The use of nanatinostat in combination with valganciclovir is a novel therapeutic approach to target EBV+ malignancies, using a low-dose of Viracta’s oral proprietary epigenetic drug, nanatinostat, to target the EBV genome and induce the expression of certain viral kinase genes. These viral genes then activate the antiviral prodrug, valganciclovir, which is converted to ganciclovir in the gut, and disrupts the DNA replication cycle. This disruption then leads to chain termination and killing of the tumor cells by inducing apoptosis.
EBV is latent in cancer cells and viral kinase genes are silenced epigenetically. Valganciclovir (VGCV), an antiviral prodrug of GCV, is inactive in the absence of the expression of viral protein kinase kinase
Induction of Viral Genes
Nanatinostat (Nstat) induces expression of EBV kinase genes which can activate GCV
Activated GCV induces apoptosis in EBV+ cancer cells
The association of viruses and cancer has been well characterized.
EBV, a member of the γ-herpesvirus family, was the first virus directly implicated in the development of a human tumor and is formally classified as a Group 1 human carcinogen by the World Health Organization (WHO). Primary infection with EBV typically occurs in childhood, occurring first in the nasopharynx and is generally asymptomatic; however, infection later in life may manifest as infectious mononucleosis. Once infected, individuals remain life-long carriers of the virus, with more than 90% of the world’s population asymptomatically infected with EBV. The EBV genome can be detected in approximately one out of one million circulating B lymphocytes.
EBV enters periods of latency during which most viral genes are epigenetically suppressed, as depicted in the figure below. In some stages, no viral proteins are expressed on the cell surface, making it difficult to develop broadly effective immunotherapies.
Latent infection and intermittent reactivation are two important characteristics of the EBV lifecycle. The maintenance of latent EBV infection requires the expression of a small subset of genes, and specific expression patterns (Types I – III) of these genes are associated with specific EBV-driven malignancies. EBV has been shown to infect B-cells, T-cells, T/NK-cells and epithelial cells, though its greatest predilection is for B-cells. EBV has been associated with a wide spectrum of human malignancies, with B-cell lymphomas being the most common, and include EBV+ diffuse large B-cell lymphoma, not otherwise specified (“EBV+ DLBCL, NOS”), Burkitt’s lymphoma (“BL”), post-transplant lymphoproliferative disorders (“PTLD”), and lymphomas associated with congenital and acquired immunodeficiencies, including HIV-related lymphomas.