Focussed ultrasound and nanomedicine offer new hope for improving effects of cancer drugs
Researchers have made a breakthrough in more precisely targeting drugs to cancers.
A number of Centre members were part of a multi-disciplinary team of biomedical engineers, oncologists, radiologists and anaesthetists that have used ultrasound and lipid drug carriers (liposomes) to improve the targeting of cancer drugs to a tumour. The new technology has been used in humans for the very first time, with ultrasound remotely triggering and enhancing the delivery of a cancer drug to the tumour.
“Reaching therapeutic levels of cancer drugs within a tumour, while avoiding side effects for the rest of the body is a challenge for all cancer drugs, including small molecules, antibodies and viruses” says Professor Constantin Coussios, Director of the Oxford Centre for Drug Delivery Devices and of the Institute of Biomedical Engineering at the University of Oxford. “Our study is the first to trial this new technique in humans, and finds that it is possible to safely trigger and target the delivery of chemotherapy deep within the body from outside the body using focussed ultrasound. Once inside the tumour, the drug is released from the carrier, supplying a higher dose of chemotherapy directly to the tumour, which may help to treat tumours more effectively for the same or a lower systemic dose of the drug.”
The 10-patient phase 1 clinical trial, supported by the Oncology Clinical Trials Office, used focused ultrasound from outside the body to selectively heat liver tumours and trigger drug release from heat-sensitive carriers, known as thermosensitive liposomes. Building on over a decade of preclinical studies, the study demonstrated the ultrasound technique to be feasible, safe, and capable of increasing drug delivery to the tumour between two-fold and ten-fold in the majority of patients. Ongoing research worldwide is investigating the applicability of this technique to other tumour types, and future research could explore the combination of ultrasound with other drugs.
All 10 patients treated had inoperable primary or secondary tumours in the liver and had previously received chemotherapy. The procedure was carried out under general anaesthesia and patients received a single intravenous dose of 50 mg/m2 of doxorubicin encapsulated within low-temperature-sensitive liposomes (ThermoDox®, Celsion Corporation, USA). The target tumour was selectively heated to over 39.5° C using an approved ultrasound-guided focussed ultrasound device (JC200, Chongqing HAIFU, China) at the Churchill Hospital in Oxford. In six out of ten patients, the temperature at the target tumour was monitored using a temporarily implanted probe, whilst in the remaining four patients ultrasonic heating was carried out non-invasively.
Before ultrasound exposure, the amount of drug reaching the tumour passively was low and estimated to be below therapeutic levels. In seven out of 10 patients, chemotherapy concentrations within the liver tumour following focussed ultrasound were between two and ten times higher, with an average increase of 3.7 times across all patients.
“Only low levels of chemotherapy entered the tumour passively. The combined thermal and mechanical effects of ultrasound not only significantly enhanced the amount of doxorubicin that enters the tumour, but also greatly improved its distribution, enabling increased intercalation of the drug with the nucleus of cancer cells ” says Dr Paul Lyon, lead author of the study.
“This trial offers strong evidence of the rapidly evolving role of radiology in not only diagnosing disease but also guiding and monitoring therapy. The treatment was delivered under ultrasound guidance and patients were subsequently followed up by CT, MRI and PET-CT, evidencing local changes in tumours exposed to focussed ultrasound” commented Professor Fergus Gleeson, radiology lead co-investigator for the trial.
“A key finding of the trial is that the tumour response to the same drug was different in regions treated with ultrasound compared to those treated without, including in tumours that do not conventionally respond to doxorubicin” adds Professor Mark Middleton, principal investigator of the study. “The ability of ultrasound to increase the dose and distribution of drug within those regions raises the possibility of eliciting a response in several difficult-to-treat solid tumours in the liver. This opens the way not only to making more of current drugs, but also targeting new agents where they need to be most effective”.
The study was published in The Lancet Oncology journal.
Prognostic biomarkers discovered for patients with malignant pleural effusion
In a collaboration spanning multiple departments within Oxford and beyond, Centre members led by Dr Ioannis Psallidas have developed a new risk score (PROMISE score) that can provide important information on patient prognosis, and guide the selection of appropriate management strategies for patients with malignant pleural effusion.
Malignant pleural effusion is defined as the accumulation of a significant amount of fluid in the pleural space, accompanied by the presence of malignant cells or tumour tissue. It is commonly associated with breast and lung metastases, but the majority of late stage cancer could develop this type of metastasis. Currently, patients suffering from malignant pleural effusion have poor prognosis, with median survival ranging from 3 to 12 months. Additionally, the incidence of this condition is on the rise due to the increase in cancer prevalence and therapy improvements that allow patients to live for longer.
The most common treatment of malignant pleural effusion is pleudodesis, which involves the induction of pleural inflammation and fibrosis to prevent fluid accumulation. To improve the stratification of treatment for patients and to aid the understanding of the mechanisms underlying disease progression, prognostic biomarkers need to be identified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion.
Researchers discovered four proteins associated with patient survival that were independent of the cancer type. The data from one protein named tissue inhibitor of metalloproteinases 1 was combined with seven clinical biomarkers to build a score that predicts risk of death within 3 months. These four proteins that were associated with predicting survival also have potential as targets for novel treatments.
Ioannis remarked ‘The PROMISE score provides a valuable tool for clinicians to help stratify patients with malignant pleural effusion. Those of which have good prognosis can be identified for clinical trials of novel treatments. The patients with poorer prognosis can be treated symptomatically, reducing the number of hospital visits and procedures, such as pleudodesis, which may result in mortality. In the future we will be to aiming to secure funding to set up trials to investigate the effects of targeting the proteins identified in this study’.
The PROMISE study results have been published in Lancet Oncology.
CRUK Science Blog: Training viruses to be cancer killers
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.
Gold nanoparticles help deliver lethal one-two punch to cancer
Tagging gold nanoparticles with a small dose of radiation has helped researchers trace the precious metal as it delivers a drug right into the heart of cancer cells, according to new laboratory research being presented at the 2016 National Cancer Research Institute (NCRI) Cancer conference.
Researchers from the CRUK/MRC Oxford Institute for Radiation Oncology have been working on better ways to transport a drug directly into the control room of cancer cells, where the chromosomes are kept. This specific drug targets a molecule – telomerase – that builds up the protective caps at the end of chromosomes called telomeres.
In most cells of the body, telomeres act like an in-built timer to ensure that the cell does not live past its expiry date. Telomeres shorten each time the cell divides. Once a critical length is reached, the cell can no longer divide and it dies. Cancer cells manage to get around this safety check by reactivating telomerase allowing them to continue to grow out of control.
One of the biggest hurdles in treating cancer is getting effective drugs into cancer cells, particularly to where the chromosomes are stored. Gold nanoparticles have proven to be well suited to being absorbed into cells, safely delivering drugs that could otherwise be blocked.
By engineering the gold nanoparticles and adding the radioactive tracer, the researchers were able to prove that their drug was reaching the desired target in skin cancer cells grown in the lab and was shutting telomerase down, halting cancer’s growth.
While the radioactive tracer was used to precisely follow the drug in this study, the same method can also be used to deliver a dose of radioactivity to cancer cells, helping to kill them. This second dose is especially powerful because inactivation of telomerase makes cancer cells more sensitive to radiation.
Professor Kate Vallis, and Cancer Research UK Oxford Centre Member, said: “Gold is precious in more than one way. We have used tiny gold nanoparticles loaded with targeted drugs to kill cancer cells in the laboratory. Our long term goal is to design new treatments for cancer patients based on this promising approach.”
Sir Harpal Kumar, Cancer Research UK’s chief executive, said: “Gold has been used in medicine for many years and this research adds further insight into its potential. Ensuring that treatment is accurately targeted at cancer and avoids healthy cells is the goal for much of cancer research, and this is an exciting step towards that.”
Dr Karen Kennedy, Director of the NCRI, said: “Research continues to shed light on how cancer cells behave and how to effectively deliver a lethal payload to the tumour. This exciting research offers that potential and needs further investigation to see how it would be used in patients. The future looks exciting with research such as this improving the way the disease is treated.”
The Cancer Research UK Oxford Centre is at NCRI 2016, if you’d like to come and talk about the work of Oxford Centre members, come to stand 19 in the Exhibition Hall.
Photo of the 2016 NCRI Conference by Simon Callaghan Photography.
Monitoring prostate cancer offers the same survival chance as surgery or radiotherapy over 10 years, but treatment reduces risk of cancer progression
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
Anti-malaria drug could make tumours easier to treat
An anti-malaria drug could help radiotherapy destroy tumours according to a Cancer Research UK-funded study published in Nature Communications.
The study, carried out at the CRUK/MRC Oxford Institute for Radiation Oncology in Oxford, looked at the effect of the drug, called atovaquone, on tumours with low oxygen levels in mice to see if it could be repurposed to treat cancer.
Radiotherapy works by damaging the DNA in cells. A good supply of oxygen reduces the ability of cancer cells to repair broken DNA. So when a tumour has low levels of oxygen, it can repair itself more easily after radiotherapy.
This means that tumours with low oxygen levels are more difficult to treat successfully with radiotherapy. They are also more likely to spread to other parts of the body.
This research showed for the first time that an anti-malaria drug slows down the rate at which cancer cells use oxygen by targeting the mitochondria, the powerhouses of the cell that make energy, a process that uses oxygen.
By slowing down the use of oxygen, this drug reverses the low-oxygen levels in nearly all of the tumours. The fully-oxygenated tumours are more easily destroyed by radiotherapy.
The drug was shown to be effective in a wide range of cancers, including lung, bowel, brain, and head and neck cancer. This older medicine is no longer patented and is readily and cheaply available from generic medicines manufacturers.
Professor Gillies McKenna, Cancer Research UK Oxford Centre Director and joint lead author alongside Dr Geoff Higgins, said: “This is an exciting result. We have now started a clinical trial in Oxford to see if we can show the same results in cancer patients. We hope that this existing low cost drug will mean that resistant tumours can be re-sensitised to radiotherapy. And we’re using a drug that we already know is safe.”
Dr Emma Smith, Cancer Research UK’s science information manager, said: “The types of cancer that tend to have oxygen deprived regions are often more difficult to treat – such as lung, bowel, brain and head and neck cancer. Looking at the cancer-fighting properties of existing medicines is a very important area of research where medical charities can make a big impact and is a priority for Cancer Research UK. Clinical trials will tell us whether this drug could help improve treatment options for patients with these types of tumour.”
