For decades, scientists and doctors have looked for ways to stop the damage that viruses cause to humans.

But in recent years, certain safe, modified viruses have emerged as potential allies to tackle cancer.

And our scientists are among those searching for new forms of cancer-killing viruses.

Previous studies have shown that some viruses naturally kill cancer cells, but how they do this has never been fully understood.

Professor Len Seymour’s lab, at the Cancer Research UK Oxford Centre, has been focusing on one particular cancer-killing virus that operates under the code name of Enadenotucirev (or EnAd for short).

And a new study, published in Molecular Therapy – Oncolytics, has revealed EnAd to have a rather unusual method of killing cancer cells.

Arthur Dyer, a researcher in Professor Seymour’s lab, and the team have installed their own version of ‘cell CCTV’ to catch the act of cell-killing on camera.

The footage below was recorded using a normal light cell microscope, commonly found in a lab that takes a snap every minute.

“Each frame is one photo taken every minute and then we’ve stuck all the photos together as a video,” says Dyer. The end result is the clip below:

Dyer explains: “Here we’ve got human lung cancer cells in a dish and we’ve infected them with a virus that’s trained to kill cancer cells.”

This lab technique has given researchers valuable intelligence as to how EnAd kills cancer cells.

“When the cells are infected with the virus they balloon up, blister and then die,” says Dyer, adding that it was a cause of cell death he’d never seen before.

“When I first saw it I thought I was going mad. It’s such a weird cell death, it seems to use up the energy in the cell which then causes it to swell.”

One of the ways in which viruses survive in the human body is by hijacking healthy cells’ internal machinery.

EnAd takes over the cancer cells’ machinery, using up the cell’s energy to such an extent that it has no more strength left to live.

“This virus needs cells that are already hyperactive,” adds Dyer, explaining that as the metabolism of cancer cells has gone haywire they make the perfect victim.

Cells normally die in a very controlled way, but these cancer cells balloon up to 2 or 3 times their size, giving the appearance of blistering.

And it’s this precise effect that gives EnAd potential to be a great cancer cell killer.

Cancer cells can disguise themselves from the body’s immune system, but when EnAd destroys cancer cells in the lab it leaves the ‘crime scene’ upturned, with lots of evidence carelessly left behind. Seymour’s team believe this could encourage the immune system to ring the alarm for other immune cells to come and investigate the scene.

And to test this further, they’ve been putting lots of versions of the virus to work in the lab.

Seymour’s team has made sure they’ve got the deadliest of cancer cell killers by using a tough training programme.

“Viruses are naturally good at killing cancer cells so even harmless ones have some ability to attack them,” says Dyer.

“But to find the best virus, we grow them repeatedly in cancer cells and compare them all head to head.”

It’s important that the virus can tell the difference between healthy tissue and cancer cells. So the team also tests them on healthy cells to make sure the viruses can’t grow in them.

“So at the same time we also look for the ones that are least able to infect normal cells,” says Dyer.

This tough selection process leaves the viruses with only one mission: to infect and destroy cancer cells.

EnAd has passed these lab examinations and is now being tested in an early stage clinical trial in a very small number of people.

“These trials are making sure the virus is safe and to find the best way to give it to the patient. Ideally we’d like to use an injection so the virus can get into the bloodstream and reach cells that have gone to other parts of the body,” says Dyer.

Some cancers can also become resistant to the ways in which treatments destroy them. But because EnAd has a different method of destroying cancer cells, Seymour’s team believes the virus might also be able to kill cancers that have become resistant to treatment.

Ultimately, the team hopes to test how it performs with other drugs and in specific types of cancer, bringing it that little bit closer to becoming a new ally for targeting cancer.

 

 

 

This blog post was originally published by Cancer Research UK. Author Gabi Beer.

Active monitoring is as effective as surgery and radiotherapy, in terms of survival at 10 years, reports the largest study of its kind, funded by the National Institute for Health Research (NIHR).

Results published in New England Journal of Medicine today, show that all three treatments result in similar, and very low, rates of death from prostate cancer. Surgery and radiotherapy reduce the risk of cancer progression over time compared with active monitoring, but cause more unpleasant side-effects.

The ProtecT trial, led by researchers at the Universities of Oxford and Bristol in nine UK centres, is the first trial to evaluate the effectiveness, cost-effectiveness and acceptability of three major treatment options: active monitoring, surgery (radical prostatectomy) and radiotherapy for men with localised prostate cancer.

Chief investigator, and Cancer Research UK Oxford Centre member, Professor Freddie Hamdy says: “What we have learnt from this study so far is that prostate cancer detected by PSA blood test grows very slowly, and very few men die of it when followed up over a period of 10 years, – around 1% – irrespective of the treatment assigned. This is considerably lower than anticipated when we started the study.

However, treating the disease radically, when found, reduces the number of men who develop spread of prostate cancer, but we do not know yet whether this will make a difference to them living longer or better, and we have been unable to determine reliably which disease is lethal, and which can be left alone.”

Between 1999 and 2009, 82,429 men aged 50-69 across the UK were tested and 1,643 diagnosed with localised prostate cancer agreed to be randomised to active monitoring (545), radical prostatectomy (553) or radical radiotherapy (545). The research team measured mortality rates at 10 years, cancer progression and spread, and the impact of treatments reported by men.

The research team found that survival from localised prostate cancer was extremely high, at approximately 99%, irrespective of the treatment assigned.

The rate of cancer progression and spread was reduced by more than half in men in the surgery and radiotherapy groups, compared with active monitoring; cancer progression occurred in one in five in the active monitoring group, as opposed to less than one in 10 in the surgery and radiotherapy groups. However, surgery and radiotherapy caused unpleasant side-effects, particularly in the first year after treatment.

There was some recovery from side-effects over two to three years. But after six years, twice as many men in the surgery group still experienced urine leakage and problems with their sex life, in comparison with those in the active monitoring and radiotherapy groups. Radiotherapy caused more bowel problems than surgery or active monitoring.

Overall quality of life, including anxiety and depression, were not affected by any treatment at any time. Half of the men stayed on active monitoring over the 10-year period and avoided treatment side effects.

“This is the first time radiotherapy, surgery and active monitoring treatments for prostate cancer have been compared directly. The results provide patients and clinicians with detailed information about the effects and impacts of each treatment so that they can make an informed decision about which treatment to have,” comments co-investigator Professor Jenny Donovan, from the University of Bristol. “Each treatment has different impacts and effects, and we need longer follow up to see how those balance out over the next 10 years.”

Professor David Neal co-investigator from the Universities of Oxford/Cambridge says: “Interestingly, we saw that disease spread was reduced by half in men who were assigned to radical treatment, but no difference in survival outcomes with either surgery or radiotherapy, and no progression of the disease in three quarters of the men in the active monitoring treatment group, over the 10 years. We need to continue to study these men to find out whether prevention of cancer progression by surgery or radiotherapy leads to better cancer control and survival in the longer term.”

Professor Freddie Hamdy added: “Longer follow-up is now required to determine the ‘trade-off’ that patients need to make between cancer outcomes and quality of life, and further research to understand how we can distinguish ‘lethal’ from ‘non-lethal’ disease”.

“It is important that this research was conducted and that wouldn’t be possible without the NIHR and its infrastructure enabling large scale RCTs to be carried out across the NHS.”

The findings of the study will play a key part in the decision to screen for prostate cancer, and are being used as part of a study investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing for screening for prostate cancer, the CAP study. The CAP study is funded by Cancer Research UK and the Department of Health

Anne Mackie, Director at Public Health England Screening comments “The National Screening Committee has been following the ProtecT trial closely. The results of this study will provide men and their doctors with key information needed to manage localised prostate cancer.”  

The ProtecT trial has published two papers in New England Journal of Medicine:

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer
Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer

 

An international collaboration of researchers, including Oxford Centre members Dr Claire Palles, Prof Ian Tomlinson, and Dr David Church,  has identified five new gene regions that increase a woman’s risk of developing endometrial cancer. Endometrial cancer is one of the most common cancers to affect women, taking the number of known gene regions associated with the disease to nine.

Endometrial cancer affects the lining of the uterus. It is the fourth most commonly diagnosed cancer in UK women, with around 9,000 new cases being diagnosed each year.

Researchers at the University of Cambridge, Oxford University and QIMR Berghofer Medical Research Institute in Brisbane studied the DNA of over 7,000 women with endometrial cancer and 37,000 women without cancer to identify genetic variants that affected a woman’s risk of developing the disease. The results have been published in the journal Nature Genetics.

Dr Deborah Thompson from the Department of Public Health and Primary Care at the University of Cambridge said: “Our findings help us to paint a clearer picture of the genetic causes of endometrial cancer in women, particularly where there no strong family history of cancer. Prior to this study, we only knew of four regions of the genome in which a common genetic variant increases a woman’s risk of endometrial cancer.

“In this study we have identified another five regions, bringing the total to nine. This finding doubles the number of known risk regions, and therefore makes an important contribution to our knowledge of the genetic drivers of endometrial cancer.

“Interestingly, several of the gene regions we identified in the study were already known to contribute to the risk of other common cancers such as ovarian and prostate.

“Although each individual variant only increases risk by around 10-15%, their real value will be in looking at the total number of such variants inherited by a woman, together with her other risk factors, in order to identify those women at higher risk of endometrial cancer so that they can be regularly checked and be alert to the early signs and symptoms of the disease.”

The study also looked at how the identified gene regions might be increasing the risk of cancer, and these findings have implications for the future treatment of endometrial cancer patients.

“As we develop a more comprehensive view of the genetic risk factors for endometrial cancer, we can start to work out which genes could potentially be targeted with new treatments down the track,” said Associate Professor Amanda Spurdle from QIMR Berghofer.

“In particular, we can start looking into whether there are drugs that are already approved and available for use that can be used to target those genes.”

The study was an international collaboration involving researchers from Australia, the United Kingdom, German, Belgium, Norway, Sweden, the United States and China. The UK part of the study received funding from Cancer Research UK.

Dr Emma Smith, Cancer Research UK’s science information manager, said: “The discovery of genetic changes that affect women’s risk of developing endometrial – or womb – cancer could help doctors identify women at higher risk, who could benefit from being more closely monitored for signs of the disease.

“It might also provide clues into the faulty molecules that play an important role in womb cancer, leading to potential new treatments. More than a third of womb cancer cases in the UK each year could be prevented, and staying a healthy weight and keeping active are both great ways for women to reduce the risk.”

Reference
Cheng, THT et al. Five endometrial cancer risk loci identified through genome-wide association analysis. Nature Genetics; 2 May 2016; DOI: 10.1038/ng.3562

 

Cancer Research UK Oxford Centre Members Prof Tim Maughan and Prof Gil McVean are among the eight medical researchers at Oxford University who have been elected as Fellows of the Academy of Medical Sciences. The honour recognises outstanding contribution to the advancement of medical science, innovative application of scientific knowledge, or conspicuous service to healthcare.

Professor Sir Robert Lechler PMedSci, President of the Academy of Medical Sciences said: ‘These new Fellows represent the amazing diversity of talent and expertise among the UK medical research community. Through their election to the Fellowship, we recognise the outstanding contributions these individuals have made to the progress of medical science and the development of better healthcare.

‘We work with our Fellowship to create the essential connections between academia, industry and the NHS and beyond, to strengthen biomedical research and facilitate its translation into benefits for society.’

The eight Oxford researchers elected are:

• Professor Timothy Maughan is Professor of Clinical Oncology and Deputy Director of the CRUK/MRC Oxford Institute for Radiation Oncology and the Cancer Research UK Oxford Centre Networking Lead. His research interests focus on the treatment of patients with colorectal cancer and he is involved in clinical trial design and execution in gastrointestinal cancers.
• Professor Gilean McVean is Professor of Statistical Genetics, Head of Bioinformatics and Statistical Genetics and Director of the Big Data Institute at Oxford University. His research covers several areas in the analysis of genetic variation, combining the development of methods for analysing high throughput sequencing data, theoretical work and empirical analysis.
• Professor Christopher Butler is Professor of Primary Care and Clinical Director of the University of Oxford Primary Care Clinical Trials Unit at Oxford University. His research focuses on common infections (especially the appropriate use of antibiotics and antibiotic resistance), and health behaviour change.
• Professor Georg Holländer is Hoffmann and Action Professor of Paediatrics and Head of the Department of Paediatrics at Oxford University. His research is interested in the development and function of the immune system in health and disease.
• Professor Sarah Lamb is Kadoorie Professor of Trauma Rehabilitation and Co-Director of the Oxford Clinical Trials Research Unit at Oxford University. Her research focuses on clinical trials and medical statistics, and she is Chief Investigator for a number of trials of rehabilitation interventions.
• Professor Martin Maiden is Professor of Molecular Epidemiology at Oxford University. His research studies the population biology and evolution of bacterial pathogens, with the objective of translating the insights obtained into benefits for human health.
• Professor Andrew Pollard is Professor of Paediatric Infection and Immunity, Director of the Oxford Vaccine Group and Honorary Consultant Paediatrician at Oxford University. His research interests focus on Current research activities include clinical trials of new and improved vaccines for children, invasive bacterial diseases in children in Nepal, studies of cellular and humoral immune responses to glycoconjugate vaccines, and development of a serogroup B meningococcal vaccine.
• Professor Elizabeth Robertson is Professor of Developmental Biology and Wellcome Trust Principal Research Fellow at Oxford University. Her research exploits mouse genetics to investigate the key signalling cues and transcriptional regulators governing cell fate decisions in the developing mammalian embryo.

The new Fellows will be formally admitted to the Academy at a ceremony on the 29th June 2016.

Technology developed in Oxford to make tumour cells fluorescent could improve surgery outcomes for men with prostate cancer. From this Autumn, the method will be offered to patients as part of a trial at the Churchill Hospital run jointly by Oxford University and Oxford University Hospitals Trust and supported by Cancer Research UK.

Fluorescent compounds show up diseased cells during keyhole operations, allowing surgeons to be more precise when removing the prostate and tissue around it. Freddie Hamdy, the Nuffield Professor of Surgery and Cancer Research UK Oxford Centre Member, said this meant doctors could avoid taking away too much tissue, or too little.

He said: “The keyhole surgery programme is doing very well, but when we look inside we cannot always see the cancer. We see the prostate and most of the structure but the cancer is not often visible to the naked eye. If we take too much then it can have an adverse impact on continence and sexual function. If we do not take enough we leave cancer cells behind. So we need to create a new eye for the surgeons.”

The new technique combines the fluorescent compound with new camera technology developed by Boris Vojnovic, of the university’s Department of Oncology. The compound illuminates cancer cells, so the surgeon can use the camera to see exactly what needs to be removed.

Prof Hamdy added: “This means when we do the surgical procedure we can take exactly the right amount of tissue and try and guarantee a good outcome.”

Each year about about 40,000 men in the UK are diagnosed with a prostate tumour, the most common cancer in men. Treating prostate cancer in its early stages can be beneficial in some cases, but the side effects of the various treatments are also potentially serious. Prof Hamdy said: “You could over-treat someone even though he may have gone through life without seeing any of the effects.”

A major trial, called ProtecT (Prostate testing for cancer and Treatment) and funded by the National Institute for Health Research, has been completed to try and help reduce over-treatment. It has been running in nine centres of the UK since 1999, with Oxford University acting as a sponsor, and has involved more than 80,000 men – making it the largest study of its kind. The study is due to report back in the coming months. A separate trial, PART (Partial prostate Ablation versus Radical prosTatectomy), is also looking at focal therapy. Because treatments for prostate cancer can have a range of side effects, scientists also want to develop new methods that reduce the burden on patients but still control the cancer. PART is comparing the effects of removing the whole prostate with those of partial destruction using high-intensity focused ultrasound.

This article originally appeared in the Oxford Mail, and can be viewed online here.