Researchers at the University of California, San Francisco, and Weill Cornell Medical College in New York City have teamed up to test an investigational drug that could be the key to beating drug resistance in certain forms of leukemia. The drug, called RI-BPI, was developed by Weill Cornell's Ari Melnick, and in a study published in Nature in May, was shown to shut down a transcription factor researchers say is responsible for conferring drug resistance to acute lymphoblastic leukemia.
"The way that it works is that it attaches to the BCL6 protein, a transcription factor that plays a very important role in the pathogenesis of B-cell lymphoma," Melnick says. "We identified part of the surface of BCL6 that was required to form these [functional silencing] complexes, and then we designed molecules that could bind to BCL6 and stop it from bringing in all this heavy machinery — so BCL6 can still go where it needs to go but it can't do anything there. [RI-BPI] stops it from working."
Researchers are unable to completely shut down BCL6 because it serves other purposes in the genome. "It's encoded for in the genomes of all animals, and it has a normal function to carry out and it is quite diverse — it has a broad set of tools that it can use," Melnick adds. "With RI-BPI, we're exclusively shutting off the tool that it uses for cancer. Animals that grow up not having BCL6 because it's been knocked out, get very sick, but animals that receive these drugs don't get sick because you're only blocking this one function of BCL6." He adds that RI-BPI is nontoxic as animals that have been given the drug continuously for a year show no ill effects.
The study showed that in ALL driven by the so-called Philadelphia chromosome — which is also implicated in other cancers — RI-BPI, in combination with Gleevec, practically shut the cancer down. As RI-BPI prevented BCL6 from conferring resistance to the cancer cells, Gleevec was able to eradicate the cells as it does in other cancers.
It was UCSF's Markus Müschen who first discovered the link between BCL6 and drug resistance in leukemia. When he realized that Melnick had developed a BCL6 inhibitor, Melnick says Müschen called him to see if they could collaborate on a study of RI-BPI in combination with Gleevec. The team is now working on studies to be able to test the drug on humans. In addition, Melnick says RI-BPI could be used in combination with other drugs for cancers other than leukemia. "There are people working in every tumor type looking at this and I know from similar collaborations with other groups, that they're working on breast cancer, lung cancer, melanoma, head and neck cancer, brain cancer. So it's being explored," he says.