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Common Virus Kills Breast Cancer Stem Cells

Molecular Therapy, April 14, 2009

Led by Dr. Patrick Lee of the Department of Microbiology and Infectious Diseases at the University of Calgary, scientists have discovered that the commonly occurring reovirus can selectively target and destroy the cancerous stem cells that cause breast cancer. Additionally, the reovirus also exhibits other beneficial cellular and molecular action by stimulating the body's immune system and natural anti-cancer defense mechanisms.

It was over a decade ago, in 1998, when Dr. Lee originally announced his discovery that the reovirus (an acronym for Respiratory Enteric Orphan virus) can kill cancer cells. Now, the discovery has been extended specifically to breast cancer stem cells, which are the "master cells" gone awry and which consequently generate cancer cells in the breast.

As Dr. Lee explains, "You can kill all the regular cancer cells in a tumor, but as long as there are cancer stem cells present, disease will recur." Indeed, it has taken the medical profession awhile to appreciate the full significance of cancer stem cells and the importance of eliminating these stem cells in any clinical cancer treatment. Cancer stem cells are difficult to kill, however, and are often highly resistant to standard chemotherapy and radiation treatments, which accounts for the low success rates of chemotherapy and radiation. As Dr. Lee further explains "Cancer stem cells are essentially mother cells. They continuously produce new cancer cells, aggressively forming tumors even when there are only a few of them. Cancer stem cells just keep churning out new cancer cells. No matter how many cancer cells you kill, you can't stop the cancer until you kill the stem cells." Even if the cancer stem cells themselves remain in very small numbers, they can still produce new tumors, in large numbers. Without eliminating the cancer stem cells in their entirety, the cancer that is produced by the stem cells can never be fully eliminated. The only way to "cure" any particular type of cancer, therefore, in the absolute sense of the word, is to get to the root of the problem and eliminate the cancer stem cells.

Now, in an effort to do exactly that, scientists are looking at ways of utilizing the reovirus as a virus-based anti-cancer therapy, which is currently being tested in 10 clinical trials, 4 in the U.K., and 6 in the U.S., under the name "Reolysin", which is marketed by the Canadian company Oncolytics Biotech. Although the current issue of the journal Molecular Therapy describes a study in which the reovirus is utilized for the specific treatment of breast cancer, the study complements and corroborates a number of other clinical and preclinical studies in which the reovirus is also utilized to treat other forms of cancer as well.

The mechanism-of-action of the reovirus is particularly advantageous as a cancer therapy, since the reovirus has been found to preferentially replicate in Ras-activated cancer cells, thereby causing virus-mediated cell death. Additionally, scientists have discovered that the tumor antigens generated by viral oncolysis (the destruction of tumor cells) may "educate" the immune system to recognize and kill similar tumor cells in the future. Based upon principles such as these, the proprietary anti-cancer product Reolysin has been formulated to replicate specifically in tumor cells that bear an activated Ras pathway, and which are therefore also deficient in their ability to activate a natural anti-viral response as mediated by PKR (protein kinase R) activity, which is present in normal cells but absent in tumor cells with activated Ras pathways, since normal cells do not possess activated Ras pathways. As the tumor cells die, the progeny viral particles in turn spread to neighboring cells, a process which in turn triggers the continuous cycle of infection, replication and cell death - a cellular cycle that repeats itself until there are no more tumor cells remaining which bear the activated Ras pathway.

The activated Ras pathway is one of the most common genetic defects that are known to predispose an individual to developing cancer, and it is believed that the activation of mutations in Ras, as well as in upstream elements of Ras, may be implicated in more than two-thirds of all human cancers. Scientists therefore hope that Reolysin may represent a novel treatment not only for Ras-activated tumor cells but also for other types of cellular proliferative disorders.

Reovirus is commonly known to inhabit the human respiratory and bowel systems, being naturally found in sewage and water supplies, but it is nonpathogenic. Its anti-cancer properties were first established after the reovirus was found to replicate so easily within Ras-activated cancer cell lines. According to Dr. Lee, "The cancer cell environment lets the virus uncoat and start reproducing more quickly than it can in normal cells. The rapidly growing mass of virus particles ruptures the infected cancer cell, releasing virus particles to infect other cancer cells in the body. So theoretically it can even kill cancers that have metastasized." Dr. Lee adds, "We suspected that reovirus might be effective against cancer stem cells, because we have shown time and again how well it destroys regular cancer cells."

Unlike most cancer studies, which use cancer cell lines that have been developed exclusively for laboratory use, Dr. Lee's study utilized fresh breast cancer tissue that was derived from a live patient. As Dr. Lee explains, "Refining this two-pronged approach to killing cancer is our next step. We are taking advantage of the natural characteristics of reovirus and the immune system itself to create a powerful virus-based anti-cancer therapy."

Additionally, Oncolytics Biotech has developed a clinical program which includes human trials that use Reolysin by itself and also in combination with radiation and chemotherapy. Headquartered in Calgary, Alberta, Oncolytics Biotech was founded in 1998 for the specific purpose of developing pharmaceutical cancer therapies that are based upon the oncolytic properties of the reovirus. Thus far, Oncolytics Biotech has concluded nine human Phase I/II clinical trials in the U.K. and the U.S. which have yielded positive interim data for lung, liver and nodal metastatic disease. Additionally, Reolysin is in Phase II/III clinical trials for patients with refractory head and neck cancers, and Oncolytics is currently in a collaborative agreement with the U.S. National Cancer Institute for the design of multiple clinical trials. Independent preclinical studies have also demonstrated that the reovirus can destroy cancers of the brain, ovary, prostate, breast and colon, in addition to melanoma and lymphoma.

Another important variable is the transcription factor p53 which normally plays a role in tumor suppression. According to Dr. Lee, "Learning how p53 works and why it loses its protective function in cancer could well lead to a cure."

In the United States, cancer is responsible for one out of every four deaths, ranking second only to cardiovascular disease in prevalence. Approximately 1.4 million people in the U.S. were diagnosed with cancer in 2008 alone, more than half of whom are expected to die from the disease. The probability of developing cancer at some point in life is approximately 50% (or one out of every two people) for the average U.S. male, and approximately 33% (or one out of every 3 people) for the average U.S. female. In 2007 the U.S. National Institutes of Health estimated that the overall annual cost for all types of cancers combined in the United States was $219.2 billion, of which $89 billion was directly attributable to medical expenses while the remaining $130.2 was attributable to lost productivity

Dr. Patrick Lee is a founding member of the Beatrice Hunter Cancer Research Institute at the Dalhousie University Medical School in Halifax, Nova Scotia.

Molecular Therapy is a journal of the American Society of Gene Therapy.



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