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.

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