Novel drug shuts down master protein key to lymphoma

Scientists have found how an experimental drug is capable of completely eradicating lymphoma in mice after just five doses.
The study, led by researchers at Weill Cornell Medical College, sets the stage for testing the drug in clinical trials of diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, itself the seventh most frequently diagnosed cancer in the US.
In the study published in journal Cell Reports, the scientists described how the powerful master regulatory transcription factor Bcl6 regulates the genome, ensuring that aggressive lymphomas survive and thrive.
They also demonstrate how the Bcl6 inhibitor, developed at Weill Cornell, effectively gums up the protein, stopping it from working.

The study's senior investigator, Dr Ari Melnick, Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell developed the first BCL6 inhibitors nine years ago, and has continued to improve upon the design of these drugs so they could be used to treat cancer patients.
In a study published in March in Nature Immunology, Melnick and his team reported that it is possible to shut down Bcl6 in DLBCL without affecting its vital role in the T cells and macrophages needed to support a healthy immune system.

The protein has long been considered too complex to target with a drug as it also is crucial to proper function of many immune system cells, not just B cells gone bad.

That finding suggested Bcl6 inhibiting drugs may have few side effects, said Melnick.
The latest study was designed to understand exactly how Bcl6 promotes DLBCL.
The researchers found that in order to help B cells produce antibodies against an infection, Bcl6 "builds a huge shopping mall-style complex" that sits on top of a stretch of the genome.
By binding onto these genes, Bcl6 deactivates the DNA, stopping genes from producing RNA and proteins.
"Bcl6 acts like a barcode reader. When it sees that barcode - the DNA sequence - it attaches there," said Melnick.
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, Melnick said.
"We now know the genes that Bcl6 is repressing and how that helps lymphoma develop and survive," Melnick said.