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.

Screen Shot 2020-06-17 at 10.54.10 AM

“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.”

 

COVID-19 and Cancer: Helpful Resources for Lymphoma Patients

The Weill Cornell Medicine Lymphoma Program team remains committed to supporting and protecting the health and safety of our patient community during this challenging time. With COVID-19 dominating the news and impacting our everyday lives, many people may be left wondering which sources to trust and which recommendations to follow when it comes to understanding the coronavirus and staying safe during this unprecedented time.

We developed this article and compiled a handful of reliable resources designed to help lymphoma patients — at our center and beyond – best navigate this rapidly changing situation.

COVID-19 Basics and General Guidelines

Physicians and staff within the division of Hematology and Oncology at Weill Cornell Medicine and NewYork-Presbyterian Hospital are here to provide guidance and support to our cancer patients and their loved ones. We encourage you to review the information outlined in our COVID-19 and Cancer Guide, where we provide answers to our patient community’s most frequently asked questions. You are also welcome to call our COVID-19 hotline at (646) 697-4000 with questions at any time.

If you have COVID-19 symptoms or suspect that you have been in contact with someone with COVID-19, contact your oncologist for further instruction. If you need in-person medical attention, your doctor will advise you regarding the necessary steps and preparations to protect you and others at the facility before you arrive. Please do not visit your doctor’s office or the emergency department without first being in touch with your healthcare team.

COVID-19 and Lymphoma

In the Lymphoma Research Foundation (LRF) webinar entitled “Coronavirus and What the Lymphoma Community Needs to Know,” our own Dr. John Leonard reviews the current medical understanding and response to COVID-19 (per March 19, 2020). Dr. Leonard explains why we all must work together to “flatten the curve,” and addresses frequently asked questions surrounding immune system suppression and the coronavirus, lymphoma treatment during the pandemic, the use of masks and transmission of the disease between different groups such as children, the elderly and pets.

The LRF also created a COVID-19 fact sheet complete with prevention tips and questions to ask your oncologist. Weill Cornell Lymphoma Program Chief Dr. Peter Martin and an infectious disease specialist contributed to and medically reviewed this information.

Appointments and Video Visits

Please know that we remain dedicated to the health and wellbeing of our lymphoma community and that continuing to provide world-class cancer care for our oncology patients is important to us. As part of our mission to provide care during this unprecedented time, the Hematology & Oncology division has been implementing extensive patient-centered precautions. These include efforts to prevent the spread of COVID-19 within our facilities and the expansion of virtual video-based appointments.

The Weill Cornell Lymphoma Program continues to be able to offer new and current patients the cancer care they need. We also provide expert, multidisciplinary care for patients with lymphoma who need medical attention for COVID-19.

Video visits allow patients to receive high-quality lymphoma care from the comfort and convenience of their own homes, while adhering to safe social distancing parameters recommended to minimize exposure to other individuals. Our video visit capabilities also extend to patients who wish to schedule a virtual second opinion.

To schedule a video visit, please follow the instructions below. Our team will work with you to obtain any necessary medical records prior to your visit. We will inform you if we believe that you are better suited for an in-person visit.

New Patients
Please call (646) 962-2800.

Existing Patients
Please call (646) 962-2064.

Learn more about video visits. Once your video visit is scheduled, use this guide to connect with your doctor.

Video visits use the same insurance coverage as in-person appointments, and your copayment and deductible still apply.

Visitor Policy

While we recognize the value of family and friends’ support throughout lymphoma diagnosis and treatment, keeping patients and their loved ones safe requires temporary limits on the number of people allowed to accompany each patient to an appointment. Please note that our policies continue to evolve during these unprecedented times. Click here for our latest COVID-19 visitation guidelines.

Additional Resources

Patients are welcome to call the WCM/NYP COVID-19 hotline – (646) 697-4000 – with any questions. Please note that this hotline is available as a public service to provide information only, and not to diagnose, treat or render a medical opinion.

Patients may also consult the following resources.

Ways to Help

It can be easy to feel powerless in the midst of a global pandemic, but there are ways that you can help. In fact, the biggest impact that people – sick or healthy – can make in the fight against COVID-19 is simply to stay at home to curb the spread of disease and its potential to overwhelm the healthcare system.

Those willing and able to contribute to Weill Cornell Medicine and NewYork-Presbyterian’s response to COVID-19 can make a donation to support the purchasing of ventilators and personal protective equipment (PPE), and the physical and emotional wellbeing of healthcare workers on the frontlines of the outbreak.

A fundraiser was also created to provide nutritious, high-quality meals to the New York City doctors, nurses and ancillary staff leading the fight against COVID-19 as part of medical intensive care units.

Precision Medicine Combination Treatment Shows Anti-Tumor Activity in Preclinical DLBCL Models

By Sucharita Mistry, PhD

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in adults. DLBCLs are aggressive and typically represent a heterogeneous collection of diseases that can be grouped into different subtypes depending on their particular genetic lesions.

One such subtype, described as the C3 or EZB cluster, features alterations in the BCL2 gene and mutations in chromatin remodeling genes such as EZH2. The malignant growth of this particular subtype of DLBCL is likely dependent on genetic abnormalities in EZH2 and BCL2. Both these oncogenes (genes with the potential to cause cancer) mediate their effects on tumor growth through distinct mechanisms, providing new opportunities for rational therapeutic strategies that inhibit EZH2 and BCL2 concurrently.

Dr. Lisa Roth and colleagues from the Weill Cornell Medicine and NewYork-Presbyterian Hospital Lymphoma Program evaluated the efficacy of EZH2 inhibitor tazemetostat and BCL2 inhibitor venetoclax as single agents and in combination using different preclinical models.

Tazemetostat and venetoclax were administered alone and in combination in a panel of DLBCL cell lines with and without mutations in EZH2 and translocation (a genetic abnormality in which a chromosome breaks and reattaches to a different chromosome) in BCL2. In DLBCL cells harboring EZH2 mutation and BCL2 translocation, the combination treatment markedly enhanced cell killing compared to either drug alone. Although these findings are encouraging, cell culture models are limited as lymphoma cells grown on a plastic surface in liquid cultures cannot recapitulate the physiologic environment within the human body.

To test the efficacy of the drugs in models with increased clinical relevance, Weill Cornell researchers established three-dimensional (3D) organoids that closely mimic the lymph node architecture in humans. The tazemetostat/venetoclax combination therapy was tested in two different novel organoid systems 1) organoids derived from lymphoma cells, and 2) patient-derived xenograft (PDX) organoids generated from a patient tumor and propagated in mice. The PDX tumor carried both EZH2 mutation and BCL2 translocation. In both types of organoids, tazemetostat and venetoclax had minimal activity as single agents, whereas the tazemetostat/venetoclax combination resulted in significant cell killing.

Using novel model systems, this study demonstrated that EZH2 inhibition combined with BCL2 inhibition results in synergistic anti-tumor effects. Learn more about the findings here.

Lisa“The synergistic anti-lymphoma activity mediated by the combination of tazemetostat and venetoclax is quite promising,” says Dr. Roth. “This combination therapy is anticipated to be especially effective as precision therapy for DLBCL patients with EZH2 mutation and BCL2 alteration.”

A clinical trial of this combination treatment is currently in development in collaboration with Drs. Ari Melnick, John Leonard and Peter Martin.