Harnessing Malt1 Inhibition For Rational Combinatorial Therapy Of Abc-Dlbcl

The MALT1 paracaspase plays a critical role in the proliferation and survival of Activated B-cell like Diffuse Large B-cell Lymphoma (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, A20 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. MALT1 is a compelling therapeutic target since: i) it is the only paracaspase in humans, ii) MALT1 knockout mice are viable, and iii) ABC-DLBCLs are biologically dependent on MALT1 activity. MALT1 is only active when forming multimeric complexes. In order to identify potential MALT1 inhibitors we biochemically engineered an obligate dimerized form of MALT1 and an enzymatic assay for high throughput screening. We screened a ∼50,000 compound chemical diversity library and identified and validated 19 distinct chemical scaffolds that inhibited MALT1 with an IC50 Given that multiple pathways contribute to ABC-DLBCL pathogenesis we hypothesized that MALT1 inhibitors would be most effective within combinatorial therapy regimens. Along these lines MI-2 strongly enhanced the activity of CHOP chemotherapy drugs against ABC-DLBCL cells. BCR signaling forms a complex network of signaling molecules beyond NF-κB, and accordingly MALT1 targeted therapy was strongly enhanced with small molecules that affect other branches of this pathway, such as PI3K inhibitors (e.g. BKM120). 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 identified 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. Citation Format: Lorena Fontan, Chenghua Yang, Venkataraman Kabaleeswaran, Laurent Volpon, Michael Osborne, Elena Beltran, Monica Rosen, Rita Shaknovich, Shao N. Yang, Randy D. Gascoyne, Leandro Cerchietti, Jose A. Martinez-Climent, J. Fraser Glickman, Katherine Borden, Hao Wu, Ari Melnick. Harnessing MALT1 inhibition for rational combinatorial therapy of ABC-DLBCL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2693. doi:10.1158/1538-7445.AM2014-2693