Cell No. 5 Interpretation of a cancer cell, provided by Angela Canada Hopkins, daughter of a cancer patient.

Cell No. 5 Interpretation of a cancer cell, provided by Angela Canada Hopkins, daughter of a cancer patient.

EBV in Human Disease and Cancer

It has long been understood that a range of viral pathogens can cause or serve as co-factors in the development of human cancers. Up to 20% of cancers are associated with infectious disease.

Epstein Barr Virus was the first virus to be directly implicated in human cancer. EBV causes mononucleosis. In most of the 95 percent of adults carry the virus it persists asymptomatically. In certain cases, such as in immuno-suppressed patients, EBV can drive formation of cancers.

Denis Parsons Burkitt first described a cancer of the lymphatic system that is now known as Burkitt’s lymphoma and identified its association with EBV. The virus’ role in cancers is now understood to be much broader. It is estimated that there are 200,000 new cases and over 140,000 deaths each year due to EBV-associated cancers.

EBV Life Cycle Schematic - Variability in viral gene expression make development of vaccines and broadly effective immunotherapies difficult.

EBV-associated malignancies are often difficult to treat as the virus maintains a dormant, or latent state in affected cells, making it resistant to antiviral drugs, which has also made development of vaccines or broadly effective immunotherapies difficult. The virus also drives multiple pro-oncogenic mechanisms such as viral proteins mimicking pro-growth signaling that drive aberrant cell division; immuno-suppressive signals that help the virus and affected cells evade detection by the immune system; and inhibition of programmed cell death pathways or tumor suppressor proteins that enable transformed cells to survive.

These pleiotropic affects often result in cancers that are highly refractory to available treatments creating a significant unmet medical need that Viracta’s viral activation therapy approach is uniquely suited to address.

The painting, above, is an interpretation of EBV+ cancer cell provided by Suzanne MannMoore.

Viracta Viral Activation Therapy Platform

Viracta’s viral activation therapeutic approach represents a platform for a highly targeted approach to treat a range of viral-associated cancers and other serious diseases.

The treatment approach has been termed a “kick-and-kill” strategy as it combines use of an epigenetic modifier drug, VRx-3996, to induce expression of latent viral genes (the “kick”) and activate herpes virus-family’s thymidine kinase. This enables conversion of an orally administered antiviral pro-drug, such as valganciclovir (marketed by Roche/Genentech as Valcyte®), to its active form to selectively eradicate cancer cells harboring the virus (the “kill”).

As represented in the diagrams, below, the approach provides a robust mechanism to selectively kill EBV+ cancer cells.

In non-dividing EBV+ cells, the approach inhibits viral replication but does not kill host cells. In replicating immune system cells, as only about 1 in 1-2 million immune cells harbor the virus, immunosuppressive effects do not appear consequential.

This therapeutic approach has been demonstrated to be highly effective in the laboratory and in a proof-of-principle clinical trials in which a prototype viral activation therapy drug demonstrated a high tumor response rate in patients with advanced EBV-related lymphoid cancers.

Notably, Viracta’s viral activation therapy approach and VRx-3996 have been shown to be well tolerated in cancer patients and not to suppress patients’ immune systems. This positions the approach for use concurrently with, or in advance of emerging immuno-oncology therapies, such as immune checkpoint inhibitors or adoptive cell therapy approaches.

VRx-3996 is an orally administered class-1 histone deacetylase-selective inhibitor that is potent inducer of targeted viral genes. VRx-3996 exhibited clinical characteristics that uniquely position it for Viracta’s viral activation therapy approach.

Cell No. 15, by Angela Canada Hopkins. This painting is an interpretation of a cancer cell dying via the process of programmed cell death, or apoptosis, the mechanism by which cancer cells are eradicated in Viracta’s viral activation therapy approach.