MALT 1 activity is a compelling therapeutic target for treatment of activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL), as the disease is biologically dependent on the protein. During, the 2014 meeting of the American Association for Cancer Research, the Melnick Lab, shared their recent findings regarding the potential of MALT1 as an ABC-DLBCL inhibitor. The MALT1 paracaspase plays a critical role in the proliferation and survival of ABC-DLBCL, the most chemo-resistant form of DLBCL. MALT1 mediates activation of the B-cell receptor (BCR) downstream of somatic mutations in signaling components such as: CD79, CARD11 or MYD88, leading to chronically activated NF-κB. MALT1 is the effector enzyme of the CARD11/Bcl10/MALT1 signalosome, a massive, high order structure that functions as an amplifier of BCR signaling to NF-κB.
Given that multiple pathways contribute to ABC-DLBCL pathogenesis we hypothesized that MALT1 inhibitors would be best utilized with combinatorial therapy regimens. Accordingly, MI-2 strongly enhanced the activity of CHOP chemotherapy drugs against ABC-DLBCL cells, especially those most resistant to doxorubicin. As BCR signaling forms a complex network of signaling molecules beyond NF-κB, MALT1 targeted therapy was strongly enhanced by small molecules that affect other branches of this pathway, such as PI3K inhibitors (e.g. BKM120), although this effect seemed to be obliterated by genetic lesions such us presence of CARD11 mutation. Finally MI-2 synergized with small molecules such as BH3 mimetics (most notably ABT-737) that target fundamental complementary survival pathways to BCR signaling in ABC-DLBCLs.
In summary, we were able to identify the first specific MALT1 inhibitor drug and demonstrated a promising role for MALT1 targeted therapy as an anchor of rational combinatorial therapy against ABC-DLBCL.