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Start-ups

Boundless Bio launches to exploit burgeoning understanding of extrachromosomal DNA

The San Diego–based biotech firm says it offers a new approach to cancer drug discovery

by Lisa M. Jarvis
September 19, 2019

Boundless Bio has formally launched with $46.4 million in funding from Arch Venture Partners and City Hill Ventures. The San Diego–based biotech firm hopes to prevent the proliferation of extrachromosomal DNA, gene fragments that recently were found to help tumors diversify, evolve, and develop resistance to cancer drugs.

In cancer cells, chunks of DNA break off from chromosomes to form circular structures called extrachromosomal DNA, or ecDNA. Although ecDNA was identified decades ago, researchers lacked good tools to study its role in cancer biology.

In the past 5 years, University of California, San Diego, professor Paul Mischel has shown that the rapidly replicating fragments contain many copies of the genetic stretches encoding for oncogenes, allowing them to be preferentially passed down from cell to cell. And in a 2017 paper (Nature, DOI: 10.1038/nature21356), his lab reported that ecDNA is present in some 40% of tumor tissues, while nearly absent in healthy tissues.

Boundless was formed after Mischel approached serial entrepreneur Ben Cravatt, a chemical biologist at the Scripps Research Institute in La Jolla, about starting a company to develop drugs targeting processes related to ecDNA. The pair brought their idea to Arch, which last year provided seed funding.

Boundless CEO Zachary Hornby says the firm’s drug targets fall into three buckets, each characterized by pathways where researchers find differences between diseased and healthy cells. The company’s first target is the enzymatic machinery required to excise DNA off the chromosome, a process Hornby says is “uniquely active in this ecDNA state.” Boundless will also try to block metabolic pathways that cells rely on when forming ecDNA. Lastly, the biotech firm will try to take out key players in DNA damage repair pathways that ecDNA depend on for survival.

Hornby says Boundless Bio’s approach is an opportunity to target cancer drivers that have long been considered undruggable—for example, known oncogenes like EGFR, Myc, and KRAS that are typically difficult or impossible to directly inhibit. “We don’t have to drug Myc because we now have this understanding of how Myc arises in the first place.”

Boundless will initially use small molecules to tackle the ecDNA-related targets—its team of 15 and growing includes in-house chemists. In the longer term, the biotech could explore other modalities based on the targets that emerge from its discovery efforts.

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