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, Ph.D., 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.
For the Boston Children's Hospital Vector blog, please click here.
Fontan L, Yang C, Kabaleeswaran V, Volpon L, Osborne MJ, Beltran E, Garcia M, Cerchietti L, Shaknovich R, Yang SN, Fang F, Gascoyne RD, Martinez-Climent JA, Glickman JF, Borden K, Wu H, Melnick A. MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo. Cancer Cell. 2012 Dec 11;22(6):812-24. doi: 10.1016/j.ccr.2012.11.003.
