By Deborah Borfitz
July 29, 2021 | Extrachromosomal DNA (ecDNA), circles of DNA outside the chromosomes but still within the nucleus of a cell, is believed to be an important but overlooked target in the treatment of amplification-driven tumors that have up to now been uniformly resistant to anti-cancer therapies. Boundless Bio is actively exploring the genes and cellular processes that underpin some crafty maneuvers of ecDNA using a precision medicine platform called Spyglass, according to Chief Scientific Officer Christian Hassig, Ph.D.
That ecDNA plays a pivotal role in human oncology was not discovered until about 15 years ago, and the evidence continues to mount, he says. Boundless Bio has already shown that ecDNA generates rapid binomial heterogeneity in tumors.
Additionally, hitting it with a higher drug dose only worsens the problem since ecDNA responds by switching up its oncogene cargo and continuing to haphazardly replicate. Since ecDNA is driving oncogenesis—and oncogene dependency can switch—Boundless Bio’s pioneering approach is to disrupt the underlying machinery that supports it, says Hassig. “We want to break this diabolical circle.”
Many copies of oncogenes are carried by ecDNA, he explains, and they are highly dysregulated. The prognosis for patients is particularly dire when they are driving tumor growth.
ecDNA has been implicated in about 14% of all tumors and the figure is closer to 35% among the metastatic patient population, says Hassig.
Rethinking Genetics
Although introduced to the world of cancer biology relatively recently, ecDNA was first identified in the 1960s by examining DNA during cancer cell division. Its presence is now known to be a common phenomenon across organisms. “The same biology that plants use to overcome weed killer, tumor cells leverage to proliferate out of control and escape cancer therapy,” says Hassig.
The nautical spyglass theme of the Boundless Bio drug discovery and patient selection platform reflects the need for a molecular-level investigation of aggressive, amplification-driven tumors “through the lens of synthetic lethal screening strategies and next-generation sequencing methods to better understand ecDNA and identify its vulnerabilities,” Hassig says. “With this approach, we can identify ecDNA vulnerabilities, develop drugs against these, and identify the patients most likely to respond to these therapies, thereby coming full circle.”
The plasticity of ecDNA affords dynamic “fine tuning” of the tumor via oncogene expression, which can impact the aggressiveness of a cancer, Hassig explains. Extrachromosomal DNA can also get quite complex—in some cases, harboring a cluster of oncogenes (e.g., MET, EGFR and MYC) in the same cell—further driving tumor growth and adaptability.
Drugs that directly inhibit oncodrivers do not work in patients with these aggressive tumors, he says, because ecDNA can generate “massive heterogeneity of copy number and oncogene composition.” Unlike chromosomal mutations where the daughter cells replicate the same set of gene copies, circles of DNA outside the chromosome multiply to make daughter cells where genetic information passes unevenly when cells divide.
For that reason, a treatment that is highly effective against gene copies residing on chromosomes can be outwitted when tumors are controlled by the constantly acquired genetic diversity of ecDNA, Hassig continues. “Heterogeneity [of cancer cells] will just evolve around the drug.”
The day-to-day work at Boundless Bio revolves around “FISHing [using fluorescence in situ hybridization] for circles and hunting for ecDNA targets and drugs,” which is essentially three parallel and highly integrated initiatives composed of target identification, drug discovery and precision medicine, Hassig says. On the diagnostic front, the goal is to create a platform called ECHO (ecDNA harboring oncogenes) that would use next-generation sequencing data already being collected by clinical laboratories to identify patients who have these most intractable cancers.