On October 26, 2020 Boundless Bio, a biotechnology company developing innovative therapeutics directed to extrachromosomal DNA (ecDNA) in aggressive cancers, reported that it will present research highlighting powerful components of its proprietary Spyglass platform at the 2020 American Society of Human Genetics (ASHG) Annual Meeting (Press release, Boundless Bio, OCT 26, 2020, View Source [SID1234569065]).
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The poster, titled "A Robust Imaging and Single-Cell Sequencing Platform to Characterize Tumor Extrachromosomal DNA (ecDNA) in Response to Therapeutic Intervention," describes elements of Boundless Bio’s broad platform for interrogating ecDNA biology. These elements couple automated cellular imaging with comprehensive single-cell genomic sequencing. The tools are part of an essential toolkit for understanding how ecDNA responds when cancers are treated with various therapeutic pressures and can be broadly applied to track how oncogenes amplify and where they are expressed following therapeutic intervention. Tumors driven by oncogene amplification are aggressive, have poor prognosis, and have proven elusive for targeted therapies. ecDNA frequently harbor oncogene amplifications and promote resistance to cancer treatment by enhancing genomic diversity and enabling cancer cells to rapidly adapt in response to therapeutic pressures.
"We are building our Spyglass platform to serve as the first robust, objective, and high-resolution tool for characterizing ecDNA and how they respond to therapeutic pressures," said Jason Christiansen, Chief Technology Officer of Boundless Bio. "This new research presented at ASH (Free ASH Whitepaper)G demonstrates that our platform can successfully track how the behavior of ecDNA in cancer shifts in the face of treatment; these insights are enabling us to develop more effective, highly-targeted treatments for patients with cancers driven by ecDNA."
Study Details
Utilizing key analytical tool elements of the Spyglass platform, scientists studied colorectal cancer cells with amplified oncogenes in the presence and absence of cytotoxic chemotherapy, demonstrating the ability to robustly characterize changes in ecDNA and chromosomally-amplified genes at the phenotypic and molecular level.
The researchers studied Colo320DM cells, containing a mixture of the MYC oncogene on ecDNA and chromosomally amplified gene populations; Colo320HSR cells with a pure chromosomally amplified MYC population; and DLD1 cells as a non-amplified control. Each arm was treated for 2 weeks with a cytotoxic chemotherapeutic agent. Cells in metaphase were collected, stained with DAPI and probed for the MYC oncogene by Fluorescence In Situ Hybridization (FISH). Whole-slide images (~10mm2) were collected using automated imaging; and custom-built software was used to automatically identify and quantify ecDNA in individual metaphase spreads. Relative changes in MYC FISH signal and localization were used to quantify the changes in ecDNA and chromosomal amplification populations before and after drug treatment.
In addition, single-cell sequencing techniques revealed molecular level information about the amplified gene regions that is complementary to the spatial information provided by image analysis. Regions of increased gene expression and open chromatin around the MYC gene are indicative of ecDNA and were not identified in the chromosomally amplified line. Further, although chromosomally amplified regions exist in both model lines, molecular level evidence demonstrated divergence in this region not discernable by imaging. When treated with cytotoxic chemotherapy, the ecDNA population was reduced and the chromosomally amplified region was selected. Together these tools demonstrated Boundless Bio’s ability to monitor and quantify dynamic changes in ecDNA in cancer cells under selective pressure.
About ecDNA
Extrachromosomal DNA, or ecDNA, are distinct circular units of DNA containing functional genes, including oncogenes, that are separated from tumor cell chromosomes. ecDNA rapidly replicate within cancer cells, causing high numbers of oncogene copies and can be passed to daughter cells asymmetrically during cell division, driving tumor heterogeneity. Cancer cells have the ability to increase or decrease copy number of oncogenes located on ecDNA to enable 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.