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New hydrogel technology has promise in breast cancer modelling

In science, a model is used as a representation of something in the real world, so that ideas and concepts may be tested out. Models have a variety uses, but in cancer biology they are often popular as they can help to mimic the complex environment seen in human   disease. Models are used to explore the effects of new drugs, understand genetic or cellular pathways on tumour development or predict the potential response of a patients cancer.

It’s in a researcher’s best interest to create a model that is as faithful to the real world as possible, so that the outcomes are accurate and can translate successfully into humans. However, the go-to models to recapitulate human cells in a lab use, a protein matrix extracted from mouse tumours, which is used to resemble the extracellular environment found human tumours. But the extent to which mouse matrix can be used is limited by its fixed extracellular matrix components, which are often not representative of the human tissue, and the inability to add or remove the individual extracellular components to explore the influence these on tumour growth.

Dr Gillian Farnie, Nuffield Department of Orthopaedics, Rheumatology and Musculorskeletal Sciences, has focused her work on developing new models that allow human breast cancer cells to be grown and researched, whilst overcoming these limitations.

A recent publication in Matrix Biology, funded by the NC3Rs, outlines a new peptide hydrogel developed by the Farnie group in collaboration with Prof Merry (University of Nottingham).  This new peptide hydrogel offers the added benefit of being customisable, by incorporating or removing specific extracellular matrix components that researchers want to test, to better understand their influence on cancer cells. It therefore allows full control over the biochemical and physical properties of the model, providing researchers with the opportunity to more accurately adapt the model to the real-life environment of human breast tumour.

The new technology’s applications are incredibly widespread and promising. For example, certain extracellular matrix proteins, when found in high quantities in a tumour, can often be associated with a poorer prognosis for a patient. Researchers may want to understand if this is a simple correlation, or if the proteins are assisting the cancer in some way, such as promoting treatment resistance. The ability to remove these proteins from a cancer model and test the response, whilst remaining faithful and accurate to human cells, is incredibly useful and can allow us to discover therapeutic targets.

Dr Gillian Farnie is currently working with the breast cancer research community to apply this new technology in multiple breast tumour research projects. The hydrogel’s applications are not limited to just matrix biology, but also in investigating areas such as the biological significance of blood vessel supply to tumours or even other cancer types outside the breast.

This new hydrogel provides an opportunity to better understand the individual influences of the extracellular matrix, mechanical properties and cell-cell interactions on breast cancer and other disease. It is an open and reproducible model that Dr Farnie is currently publishing a detailed methodology in JOVE, so that more cancer researchers can have access to the new technology.

About this research

Dr Gillian Farnie is based in the Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences.  Her research focuses on the development of patient derived pre-clinical breast cancer models that are used to examine mechanisms of inherent and induced therapy resistance, interrogating both intra-tumour heterogeneity (cancer stem cells) and the tumour microenvironment (ECM, Stroma, Immune cells).

New melanoma cancer drug in development shows promise

University of Oxford and Immunocore Ltd have investigated Tebentafusp, a new anti-tumor immune response drug for patients with metastatic melanoma

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.

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.”

Osteoporosis drug could benefit postmenopausal women with breast cancer

Drugs used to treat the bone condition osteoporosis could prevent 1000 breast cancer deaths a year, according to a large analysis of previous clinical trials.

The study published in The Lancet, showed that the drugs – called bisphosphonates – reduced the risk of breast cancer coming back, as well as significantly reducing the risk of death, in women diagnosed after their menopause with early-stage breast cancer.

Breast cancers most commonly spread to the bone, and treatment with bisphosphonates alters the bone tissue. This potentially makes the bone a more challenging environment for rogue cancer cells to survive in, reducing the risk of the cancer coming back.

To test this, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) set up by researchers at the Nuffield Department of Population Health,University of Oxford, alongside collaborators from Oxford University Hospitals NHS Trust and many other institutes, combined data from 18,766 women from 26 clinical trials, comparing women who took bisphosphonates for between two and five years, with those who had no bisphosphonates.

Postmenopausal women on bisphosphonates saw a 28 per cent reduction in the chances of their cancer coming back. Bisphosphonates also reduced the risk of dying from the disease during the first 10 years after diagnosis by 18 per cent.

Professor Robert Coleman, who led the study, said that the results show that giving postmenopausal women bisphosphonates after surgery could “prevent around a quarter of bone recurrences and one in six of all breast cancer deaths in the first decade of treatment”.

Cancer Research UK’s chief clinician, Professor Peter Johnson, said that while findings had the potential to save many lives, further in-depth research will be needed.

“This large analysis suggests that, if post-menopausal women with early breast cancer were given bisphosphonates after surgery, it could stop cancer spreading to their bones and save around 1,000 lives a year,” he said.

“Many women already get bisphosphonates to protect against bone disease, but before doctors give this drug to all post-menopausal women at high-risk of breast cancer, more thorough clinical trials are needed,” he added.

A second study by the EBCTCG, also published in The Lancet, looked at the effectiveness of different hormone therapies for breast cancer.

It’s results provide further support for recommendations by NICE that hormone therapies called aromatase inhibitors should be offered to women with early-stage oestrogen receptor (ER)-positive breast cancer, over an older hormone therapy called tamoxifen.

Researchers found that women with ER-positive breast cancer taking aromatase inhibitors for five years had a 40 per cent lower risk of dying within 10 years of starting treatment, compared to those who didn’t take hormone therapy.

This compared to a 30 per cent lower risk following five years of treatment with tamoxifen.

Aromatase inhibitors work by preventing the body from producing oestrogen, and are taken by postmenopausal women with ER-positive breast cancer. They have previously been shown to be more effective than tamoxifen in reducing the chances of cancer coming back, but the new study is the first to show a greater reduction in death rates.

The study looked at data from 31,920 women across nine international clinical trials, with each study including women who had been treated with aromatase inhibitors or tamoxifen at various times during the study.

Lead author Professor Mitch Dowsett, from The Royal Marsden and The Institute of Cancer Research, London, said the global research effort confirmed that aromatase treatment provided “significantly greater protection than that offered by tamoxifen”.

But he cautioned that aromatase therapy was not without its side-effects.

“Aromatase inhibitor treatment is not free of side-effects, and it’s important to ensure that women with significant side-effects are supported to try to continue to take treatment and fully benefit from it,” he said.

The power of such long-term analyses was welcomed by Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, who said they were crucial for bringing the best treatments to patients.

“It tends to be the discovery of new treatments that grabs the headlines, but it is just as important to maximise the benefit patients get from existing treatments, through major, practice-changing studies like this,” he said.

Both studies were funded by Cancer Research UK and the Medical Research Council.

 

References

  • Early Breast Cancer Trialists’ Collaborative Group: Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet (2015) DOI:10.1016/ S0140-6736(15)60908-4
  • Early Breast Cancer Trialists’ Collaborative Group: Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet (2015) DOI:10.1016/S0140-6736(15)61074-1

Source: Cancer Research UK in collaboration with the Press Association