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.
“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.
Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, has been categorized based on the cancer cell of origin as either activated B-cell (ABC) DLBCL or germinal center B-cell (GCB) DLBCL. Each subtype is associated with a certain degree of tumor vulnerability and a corresponding response to therapy.
The more that clinicians know about how a patient’s disease develops, the better equipped they are to devise an informed and precise treatment plan. Yet, between 10-20 percent of DLBCL cases are unclassified, providing little guidance for strategic intervention.
To shed light on the unclassified disease subtype and further define the composition of the ABC and GCB subtypes, the Weill Cornell Medicine and NewYork-Presbyterian Hospital Lymphoma Program’s Dr. John P. Leonard took part in an international research initiative led by the National Cancer Institute at the National Institutes of Health, with findings recently published in the New England Journal of Medicine.
Whereas prior studies of genetic subtyping investigated individual mutations, this research was among the first to examine how mutations in multiple genes may relate to disease pathogenesis and therapeutic response.
Researchers used next-generation sequencing technology to analyze nearly 600 DLBCL patient biopsy samples, contributed in part through the Lymphoma Program’s efforts in collaboration with the Alliance for Clinical Trials in Oncology. Based on the co-occurrence of genetic alterations that they observed, the team discovered four new genetic subtypes of DLBCL – MCD, BN2, N1 and EZB – enhancing science’s understanding of the genetic framework of this aggressive cancer.
“These findings will take us one step closer to potentially employing targeted agents as part of treatment for specific DLBCL subtypes,” says Dr. Leonard. “If we can specifically identify these lymphoma types and incorporate new agents that target relevant pathways, we will advance rational clinical trials with the aim to improve outcomes for patients based on the biology of their disease.”
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.
“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.