class of genes called long noncoding RNAs, which are pervasive in the human genome yet have limited or no protein-coding potential. His team invents new technologies for genome-wide analyses to tackle the vastness of the noncoding genome with greater comprehensiveness and precision than was previously possible. Howard’s team has discovered that long noncoding RNAs have diverse modes of action when it comes to gene control and are key contributors to some human diseases such as cancer. Now the team is focused particularly on the interplay of regulatory RNAs and chromatin, seeking out new archetypes of regulatory RNAs and novel mechanisms for gene regulation.
Dr Michelle Monje, MD, PhD, is a professor of Neurology and Neurological Sciences at Stanford University and a Howard Hughes Medical Institute Investigator. She is recognized as an international leader in the pathophysiology of glioma, especially diffuse intrinsic pontine glioma (DIPG)/H3K27M-mutated diffuse midline gliomas and a pioneer in the emerging field of Cancer Neuroscience. Her clinical focus is on childhood glial malignancies and cognitive impairment after childhood cancer therapy.
Her laboratory studies neuron-glial interactions in health and disease, with a particular focus on mechanisms and consequences of neuron-glial interactions in health, glial dysfunction in cancer therapy-related cognitive impairment and neuron-glial interactions in malignant glioma. Together with these basic studies, Michelle's research program has advanced preclinical studies of novel therapeutics for pediatric high-grade gliomas and cancer therapy-related cognitive impairment in order to translate new therapies to the clinic. She has led several of her discoveries from basic molecular work to clinical trials for children and young adults with brain tumors including a promising clinical trial of CAR T cell therapy for DIPG and diffuse midline gliomas.
Dr Jef Boeke, the founding director of The Institute for Systems Genetics at NYU Langone Health, is known for foundational work on mechanistic and genomic aspects of retrotransposition. He is a pioneer of synthetic genome construction, as he synthesized the first artificial yeast chromosome de novo. He also leads an international consortium that built the highly engineered genome of the first synthetic eukaryote, Yeast 2.0. Using big DNA technology to build mammalian gene loci in yeast and then delivering those loci and their variants to stem cells, Dr. Boeke and his team are working to understand the “instruction manuals” that specify how human genes are expressed. This research has informed technology that enables the rapid design and development of humanized mouse models for studying the treatment of diseases. Boeke has founded several biotechnology companies, including Avigen Inc., CDI Labs, and Neochromosome, Inc. Most recently, his lab developed a highly automated RT-PCR workflow and software infrastructure that is central to a COVID testing pipeline deployed by another company he helped found, the Pandemic Response Lab.
New York University
Dr Benjamin Cravatt is Professor and Norton B. Gilula Chair of Chemical Biology in the Department of Chemistry at The Scripps Research Institute. His research group is interested in developing chemical proteomic technologies that enable protein and drug discovery on a global scale and applying these methods to characterize biochemical pathways that play important roles in human physiology and disease. Dr. Cravatt obtained his undergraduate education at Stanford University, receiving a B.S. in the Biological Sciences and a B.A. in History. He then received a Ph.D. from The Scripps Research Institute (TSRI) in 1996. Professor Cravatt joined the faculty at TSRI in 1997. Dr. Cravatt’s honors include a Searle Scholar Award, the Eli Lilly Award in Biological Chemistry, a Cope Scholar Award, the ASBMB Merck Award, the RSC Jeremy Knowles Award, the AACR Award for Achievement in Chemistry in Cancer Research, the Wolf Prize in Chemistry, and memberships in the National Academies of Medicine and Sciences.
Scripps Research Institute
Harmit Malik got his Bachelors in Technology in Chemical Engineering at the Indian Institute of Technology, Mumbai, India. There, he became interested in molecular biology due to Prof. K. K. Rao and in evolution by reading Richard Dawkins' "The Selfish Gene." He then moved to the US to get his Ph.D. in Biology, at the University of Rochester, NY, under the mentorship of Prof. Thomas Eickbush, to work on the evolution of retrotransposable elements. In 1999, he moved to Seattle to the Fred Hutchinson Cancer Research Center (the "Hutch"), to do his postdoc with Dr. Steve Henikoff on the evolution of centromeres and centromeric proteins. In 2003, he started his own lab at the Hutch, where he has been ever since. Together with his colleague Michael Emerman, Malik and his trainees have used an evolutionary lens to dissect and discover both primate antiviral as well as viral adaptation strategies. By taking advantage of viral "fossils" in animal genomes and intense episodes of ancient host gene adaptation, his work has helped found the field of Paleovirology. In 2009, he was awarded an Early Career Scientist of the Howard Hughes Medical Institute and a Full Investigator in 2013. Most recently, he was awarded the 2017 Eli Lilly Prize in Microbiology, the most prestigious prize awarded by the American Society of Microbiology. In 2022, he was awarded the Edward Novitski Prize by the Genetics Society of America for 'extraordinary level of creativity and intellectual ingenuity in the solution of significant problems in genetics research’. Harmit was elected to the National Academy of Sciences in 2019 and to the American Academy of Arts and Sciences in 2022.
Fred Hutchinson Cancer Research Center
Zhijian ‘James’ Chen is an Investigator of Howard Hughes Medical Institute, and Professor in the Department of Molecular Biology at the University of Texas Southwestern Medical Center at Dallas. Prior to moving to Dallas, Chen was a senior scientist at ProScript Inc. where he helped discover the proteasome inhibitor VELCADE, a medicine used for the treatment of multiple myeloma. After joining UT Southwestern in 1997, Chen discovered the regulatory role of ubiquitination in protein kinase activation in the NF-kB and MAP kinase pathways. In addition, he discovered the Mitochondrial Antiviral Signaling (MAVS) protein that reveals a new role of mitochondria in immunity. In 2012, Chen discovered cyclic GMP-AMP synthase (cGAS) as a cytosolic DNA sensor and a new cyclic di-nucleotide signaling pathway that mediate innate immune responses in animal cells. For his work, Chen has received numerous honors including the National Academy of Science Award in Molecular Biology (2012), the American Society of Biochemistry and Molecular Biology (ASBMB) Merck Award (2015), the Lurie Prize in Biomedical Sciences from the Foundation of NIH (2018), the Breakthrough Prize in Life Sciences (2019), the Switzer Prize (2019) and the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology (2020). Chen is a member of the National Academy of Sciences.
As part of Cancer Grand Challenges, he will lead a team investigating immune responses to ecDNA in cancer.
The University of Texas Southwestern Medical Center
Roel Verhaak, PhD., is a Professor and Associate Director of the Jackson Laboratory for Genomic Medicine in Farmington, CT. The Verhaak lab studies tumor evolution and mechanisms of therapy resistance using genomic characterization and computational analyses, in particular as it relates to brain tumors. Following the observation that extrachromosomal DNA amplifications (ecDNA) drive tumor evolution in glioblastoma (DeCarvalho et al, Nat Genetics, 2018), the lab is dedicated to understand how the presence of ecDNA can be leveraged to improve cancer outcomes. Important results include showing that ecDNA is frequent across cancer (Kim et al, Nat Genetics, 2020) and the identification of ecDNA hubs as the functional units of cargo gene transcription (Yi et al, Cancer Discovery, 2021). Roel Verhaak is a recipient of the AAAS Wachtel Award, the Agilent Early Career Professor Award, and the Peter Steck Memorial Award.
Jackson Laboratory for Genomic Medicine
Vineet Bafna, Ph.D, is a Bioinformatics researcher and a Professor of Computer Science and the Halicioglu Data Science Institute at UC San Diego. He received his Ph.D. in computer science from The Pennsylvania State University in 1994 working on theoretical problems in genome rearrangements. His introduction of the breakpoint graph as an analytical tool has been an important driver of the field. After an NSF funded postdoctoral research at the Center for Discrete Mathematics and Theoretical Computer Science, Bafna was a senior investigator at SmithKline Beecham, conducting research on DNA signaling, target discovery and EST assembly. From 1999 to 2002, he worked at Celera Genomics, ultimately as director of Informatics Research, participating in the assembly and annotation of the human genome. Vineet Bafna’s research focuses cancer genomics and population genetics. He has made important contributions in the analysis of breakage fusion bridge cycles, extrachromosomal DNA, identifying the genetic signals of adaptation, analyzing experimental evolution, and proteogenomics. He has co-authored over 150 research articles in the leading journals in the field. He served as co-Director of the Bioinformatics and Systems Biology Ph.D. program from 2013-19, and was founding faculty of the Halicioglu Data Science Institute at UCSD. He has co-founded two companies: Abterra, LLC, which focuses on services and products relating to proteogenomic data, and Boundless Bio, Inc., which is targeting extrachromosomal DNA in cancer. In 2019, he was selected as a fellow of the International Society of Computational Biology.
University of California, San Diego
Professor Anton Henssen is a peadiatric oncologist who leads the paediatric oncology preclinical research program at the Charité University Hospital and heads a research group at the Experimental and Clinical Research Center of the Max Delbrück Center in Berlin. His research group that has transformed our understanding of how extrachromosomal DNA (ecDNA) contributes to genome remodeling in childhood cancers. Ultimately, his lab tries to find new ways to translate this research to improve cancer therapy. Anton is the recipient of an ERC starting grant and an endowed Mildred-Scheel Professorship. He is the recipient of many prestigious awards such as the Berlin science award and the Kind Philipp Prize.
Max Delbrück Center for Molecular Medicine; Charite Berlin
Dr. Benjamin Werner is a group leader at the Barts Cancer Institute in London, where he works on somatic evolutionary theory in healthy and cancerous tissues. He studied Physics at the University of Leipzig, did a PhD in evolutionary theory at the Max Planck Institute for Evolutionary Biology and worked on mathematical models of cancer evolution as a Post Doc at the Institute of Cancer Research in London.
Queen Mary University of London
Dr Weini Huang is a Senior Lecturer in Mathematical Biology. She has an interdisciplinary background in applied math, information systems, evolutionary biology and cancer biology. She applies evolutionary theory to model hetergenetity in biology populations, including tumour and health tissues. She has created models for ecDNA evolution and random segregation.
Queen Mary University of London
Dr Mariam Jamal-Hanjani is a lung medical oncologist and cancer researcher at the University College London Cancer Institute. Her early research in chromosomal instability and intratumour heterogeneity demonstrated the prognostic relevance of genomic instability in lung cancer. In 2012 she was awarded a CRUK Clinical Research Fellowship to complete her PhD studies for which she was awarded the McElwain and the Sylvia Lawler Scientific Prizes. In 2016 she was awarded an NIHR Clinical Lectureship to continue to her work in the field of cancer evolution in the UK-wide TRACERx and PEACE studies. In 2021 she was awarded a CRUK Career Establishment Award to study the biological processes driving metastatic disease and death in lung cancer, including tumour- and host-initiated mediators of cachexia, and failure of the adaptive immune system leading to tumour immune escape.
University College London
Serena is Professor of Genomic Medicine and Bioinformatics and an NIHR Research Professor at University of Cambridge. Following a first-class degree in preclinical science, Serena obtained a medical degree from the University of Cambridge in December 2000, sponsored by Petroliam Nasional Berhad Malaysia (PETRONAS). She trained in general internal medicine before specializing in Clinical Genetics. She has been an Honorary Consultant in Clinical Genetics at Cambridge University Hospitals NHS Foundation Trust since February 2013 and recruited patients with DNA repair defects as part of the Insignia project until December 2018.
Serena undertook a PhD at Wellcome Sanger Institute (WSI) exploring cancer using next-generation sequencing (NGS) technology in 2009. She was heavily involved in development of the whole genome sequencing (WGS) somatic variation pipeline and the development of an array of analytical principles that revealed the underlying abnormal biology of tumors – including generalized mutational signatures, imprints left by mutagenic processes that have occurred through cancer development, a novel phenomenon of localized hypermutation termed “kataegis”, and was part of the team that developed the principles of constructing a cancer evolutionary tree from a single tumour sample.
In a post-doctoral role and as an early investigator, Serena continued bioinformatic exploration of large cancer datasets, leading production and analyses of the largest cohort of WGS cancers of a single tissue-type, of 560 breast cancers. She began pursuing experimental validation of mutational signatures, dissecting mechanisms of mutagenesis using cellular models. Human induced pluripotent stem cells were used to generate CRISPR-Cas9 knockouts of DNA repair genes and were systematically treated with a variety of environmental mutagens. The results of these endeavours have revealed new insights into mechanisms of mutagenesis in human somatic cells and serve as a reference resource of validated human mutational signatures.
Serena is now lead of the Genomic Medicine theme at the NIHR Cambridge Biomedical Research Campus. Her team continues to advance the whole cancer genomics field through a combination of computational and experimental approaches, to ultimately create clinical applications. With seven patent filings in recent years, they are unravelling mutational mechanisms, developing machine-learning based clinical algorithms, and actively connecting with clinical trials to validate their algorithmic tools. They are also deeply embedded with the UK 100,000 Genomes Project and have performed quality control and pan-cancer analyses/interpretation of more than 15,000 whole cancer genomes to date.
University of Cambridge
David Arons is the Chief Executive Officer of the National Brain Tumor Society (NBTS). In his current role, David provides leadership and management for NBTS and its venture philanthropy affiliate, the Brain Tumor Investment Fund. Fighting cancer is personal to David as he lost his father to cancer as a teenager. Prior to joining NBTS, he served in leadership and external positions at the American Cancer Society in Minnesota, co-founded the Center for Lobbying in the Public Interest, and worked at Independent Sector in Washington, D.C. As a litigation attorney, he previously represented patients facing disabilities and serious health conditions. He is the author of several books, including “Power in Policy: A Funder’s Guide to Advocacy and Civic Participation,” “Strengthening Nonprofit Advocacy,” and “A Voice for Nonprofits.” David has served on the National Cancer Institute’s Council of Research Advocates and Clinical Trials Advisory Committee. In 2016, David was named to the Blue Ribbon Panel of experts selected to help advise the National Cancer Moonshot, led by former Vice President, now President Biden.
National Brain Tumor Society
Deutsche Kinderkrebsstiftung (German Childhood Cancer Foundation)