Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, has been categorized based on the cancer cell of origin as either activated B-cell (ABC) DLBCL or germinal center B-cell (GCB) DLBCL. Each subtype is associated with a certain degree of tumor vulnerability and a corresponding response to therapy.
The more that clinicians know about how a patient’s disease develops, the better equipped they are to devise an informed and precise treatment plan. Yet, between 10-20 percent of DLBCL cases are unclassified, providing little guidance for strategic intervention.
To shed light on the unclassified disease subtype and further define the composition of the ABC and GCB subtypes, the Weill Cornell Medicine and NewYork-Presbyterian Hospital Lymphoma Program’s Dr. John P. Leonard took part in an international research initiative led by the National Cancer Institute at the National Institutes of Health, with findings recently published in the New England Journal of Medicine.
Whereas prior studies of genetic subtyping investigated individual mutations, this research was among the first to examine how mutations in multiple genes may relate to disease pathogenesis and therapeutic response.
Researchers used next-generation sequencing technology to analyze nearly 600 DLBCL patient biopsy samples, contributed in part through the Lymphoma Program’s efforts in collaboration with the Alliance for Clinical Trials in Oncology. Based on the co-occurrence of genetic alterations that they observed, the team discovered four new genetic subtypes of DLBCL – MCD, BN2, N1 and EZB – enhancing science’s understanding of the genetic framework of this aggressive cancer.
“These findings will take us one step closer to potentially employing targeted agents as part of treatment for specific DLBCL subtypes,” says Dr. Leonard. “If we can specifically identify these lymphoma types and incorporate new agents that target relevant pathways, we will advance rational clinical trials with the aim to improve outcomes for patients based on the biology of their disease.”
In an interview during the 2016 American Society of Hematology Annual Meeting, Dr. John Leonard discusses results from a phase III trial where researchers compared the treatments R-CHOP to DA-EPOCH-R in DLBCL patients specifically from either the GCB or ABC subtypes.
A full link to the video of Dr. Leonard discussing the trial can be found by clicking above or be seen on Healio.com.
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.