World-first viral therapy trial in cancer patients

Thursday 19 September 2013

Islamabad, Sep 20 (Newswire): Researchers from the Ottawa Hospital Research Institute (OHRI), the University of Ottawa (uOttawa), Jennerex Inc. and several other institutions have just reported promising results of a world-first cancer therapy trial in journal Nature.

The trial is the first to show that an intravenously-delivered viral therapy can consistently infect and spread within tumours without harming normal tissues in humans. It is also the first to show tumour-selective expression of a foreign gene after intravenous delivery.

The trial involved 23 patients (including seven at The Ottawa Hospital), all with advanced cancers that had spread to multiple organs and failed to respond to standard treatments.

The patients received a single intravenous infusion of a virus called JX-594, at one of five dose levels, and biopsies were obtained eight to 10 days later. Seven of eight patients (87 per cent) in the two highest dose groups had evidence of viral replication in their tumour, but not in normal tissues.

All of these patients also showed tumour-selective expression of a foreign gene that was engineered into the virus to help with detection. The virus was well tolerated at all dose levels, with the most common side effect being mild to moderate flu-like symptoms that lasted less than one day.

"We are very excited because this is the first time in medical history that a viral therapy has been shown to consistently and selectively replicate in cancer tissue after intravenous infusion in humans," said Dr. John Bell, a Senior Scientist at OHRI, Professor of Medicine at uOttawa and senior co-author on the publication.

"Intravenous delivery is crucial for cancer treatment because it allows us to target tumours throughout the body as opposed to just those that we can directly inject. The study is also important because it shows that we can use this approach to selectively express foreign genes in tumours, opening the door to a whole new suite of targeted cancer therapies."

Dr. Bell and his team have been investigating cancer-fighting (oncolytic) viruses at OHRI for more than 10 years. JX-594 was developed in partnership with Jennerex Inc., a biotherpeutics company co-founded by Dr. Bell in Ottawa and Dr. David Kirn in San Francisco. JX-594 is derived from a strain of vaccinia virus that has been used extensively as a live vaccine against smallpox. It has a natural ability to replicate preferentially in cancer cells, but it has also been genetically engineered to enhance its anti-cancer properties.

"Oncolytic viruses are unique because they can attack tumours in multiple ways, they have very mild side effects compared to other treatments, and they can be easily customized for different kinds of cancer," said Dr. Bell. "We're still in the early stages of testing these viruses in patients, but I believe that someday, viruses and other biological therapies could truly transform our approach for treating cancer."

Although the current trial was designed primarily to assess safety and delivery of JX-594, anti-tumour activity was also evaluated. Six of eight patients (75%) in the two highest dose groups experienced a shrinking or stabilization of their tumour, while those in lower dose groups were less likely to experience this effect.

"These results are promising, especially for such an early-stage trial, with only one dose of therapy," said Dr. Bell. "But of course, we will need to do more trials to know if this virus can truly make a difference for patients. We are working hard to get these trials started, and at the same time, we are also working in the laboratory to advance our understanding of these viruses and figure out how best to use them."

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Potential molecular target to prevent growth of cancer cells identified

Islamabad, Sep 20 (Newswire): Researchers have shown for the first time that the protein fortilin promotes growth of cancer cells by binding to and rendering inert protein p53, a known tumor suppressor.

This finding by researchers at the University of Texas Medical Branch may lead to treatments for a range of cancers and atherosclerosis, which p53 also helps prevent, and appears in the current print issue of the Journal of Biological Chemistry.

"The p53 protein is a critical defense against cancer because it activates genes that induce apoptosis, or the death of cells. However, p53 can be made powerless by mutations and inhibitors like fortilin," said Dr. Ken Fujise, lead author of the study and director, Division of Cardiology at UTMB.

Fortilin, an amino acid polypeptide protein, works in direct opposition to p53, protecting cells from apoptosis. Fujise discovered fortilin in 2000 and the protein has become a central focus of his research. This study marks the first time that scientists have been able to show the exact mechanism whereby fortilin exerts its anti-apoptotic activity.

Fujise and his team used cell cultures and animal models to show that fortilin binds to and inhibits p53, preventing it from activating genes, such as BAX and Noxa, that facilitate cell death. Thus, cells that would be killed are allowed to proliferate.

"When normal cells become cancer cells, our bodies' natural biological response is to activate p53, which eliminates the hopelessly damaged cells," said Fujise. "This process explains why the majority of people are able to stay cancer-free for most of their lives. Conversely, mutated p53 genes are seen in more than half of all human cancers, making them the most frequently observed genetic abnormality in cancer."

According to Fujise, upon further research and validation of the biological mechanism described in this study, scientists can begin exploring compounds that could modulate fortilin's activity on p53.

Such a compound would be a powerful chemotherapy agent and, because p53 inhibition has also been associated with atherosclerosis, could also protect against coronary disease and its many complications, including heart attack and stroke.

"Though we are in the early stages of this research, once screening for compounds is initiated, we could have a potential new drug to investigate in a very short period of time," said Fujise. With the support of National Institutes of Health high-throughput screening programs, which make it possible to screen very large numbers of compounds against a drug target, the process of identifying a new drug could potentially be shortened to months rather than years, he added.

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MRI research demonstrates ALS attacks multiple parts of the brain

Islamabad, Sep 20 (Newswire): Recently published studies by a researcher in the Faculty of Medicine & Dentistry demonstrate that ALS -- known as Lou Gehrig's disease -- damages neurons in parts of the brain responsible for cognition and behaviour.

ALS, which stands for amyotrophic lateral sclerosis, is a fatal neurodegenerative disease that eventually leaves patients unable to move, breathe or swallow. Previous research has shown about 50 per cent of patients with ALS also have mild cognitive and behavioural changes, but between five and 15 per cent of patients can have severe changes resulting in dementia. In Canada, between 2,500 and 3,000 people live with the disease. Most die within two to five years of diagnosis.

Sanjay Kalra, a researcher in the faculty's Division of Neurology and a practising neurologist, has published two papers this year in the American Journal of Neuroradiology providing evidence that ALS affects more than just the motor cortex, the part of the brain responsible for motor function.

"ALS was previously thought to be a disease restricted to the motor system causing only weakness," says Kalra, the principal investigator in both peer-reviewed papers.
"But a significant proportion of people with ALS also have cognitive and behavioural changes. We wanted to know how ALS was impacting other parts of the brain to cause these symptoms.

"There is increasing evidence from pathological studies of ALS patients post-mortem that not just the motor system is involved. Our research supports this and demonstrates in those living with ALS, that the disease is indeed attacking other parts of the brain. The cognitive and behavioural changes we are seeing in patients are not reactive," he says. "They are not happening because someone is depressed or doesn't have initiative because he is weak. Those changes are happening because there are biological and chemical changes in parts of the brain that are responsible for behaviour and cognition."

Kalra uses magnetic resonance imaging (MRI) not to just look at pictures of the brain, but also as a means of measuring the levels of various chemicals in the brain. In his most recently published paper, he looked at two different chemicals called NAA and mIns. NAA is known as a neural marker, which means it is only found in neurons, while levels of mIns increase when there is abnormal scarring in the brain.

"If NAA is decreased, it means neurons have died or they are not working. Many papers have shown NAA to be decreased in regions where you expect it to be decreased with ALS -- the motor cortex. But our recent study shows that these levels are also decreasing in areas of the brain responsible for cognition and behaviour," says Kalra.

His paper looked at decreasing levels of NAA in the cingulate cortex -- the first time MRI had been used to measure chemicals in this region of the brain in ALS. And his most recently published paper, which came out late this summer, was the first to demonstrate that NAA was decreasing and mIns was increasing in the frontal lobe, even when there weren't signs of cognitive or behavioural issues in patients. The frontal lobe is considered the hub for cognition and behaviour in the brain.

Kalra would like to continue his research using MRI to track the changes in the brain of those who have ALS, and to evaluate new drugs. Kalra is the leading researcher in Canada to use MRI to study ALS. In November 2010, he was invited to give a presentation at Oxford University, and earlier this year he collaborated with a number of international researchers to write a commentary piece in Lancet Neurology about this growing area of research.

He first became interested in studying ALS when he was a neurology resident looking for a research project using MRI. He has continued studying the disease ever since.

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