By Lorena Fontan Gabas, PHD
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.
By Wendy Béguelin, PhD
DLBCLs are a heterogeneous group of diseases initiating from germinal center (GC) B cells. GC B cells are uniquely specialized to tolerate rapid proliferation, and physiological genomic instability, thus generating a diverse set of clones of cells encoding high affinity antibodies. The GC phenotype poses a significant risk in the malignant transformation to B cells, with epigenetic regulatory complexes playing a critical role in lymphomagenesis. During a symposium session at the recent American Association for Cancer Research, the Melnick Lab, reported how the deregulation of histone methyltransferases causes the malignant transformation of B-cells.
EZH2, which epigenetically silences genes through histone 3 lysine 27 methylation is upregulated in normal and malignant GC B cells. EZH2 is often affected by gain of function mutations in lymphomas that alter its enzymatic specificity. EZH2 mediates GC formation by transiently suppressing checkpoint genes and terminal differentiation genes through formation of bivalent chromatin domains. EZH2 somatic mutations induce germinal center hyperplasia and malignant transformation, and cooperate with other oncogenes such as BCL2. EZH2 specific inhibitors can suppress the growth of GC derived lymphoma cells in vitro and in vivo, and are currently being evaluated in early phase clinical trials. DNA methyltransferase 1 (DNMT1) is required for B cells to form GC, and GC B cells display cytosine methylation redistribution as compared to resting or naïve B cells. DLBCL in turn exhibit prominent and heterogeneous disruption of cytosine methylation distribution, with specific and distinct DNA methylation profiles occurring in different lymphoma subtypes.
Epigenetic heterogeneity is associated with unfavorable outcomes in B-cell lymphoma. This suggests that epigenetic diversity may provide a survival advantage to lymphoma cell populations. DNA methyltransferase inhibitors can reprogram lymphoma cells to develop a form of incomplete senescence that allows for a more complete response to chemotherapy treatment. These DNA methyltransferase inhibitors can be safely combined with standard lymphoma therapies for first line treatment of patients with DLBCL. However, further research will be required to confirm this targeted therapy approach for clinical use in patients.
By Rita Shaknovich MD, PHD
Diffuse large B cell lymphoma (DLBCL) is a common aggressive lymphoma that represents 30-40% of newly diagnosed cases of non-Hodgkin lymphoma, but accounts for up to 80% of lymphoma-related deaths. Although R-CHOP remains the standard first line therapy, it has more recently been associated with a frequent lack of response in DLBCL patients. This lack of response has enforced the necessity for finding alternate therapeutic targets.
At the 2014 meeting of the American Association for Cancer Research researchers from Weill Cornell Medical College reported on their recent findings. In a late breaking abstract the Shaknovich Lab reported on the potential of the IL10 receptor as a new biomarker and therapeutic target in DLBCL. The hypothesis is that DLBCL is dependent on the feed-forward autostimulatory loop that begins from the autocrine IL10 secretion and stimulation of overexpressed receptors leading to cell proliferation and that blocking the receptor would lead to cell death.
The research team of postdoctoral fellow Wendy Beguelin and research associate Seema Sawh determined that blocking IL10R results in specific inhibition of signaling through JAK1/2 and loss of phosphorylation at STAT3Y705 immediately after treatment. The inhibition of signaling through MAPK and phosphorylation of STAT3S727 came at a later time in treatment. The inhibition of signaling was sustained for days with only one drug treatment leading to induction of apoptosis. Anti-IL10R treatment resulted in significant downregulation of IL10 and IL10RA transcription, leading to interruption of IL10-IL10R autostimulatory loop.
IL10R is a novel therapeutic target in DLBCL that allows for easy detection and targeting. Shaknovich Lab is planning further animal studies and hopes to develop therapeutic antibody for clinical use in patients.