Following up on an earlier breakthrough confirming the feasibility of shutting down the Bcl6 protein — an important master regulatory transcription factor that is the key to survival for diffuse large-B cell lymphoma and other aggressive B-cell lymphomas– Weill Cornell’s Dr. Ari Melnick and other researchers recently completed a study where five doses of the experimental drug eradicated human lymphoma in mice.
Published online in the journal Cell the researchers described specifically how Bcl6 promotes the survival of DLBCL, before detailing how the Weill Cornell developed Bcl6 inhibitor effectively gums up the protein. Initially developed by Dr. Melnick nine years ago, the interim period has seen him working to improve the design for use by DLBCL and other lymphoma patients, collaborating with other world class researchers to understand how both Bcl6 and its inhibitor functions.
The researchers found that Bcl6 has two independent functions required for the survival of DLBCL. Dr. Melnick described how the first function, “builds a huge shopping mall-style complex”. This complex rests on top of a stretch of the genome. Through this binding Bcl6 deactivates the DNA, prohibiting genes from producing RNA and proteins. As Dr. Melnick noted, “Bcl6 acts like a barcode reader. When it sees that barcode — the DNA sequence — it attaches there”.
He went on, “Normally, the protein complex goes away after an immune reaction has been successfully mounted against the pathogen. But when it doesn’t, and remains stuck to the genes, DLBCL can result. That’s because Bcl6 is inhibiting genes that stop cells from dividing and that sense damage to the genome. We now know the genes that Bcl6 is repressing and how that helps lymphoma develop and survive.”
According to Dr. Melnick the second function, “acts like a switch on railroad track that routes a train in one direction or another. One track is needed when antibodies are required for an immune response, while the other keeps B cells in a constant state of division.”
Importantly the researchers were surprised to find that both the complex and the train switch attach to the Bcl6 protein at the same site. “They fit into the same keyholes on Bcl6,” Dr. Melnick said. “There are two identical binding sites on the protein surface.”
As Dr. Melnick exclaimed, “This is wonderfully serendipitous — our drug just happens to be able to overcome both of the biological mechanisms that are key to survival of aggressive lymphoma,” before adding that the inhibitor completely eradicated DLBCL in mice in a short time, with no detectable side effects.
The team is conducting additional research toward an investigational new drug application from the federal Food and Drug Admission.