A study co-authored by Boundless Bio scientific founders Paul Mischel, Vineet Bafna, Howard Chang, and Roel Verhaak describes new mechanisms by which the unique circular architecture of ecDNA drives aggressive cancer growth, resistance, and recurrence
SAN DIEGO–(BUSINESS WIRE)–Boundless Bio, a company interrogating and targeting extrachromosomal DNA (ecDNA) in aggressive cancers, today announced that research describing new mechanisms by which ecDNA drive cancer growth, resistance, and recurrence has been published in the journal Nature. The manuscript, “Circular ecDNA promote accessible chromatin and high oncogene expression,” was co-authored by Boundless Bio’s scientific founders Paul Mischel, M.D., Distinguished Professor at the University of California San Diego (UC San Diego) School of Medicine and a member of the Ludwig Institute for Cancer Research; Vineet Bafna, Ph.D., Professor of Computer Science & Engineering, UC San Diego; Howard Chang, M.D., Ph.D., Virginia and D.K. Ludwig Professor of Cancer Genomics and Genetics, Stanford University; and Roel Verhaak, Ph.D., Professor and Associate Director of Computational Biology, The Jackson Laboratory. Boundless Bio scientists Kristen Turner, Ph.D. and Nam Nguyen, Ph.D. were co-lead authors on the manuscript as well.
The paper describes, for the first time, how ecDNA encode information not only in their sequence but also in their shape, enabling a new understanding of how ecDNA drive aggressive tumor growth. ecDNA differ profoundly in their shape from human chromosomal DNA in ways that have not been well-understood, and until now, the impact of the physical shape of ecDNA on cancer biology has remained a mystery. Mischel and his collaborators conducted an in-depth analysis of the structure of ecDNA in cancer, revealing a circular structure that is organized around protein cores in a different way than normal chromosomal DNA. They showed that ecDNA are wound around protein cores in a fashion that permits a far greater level of accessibility to the transcriptional machinery than occurs on chromosomes. As a result of this unique architecture, along with the very high number of ecDNA particles inside a tumor cell, oncogenes that are amplified on ecDNA are amongst the most highly transcribed genes in a tumor.
The researchers also showed that the circular architecture of ecDNA permits new regulatory interactions that might be important in controlling gene expression in cancer. These findings enabled the team to construct topologically informed circular maps of ecDNA that may potentially prove to be of value in guiding treatment for patients. These new findings build on and expand the impact of previous work from the team, which showed that ecDNA amplification is common in cancer and that it can drive aggressive growth and treatment resistance in part through the way that DNA is passed from mother cells to daughter cells (Turner et al., Nature, 2017; Verhaak et al., Nature Reviews Cancer, 2019; de Carvalho et al., Nature Genetics, 2018; Nathanson et al., Science, 2014).
“The findings published in Nature represent a major leap forward in our understanding of both the structure of ecDNA and of the significant role that ecDNA play in promoting cancer growth and resistance,” said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. “This new research arms us with essential knowledge that will enable our team at Boundless Bio to develop the first medicines capable of targeting the underlying biology that causes overexpressed oncogenes to develop and perpetuate in tumors that historically have been difficult-to-treat.”
“This new study sheds light on how the three-dimensional architecture of ecDNA plays a critical role in driving aggressive cancer growth and provides an important bridge between cancer genomics and epigenetics,” said Dr. Mischel. “These are exciting findings that we believe will propel Boundless Bio’s efforts to develop transformative new cancer medicines that eliminate cancer cells’ ability to employ ecDNA to drive cancer.”
Extrachromosomal DNA, or ecDNA, are large circles of DNA containing genes that are outside the cells’ chromosomes and can make many copies of themselves. ecDNA can be rapidly replicated within the cell, causing high numbers of oncogene copies, a trait that can be passed to daughter cells in asymmetric ways during cell division. Cells have the ability to upregulate or downregulate ecDNA and resulting oncogenes to ensure survival under selective pressures, including chemotherapy or radiation, making ecDNA one of cancer cells’ primary mechanisms of recurrence and treatment evasion. ecDNA are rarely seen in healthy cells but are found in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.
About Boundless Bio
Boundless Bio is a biotechnology company focused on interrogating a novel area of cancer biology, extrachromosomal DNA (ecDNA), to deliver transformative therapies to patients with previously intractable cancers. For more information, visit www.boundlessbio.com.
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