Using HDAC3 Inhibitors to Reverse CREBBP Mutations in Lymphomas

A study published in Cancer Discovery indicated that histone deacetylase 3 (HDAC3) inhibition represents a novel mechanism-based immune-epigenetic therapy for cAMP-response element binding protein (CREBBP) mutant lymphomas.

Mutations of CREBBP are often found in follicular lymphoma and diffuse large B-cell lymphomas (DLBCL) and allow malignant cells to hide from the immune system. According to the authors, this research could provide insight for potential immunotherapy approaches for common forms of non-Hodgkin lymphoma.

In an interview with CancerNetwork^®, Michael Green, PhD, a lead investigator on the study and an assistant professor of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center, spoke about the results and how the research could pave the way for future advancements.

CancerNetwork^®: Could you give a brief overview of the study?

Green: We were interested in the mechanisms driven by CREBBP mutations in non-Hodgkin lymphomas, so the first major finding was that using CRISPR gene editing of lymphoma cell lines, we found that there are 2 different classes of CREBBP mutations. One with mutations in the histone acetyltransferase or HAT domain, has significantly more severe epigenetic phenotype compared to the other class of mutations. We have missense or nonsense mutations that lead to a loss of the proteins. So, this was important because all of the prior studies on these mutations have been done using knockout mice, and that really models the second class of the mutations and not the first class.

The second point is by characterizing the HAT domain mutations of CREBBP we found that it deregulates (a protein) antagonistically regulated by CREBBP on one side which activates the expression of genes and by BCL6 and HDAC3, histone deacetylase 3, which are gene repressors. So, with mutations and loss of function of CREBBP you have a repression of a large set of genes.

So, using HDAC3 selective inhibitors, we can reverse the effects of CREBBP mutations, and this leads to two major things happening. The first is that it has a selective effect on stalling the proliferation of CREBBP mutant cells, and this is through the induction of cell-cycle regulators that are repressed by BCL6, like CDKN1A. And the second is that it restores the expression of antigen presentation machinery in the interferon signaling pathway, and this promotes antitumor immunity. And so, we found, as part of the lesser part, that HDAC3 inhibition alone was sufficient to promote antitumor immunity, but it also promoted the expression of the checkpoint protein PD-L1. And so, when we combined HDAC3 inhibition with PD-L1 blockade, it was synergistic and very effective in the syngeneic animal model that we used. 

What sparked this evaluation?

This goes back to a study that I published back in 2015 where working on follicular lymphoma, we did whole exome sequencing of diagnostic biopsies and relapse biopsies from the same patient to try and identify the mutations that arise early during disease evolution and might be very good therapeutic targets. And what we found was that CREBBP mutations arise very early in the development of follicular lymphoma and they also impart a sort of immune privilege by allowing the lymphoma cells to hide from the immune system. … So, from there when I started my own lab, I decided to pursue this and try and identify ways of correcting the effect of CREBBP mutations in lymphoma.

What sort of next steps should physicians keep an eye out for in regard to this research?

I think there are a couple of important aspects for physicians. The first is that histone deacetylase inhibitors that have been used in the past have shown some activity, but the responses haven’t been durable and there’s been problems with toxicity. But these inhibitors have been primarily, you know, class specific, rather than isoform specific, and I think using a selective HDAC3 inhibitor maintains the activity of the HDAC3 inhibitor class without the on target off-tumor effects that are toxicities to T-cells for example, as well as those that cause some of the side effects that we see with other histone deacetylase inhibitors like thrombocytopenia and neutropenia. So, selectivity of histone deacetylase inhibitors is important would be number one. Number two is that, it’s not just a tumor intrinsic effect that we’re looking at here, we think that one of the more important effects of histone deacetylase inhibitors is the promotion of an anti-tumor immune response, and therefore we should start thinking about how we can potentiate that immune response by combinations with other agents like PD-1 blockers or PD-L1 blockers.

Reference:

Mondello P, Tadros S, Teater M, et al. Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma. Cancer Discovery. doi:10.1158/2159-8290.CD-19-0116.