Don’t nuke that cold sore

Researchers in the University of Calgary Health Sciences Department are determined to develop a biological, cancer-killing machine by fair means or foul.

Last month, the medical community watched excitedly as a U of C research team revealed test results of the seemingly harmless Respiratory Enteric Orphan virus as an oncolytic (cancer-attacking) treatment. Dr. Patrick Lee, a member of the team, has now revealed another striking discovery: the use of the Herpes Simplex Virus as another potential oncolytic treatment.

"The most important thing here is the conceptual breakthrough," explained Dr. Lee. "The importance of this work is that it reveals for the first time why herpes virus is effective as a cancer killer. We found that herpes, like the REO virus, makes use of the RAS pathway."

The key to both discoveries is a chain of biochemical reactions, called the RAS pathway, that cause cells to multiply. In normal human cells, the RAS pathway is tightly regulated and triggered by an extracellular messenger or stimulus. On the other hand, approximately 80 per cent of all cancer cells are able to maintain the pathway by themselves, which is why they survive and rapidly multiply.

"RAS acts like a light switch," said Dr. Lee. "Normally the light switch is turned off and when it is turned on, it is only for a few seconds. In the situation where the cell is cancerous, it is as if the switch is turned on all of the time."

Typically, viruses facilitate infection using self-produced tools and host-produced tools. In the case of HSV, researchers observed a correlation between the virus and the RAS pathway, hypothesizing that the presence of the virus caused an increase in activity. However, Dr. Lee’s research shows the opposite is true: HSV finds cells with unusually active RAS pathways then infects them.

To explain this phenomenon, Dr. Lee used an analogy in which a virus has a left arm (its own normal cell-seeking tools) and a right arm (the RAS pathway-seeking tool).

"[In HSV], the right arm comes from the RAS," explained Lee. "What we have found is that you can engineer a cancer killer by cutting the left arm off by making a deletion in the viral DNA. For a virus that has lost its own tools, it will now have no choice but to infect only those cells with very strong right arms. And what kind of cell has a strong right arm? Cancer cells."

Because of its unique behaviour, HSV may be a powerful and selective cancer-killing agent. Fortunately for Dr. Lee’s team, a clinical test of the oncolytic properties of herpes is already underway. Several years ago, Harvard neurosurgeon Dr. Robert Martuza began administering HSV to patients with brain tumours. Theoretically, the U of C discovery goes a long way toward explaining why the treatment is effective.

"Lee’s work provides an important link in our understanding of how viruses can be genetically engineered to attack cancer," said Dr. Martuza. "This research will lead to new generations of more specific oncolytic viruses."

In addition to implications in cancer treatment, the discovery could change the way herpes infections are treated. Forms of the virus (such as cold sores) are caused by persistent infection and made possible by elevated RAS activity in the host cells. Although this activity is not as high as in cancer cells, the possibility for a novel new treatment is definite.

"There are already drugs out there being used to tune down the RAS signalling pathway," said Dr. Lee. "What we have demonstrated in our paper is that you can now use these drugs to block herpes infection because when RAS is not activated, herpes can’t infect."

Dr. Lee’s findings will be published in the August issue of the biological journal Nature Cell Biology.

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