Tag: Leandro Cerchietti MD

New Approach to Treating Aggressive B-cell Lymphomas

Leandro Cerchietti
Leandro Cerchietti, M.D.

In a study published in February 2016 in Blood, researchers from Leandro Cerchietti’s lab at Weill Cornell Medicine in collaboration with the University of Montreal identified a potential new strategy for the treatment of aggressive diffuse large B-cell lymphomas (DLBCL) called double and triple hit lymphomas.

What are double and triple hit lymphomas and why they are they so difficult to treat?

Double and triple hit lymphomas have chromosomal changes in two or three genes (MYC, BCL2, and/or BCL6) which encode for proteins that have a primary role in cell growth and contribute to the development of cancer. Chemotherapy does not work well to kill these types of lymphomas. Further, patients with double and triple hit lymphomas are often older and have difficulty tolerating aggressive chemotherapy. Therefore it is essential for new, targeted therapies to be developed that are less toxic for these patients.

What did researchers find?

The researchers found that the combination of an FDA-approved antiviral medication called ribavirin and a new targeted medication called an Hsp90 inhibitor work together to kill double and triple hit lymphomas in preclinical models. Ribavirin blocks the function of a protein called eIF4E. With the inhibition of Hsp90 and eIF4E, the proteins MYC, BCL2, and BCL6 are less effective in promoting growth of lymphoma cells. The addition of ribavirin also may prevent developing resistance to treatment with the Hsp90 inhibitor.

What do these findings mean for patients? 

The lymphoma group at Weill Cornell Medicine is developing a phase I clinical trial to determine the optimal dose of an Hsp90 inhibitor and ribavirin for patients with aggressive DLBCLs that do not respond or return after initial therapy. We will evaluate tumor and blood samples before and after treatment with this combination to confirm that it negatively impacts MYC, BCL2, and BCL6 as expected. This is a promising treatment strategy in these patients and expected to be much better tolerated than chemotherapy.

Stay tuned for future updates regarding treatments for double and triple hit lymphomas at Weill Cornell.

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.

Researchers Develop New Method to Test Lymphoma Treatments

Researchers from Cornell Ithaca and Weill Cornell Medicine recently published a new study describing how organoids offer a realistic model to test new lymphoma treatments. A organoid is a tissue culture that mimics the environment where different lymphomas are found. The use of organoids could offer insights as to why some lymphoma treatments are more effective than others. As Dr. Ari Melnick explained:

“This is a game-changing technology for the field of lymphoma,” Melnick said. “These organoids allow us to better understand the complex architecture of lymphomas and how that informs the way we treat the disease – what drugs we should use and for whom, and how they interact with each other. This is a fundamental advance; no one in the world has the technology to treat patients in this way.” 

Research into lymphoma organoids are part of the P.A.Th. (Progressive Assessment of Therapeutics) program, an inter-campus collaboration between Cornell Ithaca and Weill Cornell Medicine that seeks to better translate the treatment of lymphoma patients.