Emerging Role of Epigenetic Therapies in Follicular Lymphoma and DLBCL Treatment

At the 2023 Lymphoma, Leukemia & Myeloma Congress in New York, New York, Michael Green, PhD, The University of Texas MD Anderson Cancer Center, Houston, Texas, discusses the role of epigenetic therapies in treating lymphoma. 

Transcript:

Hi, I'm Michael Green. I'm an associate professor in the department of lymphoma and myeloma at MD Anderson Cancer Center, and I'm here at the Lymphoma, Leukemia & Myeloma Congress. This morning I gave a presentation talking about the role of epigenetic therapies in lymphoma. 

Essentially, the premise for this is based upon the normal role of epigenetics in regulating a very dynamic process of development through the germinal center reaction, and how this is perturbed by different mutations that occur very frequently in follicular lymphoma (FL) and also very frequently within the EZB or C3 subtype of diffuse large B-cell lymphoma (DLBCL).

Although using epigenetic modifying agents is somewhat in its infancy, there's a lot of preclinical data and emerging clinical data with agents such as tazemetostat that support the premise that we may be able to target some of these underlying epigenetic programs that are perturbed in B-cell lymphoma.

I gave 3 specific examples of these. The most frequent mutations are in KMT2D, CREBBP and EZH2. KMT2D is a loss of function mutation in a writer, and so it can be rebalanced by targeting an eraser. In this case, KDM5 and KDM5 inhibitors have shown some efficacy in preclinical models. For CREBBP we've shown 2 different paths forward depending on the kind of mutation, either using CBP/p300 dual inhibitors or HDAC3 selective inhibitors. EZH2, of course, we've also got clinical data to support the fact that EZH2 inhibitors are very active in the setting of EZH2 mutants in lymphoma.

However, some of the data that I pointed out also supported the premise that response to these agents is not necessarily dictated by the presence or absence of mutation, but rather the activity of the underlying epigenetic program. So, there is still a significant degree of activity in the context of wild-type tumors, and much of this can be driven by, for example, interactions with the immune microenvironment and potentiation of immune synapse formation through antigen presentation and other mechanisms.

I also briefly introduced some emerging approaches for targeting the epigenome of lymphoma, specifically transcriptional chemical inducers of proximity, or TCIPs, which were recently published by Nathanael Gray and Jerry Crabtree's group from Stanford, which present a very interesting path forward and been able to recruit different transcriptional activators towards transcription factors. Thanks.

Source:

Green M. Epigenetic Approaches to Improve Lymphoma Therapy. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-21, 2023. New York, NY