Alberta Innovates- Health Solutions

Viruses and guns can be deadly weapons, but in the hands of Dr. Daphne Mew, they will save our lives.

Heritage researcher Dr. Mew combines a demanding surgical practise at Calgary's Foothills Hostpital with equally demanding cancer research at the University of Calgary. Her focus is on therapies delivered by revolutionary technologies to treat mesothelioma, a rare, deadly, and difficult-to-treat cancer. Dr. Mew's research offers a ray of hope not only for mesothelioma treatment but for other cancers too. It is focused on gene therapy, the insertion of new genetic material into cells of the body to help them fight cancer.

Mesothelioma does not respond well to such standard cancer treatments as chemotherapy and radiotherapy; palliative care is the only way to manage the disease, which on average kills patients about eight to ten months after onset.

Long associated with prolonged exposure to asbestos, mesothelioma occurs when the pleura, the lining of the chest wall, becomes cancerous. It kills by filling the chest cavity so that the heart or lungs are squeezed to a stop. In the last two decades, asbestos quality has improved tremendously as have industrial workplace conditions. That's why mesothelioma is found mainly in an older, male population who are dying from decades old asbestos exposure. However, mesothelioma is increasing in the general population at a rate of about 10% annually, an indication that asbestos exposure may be only part of the story.

Recent research suggests that a virus could be implicated in mesothelioma. This virus has a genetic sequence similar to that of a monkey virus that contaminated some polio vaccine preparations used globally up to 1963. The monkey DNA tumor virus, known as Simian Virus 40 (SV40), is known to cause cancer in mice and to transform human tissue. It does this through a recombinant DNA process; that is, the SV40 virus splices together different pieces of genetic material in order to program the cells to behave differently. The SV40-like virus, which is found in 60% of human mesotheliomas, also works by recombining genetic material.

Cells transformed with the SV40-like virus make an antigen, a protein destructive to the body. In a small percentage of cells, the antigen is made on the membrane forming the outer "skin" of the cell, marking the cell as transformed tumor cell. The role of the antigen is still not completely understood, but it is thought to stimulate a growth factor that could be essential for the development of mesothelioma. It may also stop the function of genes that suppress tumors. Dr. Mew is developing treatment that would specifically target he virus, or the antigen it produces, for use in gene therapy.

She has a number of options available to get the genetic material into the cells. One method is to load inactive cold viruses with genetic material, then "infect" the tumor cells with the virus. Ideally, the manipulated tumor then starts producing healthy copies of cells.

Another method is to insert altered retroviruses into the tumor site. In disease states, retroviruses harness the genetic machinery of healthy cells and reprogram them to become virus-producing factories. In gene therapy, the viral particles in retroviruses are punched out and replaced with specific genetic material, but the reprogramming template is left intact. These altered retroviruses then target cells that are actively making DNA, in this case the tumor cells, and program them with normal copies of DNA.

A third method being researched by Dr. Mew involves firing gold pellets loaded with genetic material directly inside the tumor cells. To do this, she uses a gun.

Dr. Mew explains, "The gene gun physically resembles a hand-held gun, but it operates on helium. The idea is to surgically clear our as much tumor mass as possible and then fire the genetic material directly into the tumor site.

Whatever the intended effect of the genetic material, whether it is to make tumors susceptible to chemotherapy or to act as tumor suppressors, the gun enables a tremendous amount of genetic material to be inserted directly into the cells."

Although there is a risk of damaging healthy tissue in the tumor region with the gene gun approach, it could be extremely useful in treating cancers that are inoperable, such as breast cancers that approach the chest wall, or head and neck cancers. If genetic material were developed to target the mutation specific to the cancer, it could be fired into the remaining tumor area without affecting healthy cells.

Currently, Dr. Mew is testing the gene gun for use in genetic immunization. Standard immunization works by introducing a protein for a disease into the body and stimulating the immune system to recognize it. Genetic immunization takes this a step further. The gene for making the protein is introduced into the human cell, and the cell then makes more of the protein, as well as specific antigens that alert the immune system to recognize it. This is thought to give better genetic recognition and better immune response. This approach might someday be used to improve the immune system's ability to fight against certain cancers that have a higher-than-average rate of remission, such as kidney cancer and melanoma. In these cases of remission, the immune system has evidently been stimulated and the disease disappears.

Dr. Mew is hoping to gain a better understanding of the origins of mesothelioma that may also shed light on how cancer tumors begin. She hopes to begin clinical trials on the therapies she has developed within the next few years.

Dr. Daphne Mew is a surgeon and Heritage researcher at the University of Calgary. She also receives support from the Alberta Cancer Board and the Alberta Lung Association.