Therapeutic approaches to Epstein–Barr virus cancers

Soldan, Samantha S.; Messick, Troy E.; Lieberman, Paul M.

doi:10.1016/j.coviro.2022.101260

Cited by 7 publications

(4 citation statements)

References 94 publications

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“…Specific monoclonal antibodies [109–113] and antiviral drugs are also available for the treatment of acute SARS‐CoV‐2 infection. By contrast, there are still no clinically approved vaccines or treatments selectively targeting EBV [114]. Further studies of the human genetic and immunological determinants of these two very different viral infections in rare IEI patients might provide new insight into the mechanisms underlying some of the common diseases associated with these infections, such as long‐COVID and EBV‐associated cancers, for which effective preventive and/or therapeutic strategies are still lacking.…”

Section: Discussionmentioning

confidence: 99%

Human genetic and immunological determinants of SARS‐CoV‐2 and Epstein–Barr virus diseases in childhood: Insightful contrasts

Pan‐Hammarström

Casanova

2023

J Intern Med

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There is growing evidence to suggest that severe disease in children infected with common viruses that are typically benign in other children can result from inborn errors of immunity or their phenocopies. Infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a cytolytic respiratory RNA virus, can lead to acute hypoxemic COVID‐19 pneumonia in children with inborn errors of type I interferon (IFN) immunity or autoantibodies against IFNs. These patients do not appear to be prone to severe disease during infection with Epstein–Barr virus (EBV), a leukocyte‐tropic DNA virus that can establish latency. By contrast, various forms of severe EBV disease, ranging from acute hemophagocytosis to chronic or long‐term illnesses, such as agammaglobulinemia and lymphoma, can manifest in children with inborn errors disrupting specific molecular bridges involved in the control of EBV‐infected B cells by cytotoxic T cells. The patients with these disorders do not seem to be prone to severe COVID‐19 pneumonia. These experiments of nature reveal surprising levels of redundancy of two different arms of immunity, with type I IFN being essential for host defense against SARS‐CoV‐2 in respiratory epithelial cells, and certain surface molecules on cytotoxic T cells essential for host defense against EBV in B lymphocytes.

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Section: Discussionmentioning

confidence: 99%

Human genetic and immunological determinants of SARS‐CoV‐2 and Epstein–Barr virus diseases in childhood: Insightful contrasts

Pan‐Hammarström

Casanova

2023

J Intern Med

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“…VK2019 is an inhibitor of EBNA1 activity 170 and is currently being tested in a clinical trial in patients with nasopharyngeal carcinoma (NCT04925544). Other inhibitors of EBV latency proteins are in development 171 . By reducing the number of latently infected cells, fewer EBV antigens and EBV-infected B cells should be present to drive an aberrant immune response to autoantigens and certain viral proteins such as EBNA1.…”

Section: Inhibitors Of Latent Viral Replicationmentioning

confidence: 99%

Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications

et al. 2023

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Epidemiological studies have provided compelling evidence that multiple sclerosis (MS) is a rare complication of infection with the Epstein-Barr virus (EBV), a herpesvirus that infects more than 90% of the global population. This link was long suspected because the risk of MS increases markedly after infectious mononucleosis (symptomatic primary EBV infection) and with high titres of antibodies to specific EBV antigens. However, it was not until 2022 that a longitudinal study demonstrated that MS risk is minimal in individuals who are not infected with EBV and that it increases over 30-fold following EBV infection. Over the past few years, a number of studies have provided clues on the underlying mechanisms, which might help us to develop more targeted treatments for MS. In this Review, we discuss the evidence linking EBV to the development of MS and the mechanisms by which the virus is thought to cause the disease. Furthermore, we discuss implications for the treatment and prevention of MS, including the use of antivirals and vaccines. Nature Reviews Neurology Review articleof these findings and how they could lead to the development of EBV-targeted MS treatments and preventative vaccines. EBV infectionEBV is a double-stranded DNA virus belonging to the herpesvirus family and was the first virus shown to cause cancer in humans. This discovery was made in the 1960s when virus particles were found in cultured cells from rapidly growing tumours around the jawbones of children from specific regions of Africa 21,22 . Since then, EBV has been detected in all parts of the world, infecting more than 90% of the population, mostly during the first two decades of life 23 . The virus is transmitted primarily by saliva and infects B cells in the oral cavity, either directly or via EBV-infected oropharyngeal epithelial cells 24 . After infection, the virus establishes latency, wherein the expression of viral proteins is markedly lowered in comparison with active infection, thereby reducing recognition of infected B cells by cytotoxic T cells 24 . EBV can exhibit different types of latency; in the more restrictive patterns, only proteins essential for EBV are expressed, including Epstein-Barr nuclear antigen 1 (EBNA1), which is needed for viral genome maintenance 25 .EBV persists in B cells for life, where it can intermittently reactivate, enabling transmission of the virus to a new host. Primary infection during early childhood is usually asymptomatic but up to 75% of individuals who are first infected during adolescence or adulthood develop IM 26 . As an oncogenic virus, EBV is known to cause several types of malignancies, including B cell lymphomas (for example, Burkitt lymphoma and Hodgkin lymphoma), T cell and natural killer cell lymphoproliferative disorders, and epithelial malignancies (for example, nasopharyngeal carcinoma and gastric cancer). In addition, EBV has been linked to diseases that are thought to have an autoimmune component such as systemic lupus erythematosus, Sjögren syndrome and MS 27,28 .

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“…Importantly, EBNA1 adopts a unique fold that is similar to other virally encoded proteins, including Kaposi's sarcoma associated herpesvirus (KSHV) LANA and human papillomavirus (HPV) E2, but is otherwise not found in the human proteome (Bochkarev et al, 1996; Malecka et al, 2019). Therefore, the inhibition of EBNA1 function is a scientifically valid and potentially selective approach to treat EBV‐associated cancers (Messick et al, 2019; Soldan et al, 2022). VK‐2019 is a highly specific inhibitor of EBNA1 DNA‐binding activity and represents the first‐in‐human direct inhibitor of EBNA1.…”

Section: Introductionmentioning

confidence: 99%

Validation of a robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of VK‐2019, a selective EBNA1 inhibitor

Davis,

Anders,

Colevas

et al. 2023

Biomedical Chromatography

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EBNA1 is an Epstein Barr virus (EBV) protein expressed in all EBV‐associated cancers. EBNA1 plays a critical role in the replication and maintenance of EBV episomes in latently infected cells. VK‐2019 was developed as a highly specific inhibitor of EBNA1 DNA binding activity and is currently in phase 1 development as a treatment for EBV‐associated carcinomas. A sensitive and reliable method was developed to quantify VK‐2019 in human plasma using liquid chromatography with tandem mass spectrometry to perform detailed pharmacokinetic studies. VK‐2019 was extracted from plasma using protein precipitation with acetonitrile. Separation of VK‐2019, two purported metabolites, and the internal standard, VK‐2019–d6, was achieved with a Zorbax XDB C18 column using a gradient flow over 6 min. VK‐2019 was detected using a SCIEX 4500 triple quadrupole mass spectrometer operating in positive electrospray ionization mode. The assay range was 0.5–500 ng/mL and proved to be accurate and precise. Dilutions of 1:10 were accurately quantified. VK‐2019 was stable in plasma at −70°C for approximately 18 months. The method was applied to assess the total plasma concentrations of VK‐2019 in a patient who received a single and multiple oral daily doses of 120 mg.

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Therapeutic approaches to Epstein–Barr virus cancers

Cited by 7 publications

References 94 publications

Human genetic and immunological determinants of SARS‐CoV‐2 and Epstein–Barr virus diseases in childhood: Insightful contrasts

Human genetic and immunological determinants of SARS‐CoV‐2 and Epstein–Barr virus diseases in childhood: Insightful contrasts

Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications

Validation of a robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of VK‐2019, a selective EBNA1 inhibitor

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