SAN DIEGO–(BUSINESS WIRE)–Boundless Bio, a company developing innovative new therapies directed to extrachromosomal DNA (ecDNA) in aggressive cancers, today announced research published in the journal Nature Genetics that demonstrates that ecDNA-based oncogene amplification drives poor outcomes for patients across many cancer types.
The manuscript, Frequent extrachromosomal oncogene amplification drives aggressive tumors, was co-authored by Boundless Bio scientists Nam-phuong Nguyen, Ph.D., and Kristen Turner, Ph.D., and 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.
The researchers used intensive computational analysis of whole-genome sequencing data from more than 3200 tumor samples in The Cancer Genome Atlas (TCGA) and the Pan-Cancer Analysis of Whole Genomes (PCAWG), totaling over 400 TB of raw sequencing data, to observe the impact of ecDNA amplification on patient outcomes. The researchers observed that ecDNA amplification occurs in many types of cancers, but not in normal tissue or in whole blood, and that the most common recurrent oncogene amplifications frequently arise on ecDNA. Notably, ecDNA-based circular amplicons were found in 25 of 29 cancer types analyzed, and at high frequency in many cancers that are considered to be amongst the most aggressive histological types, such as glioblastoma, sarcoma, and esophageal carcinoma. In addition, patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification.
The findings demonstrate that ecDNA play a critical role in cancer, providing a mechanism for achieving and maintaining high copy number oncogene amplification and genetic heterogeneity while driving enhanced chromatin accessibility and elevating oncogene transcription. ecDNA amplifications are associated with aggressive cancer behavior, potentially by providing tumors with additional routes to circumvent current treatments and other evolutionary bottlenecks. The shorter overall survival, even when stratified by tumor type, raises the possibility that cancer patients whose tumors are driven by ecDNA may not be as responsive to current therapies and may be in need of new forms of treatment.
“This important study builds on our rapidly expanding knowledge about ecDNA, showing, for the first time, that ecDNA amplifications are present in a broad range of cancer tumor types,” said Jason Christiansen, Ph.D., Chief Technology Officer of Boundless Bio. “These results point to the urgent need for therapies that can target ecDNA and interfere with their ability to drive aggressive cancer growth, resistance, and recurrence.”
“By detecting and characterizing the role that ecDNA play in driving hard-to-treat cancers, we are drawing a more accurate map of the cancer genome,” said Dr. Mischel. “It is our goal to take these findings and apply them to the development of powerful anti-cancer therapies for individuals with ecDNA-driven cancers.”
Extrachromosomal DNA, or ecDNA, are distinct circular units of DNA containing functional genes that are located outside cells’ chromosomes and can make many copies of themselves. ecDNA rapidly replicate within cancer cells, causing high numbers of oncogene copies, a trait that can be passed to daughter cells in asymmetric ways during cell division. Cancer cells have the ability to upregulate or downregulate oncogenes located on ecDNA to ensure survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells’ primary mechanisms of recurrence and treatment resistance. 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 next-generation precision oncology company 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.
About Boundless Bio’s Spyglass™ Platform
Boundless Bio’s Spyglass™ platform is a comprehensive suite of proprietary ecDNA-driven and pair-matched tumor models along with proprietary imaging and molecular analytical tools that enables Boundless’s researchers to interrogate ecDNA biology to identify a pipeline of novel oncotargets essential to the function of cancer cells that are enabled by ecDNA. The Spyglass platform facilitates Boundless innovation in the development of precision therapeutics specifically targeting ecDNA-driven tumors, thereby enabling selective treatments for patients whose tumor genetic profiles make them most likely to benefit from our novel therapeutic candidates.