It was the cellular equivalent of opening your car door and finding an active, roaring engine in the driver seat.

Scientists learned strands of DNA could occasionallyappear outside of its traditional home in the nucleus in the 1970s, when they appeared as little, innocuous circles on microscopes; inexplicable but apparently innate. But not until UC San Diegos Paul Mischel published his first study in Sciencein 2014 did researchers realize these circles were not only active but potentially overactive and driving some cancer tumors superhuman growth.

That insight and the ensuing five years of research will now get $46 million cash and company infrastructure to ramp into targeted therapies as Boundless Bio emerges from stealth mode with backing from ARCH Venture Partners and City Hill.Questions abound, from what precisely a drug would look like to what even gives rise to these wild DNA, but CEO Zachary Hornby isnt biting his tongue on the potential.

Were thinking about this as a fourth revolution in cancer therapies, Hornby, who was most recently COO of Ignyta, told Endpoints News. The first three revolutions, by Hornbys count, are chemotherapy in the 1940s, the first targeted therapies at the end of the 20th century, and the recent rise of immunotherapy.

The road to such a revolution would be long, but the embattled oncology field may be in need of new direction. A study released in April found 97% of cancer drugs tested in clinical trials failed to make it to market, and this month researchers found systemic targeting problems plagued two decades of cancer research.

The connection between this loose DNA, officially called extrachromosomal DNA or ecDNA, and cancer centers around a baffling and deadly fact about some tumors: While normal cells in a higher-order species like humans dont evolve within a generation, some cancer cells can evolve rapidly, ensuring their survival against attempted treatments. Why? How? Mischels mapping of cancer genome points to ecDNA.

Freed from a cells chromosomes, the DNA can replicate rapidly. That doesnt hurt if they code for nothing or something benign, but if they code for something that gives the cell an advantage, such as EGFR (a growth factor), the cells will grow rapidly as in any classical natural selection model. This, Hornby said, appears in over 25% of cancers, including notoriously hard to treat MET cancers.

EGFR inhibitors already exist to combat cancer cells that have already evolved (or been amplified), but Boundless Bio plans to use Mischels insights to destroy ecDNA in its early stages. Rather than attacking tumors after the cells have already amplified, the company would jam the process that gives rise to the evolution in the first place.

It opens a whole new avenue of cancer targets, including allowing us to pursue patient populations that to this point have been undruggable, Hornby said, pointing to MET and Myc. Thats just a really different approach than your typical targeted therapies.

But how they would do this is still cloudy.

Hornby said the most promising method was jamming the enzymatic machinery the molecular tools and parts that allow DNA to replicate and code proteins as their research has shown the machinery is slightly different in ecDNA than typical DNA. Another method theyre exploring is to inhibit the metabolic pathways ecDNA can use to fulfill the demands caused by its high replication rate; in other words, growing DNA that are hungry and depriving them of food could neutralize them.

Among the most notable things about Boundless potential therapies is that they may be approved for tumor type, rather than cancer type, i.e. like the new drug from Hornbys old company Ignyta, it could treat a wide range of cancers if the patient showed ecDNA was amplifying in the tumor.

The company will also invest in research to discover the underlying mechanism giving rise to ecDNA.

Originally posted here:
'A fourth revolution in cancer therapies': ARCH-backed Boundless Bio flashes big check, makes bigger promises in debut - Endpoints News

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