Multitasking with MALT1

Weill Cornell researchers identify protein target linked to cell growth and survival in non-Hodgkin's lymphoma, develop agent for targeted inactivation

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NEW YORK—An international research team has developed apotential new drug to target diffuse large B-cell lymphoma (DLBCL), bringingtogether researchers from Spain, Canada and several U.S. institutions, withpromising results published in CancerCell. DLBCL is the most common subtype of non-Hodgkin's lymphoma and theseventh most frequently diagnosed type of cancer, and activated B-cell—DLBCL(ABC-DLBCL), the target of choice for the recent study, is the mostchemotherapy-resistant form of DLBCL.
The research team, captained by two laboratories from WeillCornell Medical College, focused their attention on MALT1, a proteinresponsible for driving growth and survival in ABC-DLBCL cells. Throughhigh-throughput screening, the researchers identified an experimentalsmall-molecule agent, MI-2, that irreversibly inactivates MALT1.
"MALT1 is a bona fide therapeutic target, and with thediscovery of MI-2 we have provided a lead compound that forms the basis of anew class of therapeutic agents,"
Dr. Ari Melnick, associate professor of medicine anddirector of the Raymond and Beverly Sackler Center for Biomedical and PhysicalSciences at Weill Cornell Medical College, said in a press release. Melnick wasthe lead investigator for the study.
The team worked with mouse models of MALT1 developed byco-author Lorena Fontan, a postdoctoral fellow from Spain who had visitedMelnick's lab several times. The primary issue they faced when working withMALT1, Melnick says, is that they needed active in-vitro models of the protein, which is not active outside ofcells. Corresponding author and co-lead investigator Dr. Hao Wu, a formerfaculty member of the Department of Biochemistry at Weill Cornell MedicalCollege now at Harvard Medical School, found a biochemical method for forcingMALT1 into an active configuration, allowing the team to screen for agents thatmight work against the protein.
MALT1 is highly active in ABC-DLBCL, and is a type ofprotease protein that cleaves other proteins. In the case of ABC-DLBCLs, whenMALT1 slices proteins, it leads to the activation of growth-promoting moleculesand halts the function of other proteins that inhibit cancer cell growth. MI-2was found to tightly bond to MALT1, preventing it from cutting other proteinsand 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 factthat MALT1 is not responsible for any biological processes essential for life.
Melnick says that as of yet, it is not known "how broad aspectrum of lymphomas are dependent on MALT1," though its significance inABC-DLBCL is undeniable. The protein is also implicated in MALT1 lymphoma, alower-grade version of the cancer. As for other cancer types, he says it isbelieved that it plays a significant role beyond the realm of lymphomas, and itmight even have potential in inflammatory and autoimmune diseases.
"MALT1 has been shown to play a role in this kind of signalrelevant to autoimmune disease and T cell function," says Melnick. "In mylaboratory we don't really have models for autoimmune diseases, but we'd lovefor 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 translatableto the clinic," so they are working with colleagues in chemistry to makemodifications before it can be tested in humans. They are also working on the"combinatorial aspect, first with chemotherapy drugs, but also other targetedagents that we think might be interesting." The eventual hope, says Melnick,would be to tone down the chemotherapy and instead "develop regimens that arecompletely targeted in nature based on rational combinatorial therapy."
"No single drug can cure lymphoma. This is why we need tocombine agents that can strike-out the different cellular pathways thatlymphoma cells use to survive," said Melnick in a press release. "We want toeliminate 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 creatingeffective combinational molecular targeted therapy regimens to reduce treatmenttoxicity and improve lymphoma patient outcomes."
The study, "MALT1 small molecule inhibitors specificallysuppress ABC-DLBCL in vitro and in vivo," was funded by the Leukemia& Lymphoma Society, Burroughs Wellcome Foundation, the ChemotherapyFoundation and the Beverly and Raymond Sackler Center for Physical andBiomedical Sciences at Weill Cornell Medical College.

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