The study reveals replication stress in ecDNA enabled cancers as a unique vulnerability and therapeutic strategy for treating gene amplified cancers

Boundless Bio, a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) in oncogene amplified cancers, today will present a new finding at the American Association for Cancer Research (AACR) Annual Meeting 2022, held in New Orleans and virtually from April 8-13, 2022. The poster, Replication stress and the inability to repair damaged DNA, the potential “Achilles' heel” of ecDNA+ tumor cells, is available to registered attendees online starting today and for in-person presentation on April 11, 2022 at 1:30 PM - 5:00 PM CT.

"Replication stress has long been known to be a driver of genomic instability in cancer,” said Christian Hassig, Ph.D., Chief Scientific Officer of Boundless Bio. “This study demonstrates ecDNA-enabled gene amplified cancers have inherently high replication stress, thereby providing a unique point of intervention for our novel ecDNA-directed therapeutics (ecDTx). This work is an important scientific advancement both in our understanding of gene amplifications on ecDNA and in translating the science into novel therapeutics for patients with gene amplified cancers who currently have few treatment options.”

Boundless Bio previously demonstrated that cancers with oncogenes amplified on ecDNA are associated with poor clinical prognosis¹ and generally do not respond to targeted therapies, underscoring the urgent need to identify clinical strategies to treat ecDNA amplified cancers. For the first time, we present data showing a relationship between ecDNA and DNA replication stress, a known form of genomic instability that contributes to oncogenesis and tumor evolution. While the drivers of replication stress remain unclear, excessive replication stress leads to extensive DNA damage and cancer cell death. The results demonstrate ecDNA-enabled colorectal cancer cells have intrinsically elevated levels of replication stress and are hypersensitive to replication stress inducing agents. These novel findings highlight replication stress as a potential synthetic lethal approach in ecDNA amplified cancers.

Poster available at Boundless Bio website.

Reference

¹Kim, Nguyen, Turner et al. Nature Genetics 2020

About ecDNA

Extrachromosomal DNA (“ecDNA”) are circular units of nuclear DNA found within cancer cells, and which contain highly transcriptionally active genes, including oncogenes, but are physically distinct from chromosomes and lack centromeres. ecDNA replicate within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells have the ability to increase or decrease copy number of select oncogenes located on ecDNA to enable survival under selective pressures, including targeted therapy, immunotherapy, chemotherapy, or radiation, thereby making ecDNA one of cancer cells’ primary mechanisms of growth, recurrence, and treatment resistance. ecDNA are not found in healthy cells but are present 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 oncogene amplified cancers.

For more information, visit www.boundlessbio.com.

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