A team of researchers led by Stanford University and San Diego-based Boundless Bio have identified an oral small molecule that specifically targets extrachromosomal DNA (ecDNA) in cancer cells, preventing the DNA from repairing itself. When tested in mice, the compound—named BBI-2779—shrank gastric tumors and prevented the cancer from developing resistance to another cancer drug.
The results were published in Nature on Nov. 6.
Boundless Bio is now moving forward to see if BBI-2779 has the same effect in humans, according to a Nov. 6 Cancer Research UK release emailed to Fierce Biotech. The research team included scientists from the Francis Crick Institute and University College London.
Used alone, BBI-2779 inhibited tumor growth by 64% compared to mice given placebo. Another drug used alone, infigratinib, inhibited growth by 97%, but lost its effectiveness over time as the cancer evolved resistance to it. When the two drugs were given in combination, it led to lasting tumor regression without the development of resistance.
In healthy human cells, DNA is neatly packaged into bundles called chromosomes. But in cancer cells, loose strands of DNA bunch together outside of chromosomes, and often contain genes that contribute to disease emergence and progression.
Because it exists outside the protection of chromosomes, ecDNA is at regular risk of damage. The appearance of mutations can spur disease progression, but too many errors in the DNA can lead to cancer cell death.
Cancer cells rely on a protein called CHK1 to repair damaged ecDNA; BBI-2779 binds to CHK1 and inhibits it, allowing DNA damage to accumulate until the cancer cell succumbs.
The researchers also published two other papers in Nature on the same day. In one, the scientists analyzed 14,778 patients with 39 tumor types and found that 17.1% of the tumor samples contained ecDNA; this ecDNA was more prevalent in metastatic cancers and was associated with tumor progression.
In the other, the researchers reported that different ecDNA molecules can be passed down together to daughter cells during cell division, even though they don’t sit on the same chromosome (or on any chromosome at all).