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.

 

Lymphoma in the News: Two Important Studies Take Us One Step Closer to Personalized Lymphoma Therapy

By Peter Martin, MD and Olivier Elemento, PhD

Based on multiple randomized phase 3 studies initiated over a decade ago, R-CHOP chemotherapy is the standard of care for first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL). However, sometimes R-CHOP is not successful. Fortunately, our understanding of lymphoma has evolved over the past decade.

It is increasingly clear that “DLBCL” is a heterogeneous group of related tumors. Studies using gene expression profiling [1], have revealed that DLBCL can be divided into three subgroups based on the probable cell of origin (i.e., the cell from which the lymphoma was derived): activated B-cell like DLBCL (ABC), germinal center-like DLBCL (GCB), and a third group, termed “type 3”, that doesn’t possess any specific characteristics (click here to read the abstract). So far, the clinical relevance of differentiating between the ABC and GCB subtypes of DLBCL remains somewhat unclear. Nonetheless, studies done at Weill Cornell Medical College and elsewhere have suggested that certain treatments might preferentially benefit one subtype (see here and here). As a result, ongoing clinical trials are evaluating newer therapies targeted to the appropriate subgroup.

Just as we are beginning to understand the significance of DLBCL gene expression profiles, recent technological advances in DNA sequencing are making the rapid, high-resolution sequencing of a tumor’s entire genome (DNA code) possible and affordable [2]. Two recently published papers describe the results of long-term efforts by two different groups to sequence the genome of DLBCL tumors.

A Groundbreaking Study

In a paper entitled “Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma” published in the journal Nature, Gascoyne, Marra and colleagues describe the results of a groundbreaking study. The researchers sequenced the entire DNA code from lymphoma tumors and compared the results to normal DNA obtained from the same patients. They were able to identify several genes that were mutated in the tumors but not in the normal DNA. Using these data, they were able to identify 109 genes with a potential role in lymphoma. Continue reading “Lymphoma in the News: Two Important Studies Take Us One Step Closer to Personalized Lymphoma Therapy”