On May 29, 2020 Boundless Bio, a company interrogating and targeting extrachromosomal DNA (ecDNA) in aggressive cancers, reported that it will present data at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Annual Meeting that highlight ecDNA’s relationship with biomarkers associated with response to immunotherapy in gastric cancer and therefore the importance of identifying ecDNA patient populations (Press release, Boundless Bio, MAY 29, 2020, View Source [SID1234558716]).
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The poster, "Extrachromosomal DNA (ecDNA) carrying amplified oncogenes as a biomarker for insensitivity to checkpoint inhibitor treatment in gastric cancer patients," will be presented on Friday, May 29, in ASCO (Free ASCO Whitepaper)’s Developmental Therapeutics – Immunotherapy session. The presentation can be accessed starting at 8:00 a.m. EDT (Abstract 3123, Presentation 187) as part of ASCO (Free ASCO Whitepaper)’s on-demand content; ASCO (Free ASCO Whitepaper) is being held virtually this year due to COVID-19.
ecDNA are identified with high frequency across many solid tumor types and thought to be one of the key drivers of the most aggressive cancers – specifically, those cancers characterized by high copy number amplifications of oncogenes. Tumors enabled by ecDNA have a distinct fitness advantage of producing multiple oncogene copies, which drives tumor aggressiveness, rapid progression, and resistance to standard treatment options.
"The analysis being presented today demonstrates that the presence of ecDNA in gastric cancer is negatively associated with biomarkers typically associated with response to checkpoint inhibitor therapies. The implication is that the presence of ecDNA in solid tumors potentially renders these cancers unresponsive to immunotherapy and highlights the importance of creating therapies that directly address cancer cells’ ability to employ ecDNA to grow and resist standard of care treatments," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "Boundless Bio is committed to continuing to elucidate the role of ecDNA in cancer biology, oncogene amplification, and tumor adaptability and to bringing the first medicines leveraging these insights to patients with intractable cancers."
Study Details
The analysis examined whether patients with gastric tumors that possess ecDNA represent a subset of patients that lack biomarkers associated with clinical response to anti-PD-1 checkpoint inhibitor therapy. Boundless Bio researchers employed computational analysis to determine the ecDNA status of a cohort of gastric cancer patients (N = 108) whose whole genome sequencing data were publicly available in The Cancer Genome Atlas (TCGA). The cohort was grouped into five molecular subtypes:
Microsatellite instability (MSI)
Epstein-Barr virus (EBV)
Genomically stable (GS)
Chromosomal instability (CIN)
ecDNA positive (ecDNA)
Additionally, the relationships among the molecular subtypes above and common biomarker signatures associated with response to checkpoint inhibitors were assessed:
MSI status
PD-L1 levels
Tumor mutational burden (TMB)
Tumor immune signature (TIS)
The analysis found that 32% of gastric cancer patients in the cohort were positive for ecDNA signatures, and those ecDNA+ patients were mutually exclusive from the 23% of patients who showed MSI high (MSI-H), which is associated with response to checkpoint inhibitors, such as pembrolizumab, in gastric cancer. Further, it found that the ecDNA-positive subtype had statistically significantly lower TIS than all of the other molecular subtypes (p-value < 0.05), except for the tumors marked by the CIN subtype (p-value = 0.09). The ecDNA-positive subtype also had lower PD-L1 expression than all the other molecular subtypes but the GS and CIN subtypes.
Overall, the analysis demonstrated that patients whose tumors are ecDNA positive are a unique population that displays a signature that lacks the hallmark biomarkers that predict response to checkpoint inhibitor therapy, implying that ecDNA+ patients may not respond to standard of care immunotherapies. Boundless Bio is developing novel therapeutic strategies directed to mechanisms critical for ecDNA function in cancer.
About ecDNA
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, targeted therapy, immunotherapy, 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.