Tag: lymphoma research

Targeting New Pathways for the Treatment of an Aggressive Form of B-Cell Lymphoma

lecBy Leandro Cerchietti, MD

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and fast-growing lymphoma that is the most common form of non-Hodgkin lymphoma in the United States. Nearly 1/3 of DLBCL patients experience relapse. The outcome can be worse for patients with DLBCL that harbor activation of multiple oncogenes. An oncogene is a gene that can “hit” a cell to transform it into a cancer cell. Some cells are “hit” with more than one oncogene. When hit by two or three oncogenes they transform into a very aggressive lymphoma called double-hit and triple-hit lymphomas (DH/TH). These DH/TH are largely insensitive to combinatorial chemotherapy and are more frequently found in the elderly. To grapple with the complexities of treatment of DH/TH lymphomas, alternate pathways for the development of future treatments must be found by researchers.

The three oncogenes that could drive these lymphomas are MYC, BCL2 and BCL6, but it is not know whether all three work simultaneously. In a paper recently published in OncoTarget, researchers from my lab at Weill Cornell Medicine found that DLBCL cells that survive BCL6 targeted therapy induce a phenomenon of “oncogene-addiction switching” and super activate one of the other oncogenes, preferentially BCL2. The activation of BCL2 by the anti BCL6 therapy allows lymphoma cell to survive this targeted treatment. My team found that to be effective in killing lymphoma cells a therapy should inhibit both the BCL6 and BCL2 oncogenes.

This phenomenon occurs because these three oncogenes share the regulation of common pathways responsible for the survival of DLBCL. If one oncogene is targeted, the others can take the leading role. In the case of BCL6, specific targeting of BCL6 releases BCL2 inducing on-target feedback resistance to this therapeutic strategy. However, this “oncogene-addiction switching” mechanism can be harnessed to develop rational combinatorial therapies for DLBCL.

An alternative strategy to target DH/TH DLBCLs could be to simultaneously dismantle all three oncogenic networks. In a separate paper recently published in Blood, researchers from my lab and the University of Montreal found another potential therapeutic pathway for the treatment of these aggressive DLBCLs. They found that the protein Hsp90 binds to and maintains activity in eIF4E a protein that controls MYC, BCL6, and BCL2 networks. Inhibition of eIF4E using the antiviral drug Ribavirin decreases simultaneously MYC, BCL6, and BCL2 avoiding “oncogene-addiction switching” and inducing regression of DH/TH DLBCLs. The researchers used a novel pre-clinical model of lymphoma called “patient-derived tumorgrafts”, that are mouse models faithfully resembling the complexity of human lymphomas.

They also found that DH/TH could be targeted with Hsp90 inhibitors. Still targeting Hsp90 activity has met with limited success in the past due to the counter regulatory elevation of Hsp70, which induces resistance to Hsp90 inhibitors. However, researchers were able to identify Hsp70 as a target for eIF4E. Accordingly the combination of eIF4E and Hsp90 inhibitors should result in a potential new pathway for the development of new treatments for DLBCL, an approach WCM clinicians will test in future clinical trials.

“Improving the Odds”: Clinical Care & Research for Lymphoma Patients

The latest issue of Weill Cornell Medicine, the magazine of Weill Cornell Medical College and Weill Cornell Graduate School of Medical Science, profiled the lymphoma program and the improvements in treatment and better outcomes being developed by our physicians and researchers on behalf of our lymphoma patients. If you turn to page 30 of the reader you can find the full article.

A full list our our open clinical trials is available.

Researchers Find New Role of Gene that Could Lead to New Strategies for the Treatment of B-Cell Lymphomas

The activation-induced cytidine deaminase (AID) gene has long been understood to play a role in the body’s defense against pathogens. The AID gene ensures that the B-cells responsible for antibody production can generate the antibodies that defend the body. Recently a team of research scientists at Weill Cornell Medical College published results outlining a new role for the AID gene. In these first of their kind findings researchers demonstrated the epigenetic role of the gene:

“…the researchers discovered that the enzyme encoded by the AID gene is also involved in removing chemical tags from DNA. These tags, known as methyl groups, regulate gene expression. Removing these methyl groups, a process called hypomethylation, allows B cells to rapidly change their genome in preparation for antibody production.”

“AID is a gene traditionally not known to be linked to DNA methylation, but we found that it is a player in removing methyl groups — the first time anyone has found molecules that perform this powerful form of gene regulation,” said co-senior author Dr. Olivier Elemento, an associate professor of computational genomics in the Department of Physiology and Biophysics who heads the Laboratory of Cancer Systems Biology in the Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell and co-chairs the Meyer Cancer Center Program in Genetics, Epigenetics and Systems Biology. “What is interesting is that many tumor types, and that includes B-cell lymphomas, tend to be linked to global — genome-wide — hypomethylation, compared to normal cells. How hypomethylation occurs is not well understood. AID is so far the only enzyme that has been directly linked to this active process. So AID or related enzymes could be involved in other cancers as well.”

These new findings have the potential to reveal a new cause of blood cancers and lead to the development of new strategies to treat B-cell lymphomas.