New Research Points to HDAC3 Inhibition as a Potential Game-Changing Treatment for Specific Lymphoma Subtypes

By Sucharita Mistry, PhD

B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are blood cancers of the immune cells. A vast majority of B-cell lymphomas typically display a high frequency of genetic alterations. Since lymphomas show remarkable genetic diversity, a big challenge for scientists is not only to determine which genes are mutated in these diseases, but also to identify “actionable” genetic alterations that can respond to targeted therapies.

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“Discovering how different mutations are involved in causing the disease is a major key to advancing novel mechanism-based precision therapies and immunotherapies for lymphomas, with potentially less toxic side-effects,” says Dr. Ari Melnick, a world-renowned physician-scientist at Weill Cornell Medicine.

Dr. Melnick led groundbreaking research that defines the genetic underpinnings of CREBBP mutation in lymphomas, paving the way for new therapeutic avenues. The findings of this study were recently published in Cancer Discovery.

The CREBBP gene encodes a kind of histone acetyltransferase (HAT), an enzyme that introduces small chemical tags called acetyl groups on histones, which are the major structural proteins of chromosomes. The chemical modifications on histones are termed as epigenetic changes, and they determine whether genes are turned on or off. The CREBBP gene, which is an epigenetic modifier, is frequently mutated in DLBCL and FL.

The Melnick research team, in collaboration with scientists at the MD Anderson Cancer Center, characterized the functional consequences of CREBBP mutation in lymphomas. Using a powerful CRISPR gene-editing technology, the researchers engineered lymphoma cell lines that differed only in the CREBBP mutation status. The research team discovered two different types of CREBBP mutations that either truncate the protein or inactivate the HAT domain, the latter associated with poor clinical outcomes.

This study showed that CREBBP mutation disrupts key biological pathways resulting in abnormal silencing of tumor-suppressive and antigen-presenting pathway genes. This disruption allows lymphoma cells to hide from the immune system so that they cannot be recognized and attacked by the T-cells that play an essential role in the body’s immune response.

More importantly, the malfunction in immune surveillance was restored by an HDAC3 inhibitor, a drug that specifically reverses the histone acetylation defect caused by CREBBP mutation. Notably, selective inhibition of HDAC3 reversed the epigenetic abnormalities, halted lymphoma growth and induced the expression of major histocompatibility (MHC) class II protein, enabling the T cells of the immune system to recognize and kill lymphoma cells. The research team also demonstrated that combination of an HDAC3 inhibitor with an immune checkpoint inhibitor (PD-1/PD-L1 blockade) results in synergistic anti-lymphoma immunity effects.

These findings uncover a novel mechanistic link between CREBBP mutation and immune surveillance dysfunction in lymphomas that can be counteracted by an HDAC3 inhibitor, providing a potentially game-changing approach for restoring anti-tumor immunity.

“HDAC3 inhibition provides an attractive therapeutic avenue for DLBCL and FL and may have enhanced potency in CREBBP-mutant tumors,” says Dr. Melnick. “We are very excited to translate this research into clinical trials that could potentially lead to the development of novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas.”

 

Re-Thinking Epigenetic Therapies for B-Cell Lymphoma

Histone deacetylase inhibitors (HDACi) are small molecules that alter the function of histones, or proteins that bind to DNA and help to determine chromosome shape and gene activity. In cancer treatment, HDACi are traditionally considered epigenetic drugs because of their capacity to modify gene expression to halt tumor cell division, but new research from the Cerchietti Research Laboratory at Weill Cornell Medicine poses rationale for studying the inhibitors’ biological effects through a different lens – their impact on cell metabolism.

Benet Pera, Ph.D., along with Weill Cornell colleagues, as well as researchers from the Helmholtz Institute of Computational Biology in Germany and the Lady Davis Institute for Medical Research in Canada, conducted the study to improve the efficacy of HDACi in people with B-cell lymphoma, which is relatively low compared to that in T-cell lymphoma. Several HDACi, including vorinostat and romidepsin, have been approved by the United States Food and Drug Administration (FDA) for treatment of certain T-cell lymphoma subtypes.

Contrary to their namesake, histone deacetylase inhibitors are able to affect a long list of non-histone proteins, among them metabolic enzymes. These agents can be more appropriately referred to as lysine deacetylase inhibitors (KDACi). Due to the activity of KDACi in proteins involved in metabolic pathways, Pera et al. investigated the effects of the KDACi panobinostat in the cell metabolism of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients enrolled in a phase II trial. Metabolic profiling of the patients’ plasma before and after KDACi-treatment demonstrated that panobinostat prompts DLBCL cells to rely on a certain metabolic pathway, the choline pathway, for survival. The scientists found that in the lab, treating the cancer cells with a choline pathway inhibitor in combination with panobinostat produced superior anti-lymphoma effects in vitro and in animal models.

benet-pera“We are studying these so-called ‘epigenetic’ drugs from a different angle, hoping that metabolomics might hold the key to improving their clinical efficacy,” says Dr. Pera.

The research data recently published in the open-access journal EBioMedicine help to substantiate the team’s innovative re-application of epigenetic reagents, demonstrating the value and promise of the metabolic mechanisms by which KDACi/HDACi can improve current therapeutic options for people with B-cell lymphoma. The results also highlight the need to explore the unknown biological effects of this class of drugs before they can be successfully implemented in a clinical setting.

Global Collaboration: Lymphoma Researchers Attend Workshop at Shanghai Institute of Hematology

In early July, several researchers from the Weill Cornell Medicine/NewYork-Presbyterian (WCM/NYP) Lymphoma Program traveled to Shanghai, China to participate in the first Lymphoma Research Workshop, jointly sponsored by WCM/NYP and Shanghai Institute of Hematology (SIH). The workshop aimed to foster clinical and translational research exchange and collaboration, with the goal of further global alliance with leading Chinese institutions.

Our own Drs. Leandro Cerchietti, Peter Martin, Ari Melnick, Kristy Richards, and Jia Ruan were in attendance. Drs. Melnick and Ruan co-organized the workshop with Drs. Saijuan Chen and Weili Zhao from SIH. SIH and its affiliated Ruijin Hospital (RJH) is a leader in human genomics and lymphoma research in China.

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Dr. Ari Melnick (Left) and Dr. Jia Ruan

Dr. Melnick began by introducing the lymphoma research missions at WCM/NYP and provided an overview of our translational program, which integrates state-of-the-art genetic, epigenetic, and proteomic approaches to study lymphoma pathogenesis and inform development of mechanism-based therapeutics.

Dr. Zhao followed with a review of the recent lymphoma program developments at Ruijin Hospital, which focuses on building a multi-disciplinary diagnosis and treatment team. RJH’s translational development has been aimed at building a lymphoma biobank, next-generation sequencing, system biology, and biomarker investigations to support clinical research.

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Dr. Peter Martin (Left) and Dr. Leandro Cerchietti

On the project level, Dr. Cerchietti discussed bench-to-bedside translation of epigenetic modifying agents, such as novel treatments that sensitize chemotherapy responses in patients with diffuse large B-cell lymphoma (DLBCL). Dr. Martin then provided a comprehensive overview of the management approach for DLBCL in the U.S., reviewing important study design and findings of DLBCL clinical trials that incorporated novel agents, including epigenetic modifiers. Dr. Richards spoke about promises and challenges in canine lymphoma research in both the disease and drug development models.

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Dr. Kristy Richards

Additionally, Dr. Pengpeng Xu from RJH presented preliminary data of a phase 1 study using an epigenetic hypomethylating agent in combination with chemotherapy for DLBCL patients. This joint clinical project developed from the two institutions’ shared translational interest and expertise in exploring therapeutic potential of epigenetic agents in lymphoma.

Drs. Ruan and Melnick concluded the workshop by thanking the hosts at the Shanghai Institute of Hematology and Ruijin Hospital for their gracious hospitality. Faculty from both institutions are impressed by the progress of the ongoing collaboration and support further development of translational and clinical projects in the future, including academic exchange and joint translational and clinical trials.