Stopping the spread

C&I Issue 11, 2013

A great deal of cancer research is currently under way to combat primary tumours that grow at the site on the body where cancer begins. However, there still exists a crucial need to find a treatment that can address metastatic cancer that has spread from the part of the body where it originated to another body part, such as bone, liver or lungs. Each year, at least 2.6m people in the developed world die of cancers that have metastasised.

Under a microscope, metastatic cancer cells generally look the same as cells of the original cancer. Moreover, metastatic cancer cells and cells of the original cancer usually have some molecular features in common, such as the expression of certain proteins or the presence of specific chromosome changes.

Although some types of metastatic cancer can be cured with current treatments, most cannot. Nevertheless, treatments are available for all patients with metastatic cancer. In general, the main goal is to control the growth of the cancer or to relieve symptoms. In some cases, metastatic cancer treatments may help prolong life. However, most people who die of cancer, die of metastatic disease.

Treating metastatic cancer

Metastatic cancer may be treated with systemic therapy, for example, chemotherapy, biological therapy, targeted therapy, hormonal therapy; local therapy such as surgery, radiation therapy; or a combination of these treatments. The choice generally depends on the type of primary cancer; the size, location, and number of tumours; the patient’s age and general health; and the types of treatment the patient has had in the past.

Conventionally, metastasis is treated based on the original site of the cancer. For example, if a person has breast cancer and cancer spreads to the liver, it is still treated with the same drugs used for breast cancer because the cancer cells themselves have not changed, they are just living in a new place.

Of course, treatment with radiation or chemotherapy has drawbacks. Radiation can kill healthy cells along with cancer cells. As for chemotherapy, it works by targeting fast-growing cells, like those typically found in rapidly growing tumours. But while chemotherapy can shrink tumours, they often grow back and become resistant, or refractory to the treatment. To combat this resistance, chemotherapy is now often used in combination with other treatments that have different mechanisms for attacking and killing cancer cells. Doctors must be cautious when combining treatments to ensure that the regimen does not become too toxic for patients to tolerate. The goal is to introduce drugs that can be used synergistically with chemotherapy to not only extend life, but to improve quality of life while undergoing treatment.

A different approach

Oncolytics Biotech in Calgary, Canada, in partnership with the NCIC Clinical Trials Group and the US National Cancer Institute, is developing a different treatment that not only addresses cancers within particular organs but also might help beat the ‘mets’, as metastatic cancers are also known.

Our approach involves using certain viruses to infect, multiply within and subsequently destroy cancer cells. Drugs based on such viruses can target the tumour and protect normal tissue, an approach known as virotherapy or oncolytic virus therapy. This involves the conversion of viruses into cancer-fighting agents by reprogramming them to attack cancerous cells, while healthy cells remain relatively undamaged.

Several types of these viruses, known as oncolytic viruses, have been developed to date. These include the reovirus, the adenovirus, the Newcastle-disease virus, and the poxvirus; further types include picornaviruses and vesicular stomatitis virus. It may come as a surprise to some that the cold sore or Herpes simplex virus is also under consideration as an oncolytic virus.

Oncolytics’ investigational drug treatment, Reolysin, is a proprietary formulation of a virus known as the human reovirus. Reovirus is found everywhere in nature and has been isolated from untreated sewage, river and stagnant waters. Exposure to reovirus is common in humans, with half of all children by the age of 12 having been exposed and up to 100% testing positive by adulthood.

Reovirus actively reproduces itself within cells that possess a particular structural feature—known as an ‘activated Ras pathway’—that is shared by more than two-thirds of all cancer cells.

Tumours bearing an activated Ras pathway can’t activate the anti-viral response mediated by the host cellular protein, PKR. Studies have shown that reovirus actively replicates in transformed cell lines with an active Ras signaling pathway, eventually killing the host cell and freeing the viral progeny that go on to infect and kill more tumour cells. When normal cells are infected with reovirus, the immune system can neutralise the virus. Approximately one-third of human cancers have activating mutations in the Ras gene itself. It is possible that more than two-thirds of cancer cells have an activated Ras signaling pathway because of activating mutations in genes upstream or downstream of Ras.

Reolysin’s discovery dates to the early 1990s, when a University of Calgary researcher, Patrick Lee, was doing research on reoviruses. By the end of 1995, Lee and two colleagues, Matt Coffey and Jim Strong had the hypothesis that there might be a reovirus treatment for cancer. In 1998, they submitted the first patent on the use of the reovirus to treat cancer, and then assigning it to Oncolytics Biotech the following year in order to start development to turn the reovirus into a treatment.

Three factors seem to contribute to the possibility that metastatic disease would be susceptible to treatment with Reolysin. First, reovirus appears to spread particularly easily to organs where metastasis is common, so a concentration of the drug can be built up in those regions of the body. Secondly, the cells that colonise a tumour to form the metastasis are believed to harbour genetic defects that provide a more accommodating environment for reovirus to colonise. Finally, a growing body of literature suggests Ras activation is required for metastasis to occur in the first place. Oncolytics believes its treatment is most effective in conjunction with chemotherapy; we are studying the effect of Reolysin in combination with the chemotherapy drugs carboplatin and paclitaxel.

Reolysin is now being tested in a randomised setting in head and neck cancer, non-small cell lung cancer, colorectal cancer, castration-resistant prostate cancer, drug-resistant ovarian cancer, breast and pancreatic cancer. All of these indications are associated with metastatic disease.

Most recently, in May 2013, Oncolytics reported preliminary data from a Phase 2 clinical trial showing that Reolysin, in combination with carboplatin and paclitaxel, reduced the size of tumours in patients with metastatic melanoma, a type of skin cancer. Three of 14 patients exhibited a partial response to the treatment, and an additional seven patients had stable disease for a disease control rate of 71.5%.

So could a virus finally be the key to beating the mets?

Future research studies will give us an even clearer perspective on whether ours, or some other virus-based treatment like it, offers the most effective route forward. There may be new hope on the horizon for patients with metastatic disease, a hope coming from within the human body itself.

Examining the mechanisms of metastasis

Cancer cell metastasis usually involves several steps. The first is ‘local invasion’, in which cancer cells invade nearby normal tissue. This is followed by ‘intravasation’, where cancer cells invade and move through the walls of nearby lymph vessels or blood vessels. Next comes ‘circulation’, in which cancer cells move through the lymphatic system and the bloodstream to other parts of the body. Subsequent to this is ‘arrest and extravasation’, where cancer cells arrest, or stop moving, in small blood vessels called capillaries at a distant location. They then invade the walls of the capillaries and migrate into the surrounding tissue. ‘Proliferation’ occurs next, during which cancer cells multiply at the distant location to form small tumours known as micrometastases. Finally, a process called ‘angiogenesis’ occurs, in which micrometastases stimulate the growth of new blood vessels to obtain a blood supply. A blood supply is needed to obtain the oxygen and nutrients necessary for continued tumour growth.

The ability of a cancer cell to metastasise successfully depends on several factors. Not all cancer cells, by themselves, have the ability to metastasise. In addition, the non-cancerous cells at the original location may be able to block cancer cell metastasis. Furthermore, successfully reaching another location in the body does not guarantee that a metastatic tumour will form. Metastatic cancer cells can lie dormant or not grow at a distant site for many years before they begin to grow again, if at all.

When symptoms of metastatic cancer occur, the type and frequency of the symptoms will depend on the size and location of the metastasis. For example, cancer that spreads to the bone is likely to cause pain and can lead to bone fractures, while cancer that spreads to the brain can cause a variety of symptoms, including headaches, seizures, and unsteadiness.

Sometimes, cancer is discovered only after a metastatic tumour causes symptoms. For example, a man whose prostate cancer has spread to his pelvis may have lower back pain before he experiences symptoms from the original tumour.

Brad Thompson is president and ceo of Oncolytics Biotech based in Calgary, Canada

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