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Author: Louise Stanley

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Triple-drug combo could prove key weapon in fight against cancer

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials, Experimental medicine.

Combining three existing drugs – a commonly-used anti-epileptic, a contraceptive steroid and a cholesterol-lowering agent – could form an effective and non-toxic treatment for a range of aggressive blood cancers, a new study reveals.

The discovery by University of Birmingham scientists has led to a £1 million funding award from Blood Cancer UK to run a randomised clinical trial to test the new drug combo against another experimental agent (Danazol) in patients living with Myelodysplastic Syndromes (MDS).

Over 7,000 people in the UK have MDS and many patients die because their disease transforms into acute myeloid leukaemia (AML) – an even more aggressive blood cancer. The general outlook for AML is poor, but when AML arises from MDS it is worse.

Left untreated, AML kills patients quickly by crippling production of normal blood cells. AML is most prevalent in elderly people – many of whom cannot tolerate ‘traditional’ treatment of intensive chemotherapy because of their age and frailty.

Scientists at the University of Birmingham had already discovered that mixing bezafibrate (BEZ – cholesterol-lowering) with medroxyprogesterone acetate (MPA – contraceptive steroid) eased a range of blood cancers including AML, chronic lymphocytic leukaemia (CLL) and non-Hodgkins lymphoma.

Now clinical trials show that adding valproic acid to a low-dose combination of the other two drugs offers enhanced killing of AML cells – giving the low-dose triple-drug combo (VBaP) a cancer-busting impact similar to a high dose of BEZ and MPA (BaP).

Researchers from the University of Birmingham have published their findings in British Journal of Cancer.

Co-author Professor Chris Bunce, commented: Using existing drugs to treat conditions outside of their approved indications is a proven approach to generate effective low-toxicity therapies. We believe that treating patients earlier with low toxicity therapies is the most effective clinical strategy for improving patient outcomes.”

Earlier clinical trials had shown that low-doses of BaP given to patients who could not have chemotherapy produced no toxic side effects and helped patients to boost their production of blood cells.

However high doses of the dual combo were not well tolerated, due to the frail nature of the patients caused by their age, poor kidney function, disease and, in some cases, prior chemotherapy treatments.

Co-author Dr Farhat Khanim commented: “A major challenge in our previous BaP trials has been the focus on elderly patients for whom more intensive therapies were not option.

“For many of these patients there are very few treatment options other than regular transfusions to combat life-threatening deficits in red cells and platelets and antibiotic control of frequent life threatening infections.

“It is therefore an attractive option to consider testing VBaP in MDS patients. As the drug combination may have profound impact on quality of life and survival of these patients.”

Artificial Intelligence project aims to improve diversity and equality in AI systems

Written by Louise Stanley on . Posted in Health inequalities.

A new project has been launched across BHP members, aiming to address racial and ethical health inequalities using artificial intelligence (AI).

STANDING Together, being led by BHP founding member University Hospitals Birmingham NHS Foundation Trust (UHB), aims to develop standards for datasets that AI systems use, to ensure they are diverse, inclusive and work across all demographic groups. The resulting standards will help regulators, commissioners, policymakers and health data institutions assess whether AI systems are underpinned by datasets that represent everyone, and don’t leave underrepresented or minority groups behind.

Xiao Liu, Clinical Researcher in Artificial Intelligence and Digital Healthcare at the University of Birmingham and UHB, and STANDING Together project co-leader, said: “We’re looking forward to starting work on our project, and developing standards that we hope will improve the use of AI both in the UK and around the world. We believe AI has enormous potential to improve patient care, but through our earlier work on producing AI guidelines, we also know that there is still lots of work to do to make sure AI is a success stories for all patients. Through the STANDING Together project, we will work to ensure AI benefits all patients and not just the majority.”

NHSX’ NHS AI Lab, the NIHR, and the Health Foundation have awarded in total £1.4m to four projects, including STANDING Together. The other organisations working with BHP on STANDING Together are the Massachusetts Institute of Technology, Health Data Research UK, Oxford University Hospitals NHS Foundation Trust, and The Hospital for Sick Children (Sickkids, Toronto).

The NHS AI Lab introduced the AI Ethics Initiative to support research and practical interventions that complement existing efforts to validate, evaluate and regulate AI-driven technologies in health and care, with a focus on countering health inequalities. Today’s announcement is the result of the Initiative’s partnership with The Health Foundation on a research competition, enabled by NIHR, to understand and enable opportunities to use AI to address inequalities and to optimise datasets and improve AI development, testing and deployment.

Brhmie Balaram, Head of AI Research and Ethics at NHSX, said: “We’re excited to support innovative projects that demonstrate the power of applying AI to address some of our most pressing challenges; in this case, we’re keen to prove that AI can potentially be used to close gaps in minority ethnic health outcomes. Artificial intelligence has the potential to revolutionise care for patients, and we are committed to ensuring that this potential is realised for all patients by accounting for the health needs of diverse communities.”

Dr Indra Joshi, Director of the NHS AI Lab at NHSX, added: “As we strive to ensure NHS patients are amongst the first in the world to benefit from leading AI, we also have a responsibility to ensure those technologies don’t exacerbate existing health inequalities. These projects will ensure the NHS can deploy safe and ethical Artificial Intelligence tools that meet the needs of minority communities and help our workforce deliver patient-centred and inclusive care to all.”

The STANDING Together team can be contacted at contact@datadiversity.org

Birmingham leads the way in delivery of a new advanced therapy in uveal melanoma

Written by Louise Stanley on . Posted in Cancer outcomes, Experimental medicine.

BHP founder-member University Hospitals Birmingham is the first site in the UK to treat a uveal melanoma patient with the new therapy Tebentafusp outside a clinical trial. Uveal melanoma is a rare cancer situated within the eye. This initiative is being led by Dr Leila Khoja, Immunotherapy lead for the Birmingham Experimental Cancer Medicine Centre (ECMC) and senior clinical lecturer at another of BHP’s founder members, the University of Birmingham.

Developed by Immunocore PLC, Tebentafusp is a bispecific immunotherapy drug, a type of advanced therapy. Immunotherapies harness the body’s immune system to fight cancer, helping it to attack it and to prevent tumours from growing. However, in some tumours the immune response is inadequate to control the tumour and, even in tumours that respond, resistance to treatment can develop. Tebentafusp’s mechanism of action enables it to attach to the tumour and simultaneously to T-cell immune cells. This means that it is able to pull in and activate tumour specific T-cells in hard to treat tumours.

Birmingham participated in the phase II study of Tebentafusp, and the results were published in Clinical Cancer Research. This led to a phase III trial, where it was shown to offer patients better outcomes in terms of survival, when compared with standard drugs offered by their clinical teams.  It is the first drug of this type for a solid tumour that has been proven to offer this benefit to patients. Regulatory approval for Tebentafusp is in process, but the drug is currently available through a compassionate use programme.

Transferring Tebentafusp into standard clinical care for patients with solid tumours is challenging, as specialist pharmacy, nursing and junior doctor skills are required. Hospitals also need to have sufficient capacity to deliver infusions of the drug on an inpatient basis, as the dose is increased over a three week period, before it can be provided on an outpatient basis. The development of this programme will create a model for similar therapies in the future, and Birmingham ECMC is currently facilitating the setup of clinical trials in this field.

These initiatives underline the importance of the Birmingham ECMC and Midlands Wales Advanced Therapy Treatment Centre (MW-ATTC) networks in supporting the delivery of the innovative therapies of the future, training staff and providing the infrastructure required.

close up of a female child's blue eyes

Genetic diagnosis leads the way in childhood eye cancer treatment

Written by Louise Stanley on . Posted in Cancer outcomes, Early diagnosis and detection.

Experts from BHP member Birmingham Women’s and Children’s NHS Foundation Trust have transformed the treatment of children’s eye cancer with pioneering new research.

Dr Trevor Cole and Dr Amy Gerrish are the first in the country to develop a treatment called Cell-free DNA for the care of retinoblastoma – a rare type of cancer which typically develops in early childhood and affects around 50 children in the UK every year.

The specialist service based in our Children’s Hospital is one of the top centres in the world for treating the condition.

Until recently, diagnosing the genetic cause of retinoblastoma was only possible if the affected eye was removed as part of a treatment. However, thanks to research carried out by our team, we can now diagnose the genetic cause without removing the eye.

This procedure involves using a tiny volume of fluid taken carefully from the inside of the eye (a tenth of a millilitre) to predict whether the child’s other eye will be affected or any of their siblings or future children. Now, genetic diagnosis is even possible during pregnancy.

Dr Cole said: “Those who carry the germline Rb1 mutation that causes retinoblastoma have a 50 per cent risk of passing it to their children. However, non-invasive prenatal diagnosis is now possible in most pregnancies shown to be at risk of inheriting the gene mutation.”

Kirstie McLaughan, from High Wycombe, mum to three-year-old Aria and Kaleb, aged nine, underwent prenatal testing at our hospital when she was pregnant with her daughter.

“My partner, Callum, was diagnosed with retinoblastoma as a child, so we knew there was a risk that our children would develop the condition. In June 2012, my son was diagnosed with retinoblastoma, and we were transferred to Birmingham Children’s Hospital to begin treatment.”

Kaleb was told he was out of risk at the age of three following treatment our specialist retinoblastoma centre. “We couldn’t have asked for better care,” added Kirstie. “They really are an amazing team at the Eye Department. They couldn’t have done any more; they were so welcoming and friendly and were always on the other end of the phone should I have any questions or worries.”

When Kirstie found out a few years later that she was pregnant with their daughter, Aria, she knew there was a 50 per cent chance she would also inherit the gene that causes the condition. However, doctors at Birmingham Women’s Hospital could carry out genetic testing during pregnancy, taking a simple blood test from Kirstie.

“I had non-invasive prenatal testing when I was pregnant with Aria. The test meant that if my daughter also had retinoblastoma, we could begin treatment right away,” explained Kirstie. “Luckily, the test came back all clear. It was such huge relief. It meant I didn’t have added worry or stress during my pregnancy.

“The team are amazing. The difference in testing available from when Kaleb was treated to when Aria was born really is extraordinary; their research is outstanding.”

Back in 2020, the team won the Ulverscroft David Owen Prize for this ground-breaking research.

Dr Cole and Dr Gerrish’s Cell-free DNA in retinoblastoma research is leading the way in transforming how we treat children’s eye cancer, providing significant savings for the NHS and less stress for patients and their families.

community group meeting - people gathered around a table on sofas

SPIRIT-PRO extension: guidelines for inclusion of patient-reported outcomes in protocols of clinical trials

Written by Louise Stanley on . Posted in Clinical trials, Health inequalities.

Patient Reported Outcomes (PROs) can provide valuable evidence on the impact of disease and treatment on patients’ symptoms, function and quality of life. High-quality PRO data from trials can inform clinical care, regulatory decisions and health policy. However, problems such as poor data collection, analysis, reporting and interpretation often reduce or negate their value. This paper attempts to raise standards by enhancing the international SPIRIT-PRO guidelines that were created to optimise the design of clinical trials and encourage the consistent, high-quality reporting of PROs and ultimately to inform patient-centred care. This case study originally appeared on the HDR UK website – visit to read further health data case studies.

Challenge

The PRO content of past trial protocols has often been incomplete or unclear leading to research waste. An appraisal of the PRO content of >350 past trial protocols showed that many lacked the specific information needed for high-quality PRO data collection and evidence generation. As a result this may lead to poor quality or non-reporting of PRO trial results, which may hinder the potential for PRO evidence to be used in regulatory decision-making, health policy and clinical care

The SPIRIT-PRO guidance and the subsequent SPIRIT-PRO Extension (a 16-item checklist intended to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection) were created to establish standards to improve the content and quality of trial protocols. However, further work is required to support uptake and implementation.

Solution

A team led by Melanie Calvert, NIHR Senior Investigator, Professor of Outcomes Methodology at the University of Birmingham and Director of Centre for Patient Reported Outcomes Research and Professor Madeleine King, University of Sydney, have developed tools to support the use of SPIRIT-PRO by researchers to generate high quality PRO data to inform patient care. This includes a protocol template, detailed descriptions and examples of good practice.

Impact and outcomes

While trial protocols are the foundation for study planning, conduct, reporting and appraisal, they vary greatly in content and quality. By providing specific recommendations about PRO endpoints it is possible to improve the situation – providing valuable information for clinicians and patients about the risks, benefits and tolerability of an intervention.

The work carried out by Prof. Calvert, Prof. King, Dr Olalekan Aiyegbusi with international collaborators (supported by UCB Pharma, Macmillan Cancer Support, the NIHR and HDR UK) has the potential to dramatically improve the quality and value of PRO data gathering and reporting in clinical trials. This in turn has far-reaching implications for care – allowing patients and their care teams to understand how an intervention will affect someone, whether it is appropriate or if an alternative should be considered.

Patient and Public Involvement and Engagement

Patient partners were involved in the design, conduct, reporting and dissemination plans of the research. This included the development of the SPIRIT-PRO Extension, the paper, protocol template, tools to support implementation by patient partners. Patient partners are included as co-authors.

Insights from the HDR UK Impact Committee

The HDR UK Impact Committee serves to raise the profile of both ours and our contributors’ outputs. The Impact Committee are keen to celebrate significant impacts which clearly demonstrate the value of of our mission to unite the UK’s health data to enable discoveries that improve people’s lives.

Contact

Prof. Calvert: m.calvert@bham.ac.uk

nurse discusses bowel disease with a patient. plastic model of bowel in foreground.

Scientists discover new pathway that prevents bowel cancer treatment from working

Written by Louise Stanley on . Posted in Cancer outcomes, Experimental medicine.

Leading scientists at BHP founder-member the University of Birmingham have discovered a previously unknown pathway that prevents specific drugs from working in patients with bowel cancer.

The research findings pave the way for increasing the number of bowel cancer patients who can be successfully treated, say the scientists.

Bowel cancer, also called colorectal cancer, affects the large bowel, which is made up of the colon and rectum. It is the fourth most common cancer in the UK, with over 42,000 people diagnosed with bowel cancer every year in the UK. It is also the second biggest cancer killer, with 16,000 people with bowel cancer dying in the UK every year.

The University of Birmingham-led research involved the study of 184 tumour samples and medical records of bowel cancer patients participating in the COIN trial, as well as research carried out in mice, cell cultures, and a laboratory model for pre-malignant colorectal cancer.

Co-senior author Andrew Beggs, Professor of Cancer Genetics & Surgery at the University of Birmingham, explained: “About 60% of bowel cancers are sensitive to drugs called anti-EGFR inhibitors which work by blocking a key pathway in these cancers.

“However, despite this, in cancers that should be sensitive to them, these drugs only work in patients about 50% of the time.”

Co-senior author Dr Fedor Berditchevski, also of the University of Birmingham, added: “Scientists have previously found that if bowel cancer patients have a mutation in a gene called RAS, the anti-EGFR inhibitors will not work.

“However, our research has now discovered a new pathway involving a tetraspanin protein called TSPAN6 that is frequently inactive in bowel cancer patients and this makes these drugs less effective. Crucially, our research also shows that if this pathway is active in a patient’s cancer then the drug will work, irrespective of whether they have a mutation in RAS or not.”

First author Dr Regina Andrijes, a Postdoctoral Fellow at the University of Birmingham, concludes: “This is the first time a tetraspanin protein has been shown to be directly involved with bowel cancer. Our research findings show that this new pathway could act as a biomarker for treatment with anti-EGFR drugs in bowel cancer, increasing a patient’s chance of survival and the number of patients who could benefit from these drugs who previously would not have.”

The researchers are now set to undertake a clinical trial of using this marker to better identify patients for anti-EGFR treatment.

The study, published in the Proceedings of the National Academy of Sciences (PNAS), was carried out in collaboration with fellow BHP member University Hospitals Birmingham NHS Foundation Trust, working with Semmelweis University in Hungary, and Assiut University in Egypt.