Tag: diffuse large B-cell lymphoma

AACR 2014: How deregulation of histone methyltransferases drive malignant transformation of B-cells

wendybeguelinBy 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.

AACR 2014: IL10 autoregulatory loop displays promise as new therapeutic target for DLBCL

shaknovich_rBy 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.

Novel Therapeutic Strategies for Targeting the Lymphoma Microenvironment

Ruan Face By Jia Ruan, MD, PhD

Although conventional chemotherapy is primarily aimed at tumor cells, we now know of the importance of neighborhood cells, included within the tumor mass. These include endothelial cells and pericytes that form blood vessels, macrophages that mediate inflammation, and fibroblasts and extracellular matrix proteins that build matrix and scar tissues. The interaction between the tumor cells and their neighborhood is collectively known as the tumor microenvironment. Given the importance of the tumor microenvironment in maintaining tumor growth and developing resistance to conventional chemotherapy, novel strategies that target the microenvironment are under active investigation. Clinical researchers led by, Dr. Jia Ruan, have recently published 2 important studies on developing novel therapeutic strategies that target lymphoma angiogenesis (blood vessel formation) and lymphangiogenesis (lymphatic vessel formation) within the tumor microenvironment.

The first study was published in the leading hematology journal Blood in collaboration with Dr. Leandro Cerchietti, a lymphoma biologist, and Dr. Katherine Hajjar, a vascular biology expert, both at Weill Cornell Medical College. The study found that pericytes, the vascular accessory cells surrounding the endothelial cells, are important players in lymphoma tumor angiogenesis, and represent potentially novel therapeutic targets for anti-lymphoma therapy. Specifically, the Weill Cornell lymphoma researchers treated human diffuse large B-cell lymphoma (DLBCL) growing in mouse models with an oral drug called imatinib. This incapacitated a critical cell surface receptor within the pericytes, namely platelet-derived growth factor receptor β (PDGFRβ), which is important for the survival of the pericytes and its communication with the endothelial cells. As a result, lymphoma-associated microvascular blood vessel formation was reduced due to programmed-cell death of both pericytes and endothelial cells. This ultimately translated into therapeutic effect of lymphoma growth impairment. This study provided proof of principal that targeting non-tumor vascular cells within the lymphoma microenvironment can result in significant inhibition of lymphoma growth, providing the basis for more refined consideration of anti-angiogenesis as a treatment strategy for lymphoma patients.

The second study published in Cancer Research, in collaboration with Dr. Lijun Xia, a glycoprotein and vascular biology expert at the Oklahoma Research Foundation. The researchers found that 1) lymphatic vessels, which form the vascular network known as lymphangiogenesis, contributed to the growth and spreading of lymphomas in an experimental model of mantle cell lymphoma (MCL), and 2) treatment with the immunomodulatory drug lenalidomide potently inhibited the growth and spreading of MCL by disabling tumor lymphangiogenesis. Mechanistically the researchers demonstrated that treatment with lenalidomide reduced the number of MCL-associated macrophages and their production of a growth factor important for the formation of lymphatic vessels, namely vascular endothelial growth factor-C (VEGF-C). This is the first study to address the potential importance of lymphangiogenesis in lymphoma growth, and provided a novel perspective of the mechanisms of action of lenalidomide in lymphoma therapy. This pre-clinical study synergizes with our recent clinical data displaying high response rates and durable remissions with the biologic combination of lenalidomide + rituximab in patients with previously untreated MCL.

Both studies open potentially new novel paths to treating lymphoma, exemplifying the Lymphoma Program’s commitment to the bench-to-bedside translational research that brings cutting-edge science to patient care.

References

1. Blood. 2013 Jun 27:121(26):5192-202. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.

2. Cancer Res. 2013 Dec 15:73(24):7254-64. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma.