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Multitasking with MALT1
NEW YORK—An international research team has developed a potential new drug to target diffuse large B-cell lymphoma (DLBCL), bringing together researchers from Spain, Canada and several U.S. institutions, with promising results published in Cancer Cell. DLBCL is the most common subtype of non-Hodgkin's lymphoma and the seventh most frequently diagnosed type of cancer, and activated B-cell—DLBCL (ABC-DLBCL), the target of choice for the recent study, is the most chemotherapy-resistant form of DLBCL.
The research team, captained by two laboratories from Weill Cornell Medical College, focused their attention on MALT1, a protein responsible for driving growth and survival in ABC-DLBCL cells. Through high-throughput screening, the researchers identified an experimental small-molecule agent, MI-2, that irreversibly inactivates MALT1.
"MALT1 is a bona fide therapeutic target, and with the discovery of MI-2 we have provided a lead compound that forms the basis of a new class of therapeutic agents,"
Dr. Ari Melnick, associate professor of medicine and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, said in a press release. Melnick was the lead investigator for the study.
The team worked with mouse models of MALT1 developed by co-author Lorena Fontan, a postdoctoral fellow from Spain who had visited Melnick's lab several times. The primary issue they faced when working with MALT1, Melnick says, is that they needed active in-vitro models of the protein, which is not active outside of cells. Corresponding author and co-lead investigator Dr. Hao Wu, a former faculty member of the Department of Biochemistry at Weill Cornell Medical College now at Harvard Medical School, found a biochemical method for forcing MALT1 into an active configuration, allowing the team to screen for agents that might work against the protein.
MALT1 is highly active in ABC-DLBCL, and is a type of protease protein that cleaves other proteins. In the case of ABC-DLBCLs, when MALT1 slices proteins, it leads to the activation of growth-promoting molecules and halts the function of other proteins that inhibit cancer cell growth. MI-2 was found to tightly bond to MALT1, preventing it from cutting other proteins and inactivating the protein in human samples of ABC-DLBCL. When tested in mice, MI-2 halted cancer growth without toxicity, which Melnick credited to the fact that MALT1 is not responsible for any biological processes essential for life.
Melnick says that as of yet, it is not known "how broad a spectrum of lymphomas are dependent on MALT1," though its significance in ABC-DLBCL is undeniable. The protein is also implicated in MALT1 lymphoma, a lower-grade version of the cancer. As for other cancer types, he says it is believed that it plays a significant role beyond the realm of lymphomas, and it might even have potential in inflammatory and autoimmune diseases.
"MALT1 has been shown to play a role in this kind of signal relevant to autoimmune disease and T cell function," says Melnick. "In my laboratory we don't really have models for autoimmune diseases, but we'd love for people who work on that to test this out."
Moving forward, Melnick says the team's next step is "multi-pronged." The MI-2 drug, he says, is "pretty close to being translatable to the clinic," so they are working with colleagues in chemistry to make modifications before it can be tested in humans. They are also working on the "combinatorial aspect, first with chemotherapy drugs, but also other targeted agents that we think might be interesting." The eventual hope, says Melnick, would be to tone down the chemotherapy and instead "develop regimens that are completely targeted in nature based on rational combinatorial therapy."
"No single drug can cure lymphoma. This is why we need to combine agents that can strike-out the different cellular pathways that lymphoma cells use to survive," said Melnick in a press release. "We want to eliminate the use of toxic chemotherapy in the treatment of lymphoma patients, and these new study findings take us one step closer to our goal of creating effective combinational molecular targeted therapy regimens to reduce treatment toxicity and improve lymphoma patient outcomes."
The study, "MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo," was funded by the Leukemia & Lymphoma Society, Burroughs Wellcome Foundation, the Chemotherapy Foundation and the Beverly and Raymond Sackler Center for Physical and Biomedical Sciences at Weill Cornell Medical College.