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Treating lymphoma is now a bit EZ-er.

ABSTRACT: Tazemetostat represents the first epigenetic therapy approved for the treatment of follicular lymphoma (FL). It inhibits the activity of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase, the first of a multitude of epigenetic regulators that have been identified as recurrently mutated in FL and germinal center diffuse large B-cell lymphoma. In this review, we discuss the initial discovery and ongoing exploration of the functional role of EZH2 mutations in lymphomagenesis. We also explore the path from the preclinical development of tazemetostat to its approval for the treatment of relapsed FL, and potential future therapeutic applications. We discuss the clinical data that led to the approval of tazemetostat and ongoing research into the function of EZH2 and of tazemetostat in lymphomas that derive from the germinal center, which could increase the applicability of this drug in the future.

SUBMITTER: Morin RD

PROVIDER: S-EPMC8095133 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Treating lymphoma is now a bit EZ-er.

Morin Ryan D RD Arthur Sarah E SE Assouline Sarit S

Blood advances 20210401 8

Tazemetostat represents the first epigenetic therapy approved for the treatment of follicular lymphoma (FL). It inhibits the activity of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase, the first of a multitude of epigenetic regulators that have been identified as recurrently mutated in FL and germinal center diffuse large B-cell lymphoma. In this review, we discuss the initial discovery and ongoing exploration of the functional role of EZH2 mutations in lymphomagenesis. We also ...[more]

PMID: 33904892

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Project description:Influenza viruses (IVs) are a continual threat to global health. The high mutation rate of the IV genome makes this virus incredibly successful, genetic drift allows for annual epidemics which result in thousands of deaths and millions of hospitalizations. Moreover, the emergence of new strains through genetic shift (e.g., swine-origin influenza A) can cause devastating global outbreaks of infection. Neuraminidase inhibitors (NAIs) are currently used to treat IV infection and act directly on viral proteins to halt IV spread. However, effectivity is limited late in infection and drug resistance can develop. New therapies which target highly conserved features of IV such as antibodies to the stem region of hemagglutinin or the IV RNA polymerase inhibitor: Favipiravir are currently in clinical trials. Compared to NAIs, these treatments have a higher tolerance for resistance and a longer therapeutic window and therefore, may prove more effective. However, clinical and experimental evidence has demonstrated that it is not just viral spread, but also the host inflammatory response and damage to the lung epithelium which dictate the outcome of IV infection. Therapeutic regimens for IV infection should therefore also regulate the host inflammatory response and protect epithelial cells from unnecessary cell death. Anti-inflammatory drugs such as etanercept, statins or cyclooxygenase enzyme 2 inhibitors may temper IV induced inflammation, demonstrating the possibility of repurposing these drugs as single or adjunct therapies for IV infection. IV binds to sialic acid receptors on the host cell surface to initiate infection and productive IV replication is primarily restricted to airway epithelial cells. Accordingly, targeting therapies to the epithelium will directly inhibit IV spread while minimizing off target consequences, such as over activation of immune cells. The neuraminidase mimic Fludase cleaves sialic acid receptors from the epithelium to inhibit IV entry to cells. While type III interferons activate an antiviral gene program in epithelial cells with minimal perturbation to the IV specific immune response. This review discusses the above-mentioned candidate anti-IV therapeutics and others at the preclinical and clinical trial stage.

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Treating lymphoma is now a bit EZ-er.

Publications

Treating lymphoma is now a bit EZ-er.

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