Forcing lymphoma cells into withdrawal, one subtype at a time

Could one of these molecules break the back of a treatment-resistant kind of lymphoma?

It used to be that there were two kinds of lymphoma, a cancer of the white blood cells: Hodgkin’s lymphoma, and everything else (aka non-Hodgkin’s lymphoma). Now doctors recognize more than 20 different types of non-Hodgkin’s lymphoma, based on cell type, genetic/genomic features, what the cells look like under a microscope, where the tumors form, etc.

With greater knowledge of what makes a lymphoma a lymphoma has also come the recognition that each type, subtype and sub-subtype responds to the same treatment differently—or not at all.

That’s led to a more targeted approach to discovering and developing anti-lymphoma drugs, based on the unique molecular features of a particular subtype. A team of researchers including Hao Wu, PhD, of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, is getting good traction focusing on one especially hard-to-treat lymphoma.

Together with collaborators in New York and Spain, Wu is helping develop new drugs for activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), which is highly resistant to standard chemotherapies. The team is going after MALT1, a protein that allows lymphoma cells to keep their growth machinery running continuously. These cells are effectively addicted to MALT1: If the protein is blocked or shut off, they die.

Wu—who is also a member of Harvard Medical School’s Department of Biological Chemistry & Molecular Pharmacology—and her colleagues developed a way to screen a library of more than 46,450 prospective drugs for MALT1-blocking activity. In Cancer Cell the team reports that one of those thousands, called MI-2, was particularly effective, a result borne out in biochemical, cell line, tumor cell and animal model studies. As a bonus, MI-2 was non-toxic in the animal model.

The team is now developing different versions of MI-2 in an effort to increase its power while keeping toxicity low. But for the moment, they can say that they are on the path to discovering a new option for patients with this kind of treatment-resistant lymphoma.

“We are excited about this discovery and hope to use structural biology and chemistry to further optimize the compound for future clinical applications,” says Wu.