Higher testosterone levels in men linked to greater melanoma risk

1 in 36 UK males and one in 47 UK females will be diagnosed with melanoma skin cancer in their lifetime. However, 86% of melanoma cases were preventable, as many cases are caused by UV ray exposure, but other factors can also play a role in who is most at risk, such as age and genetics.

A recent study lead by Dr Eleanor Watts at the Nuffield Department of Population Health has now found that testosterone is one of these risk factors. Published in the International Journal of Cancer, the team found that men with high levels of testosterone have an increased risk of developing a potentially deadly type of skin cancer. This was a result of studying blood samples hormone data. collected by the UK Biobank from 182,600 men and 122,100 postmenopausal women aged 40 to 69.

The researchers looked both the total level of testosterone in the blood samples, as well as levels that were freely circulating. They then used national registries and NHS records to explore whether participants went on to develop or die from cancer.

The results show that by 2015-16, after being followed for an average of seven years, 9,519 men and 5,632 postmenopausal women – 5.2% and 4.6% of participants respectively – had been diagnosed with a malignant cancer. By excluding other, non-melanoma diagnoses and accounting for other factors, they found that for men, higher levels of testosterone, whether freely or in total, were associated with a greater risk of developing malignant melanoma.

Specifically, each 50 pmol/L increase in free testosterone was found to raise the chance of developing this cancer by 35%. 90% of men included in the study had free testosterone concentrations of between 130 pmol/L and 310 pmol/L.

Among other findings, higher levels of freely circulating testosterone were associated with a greater risk of prostate cancer in men, while in post-menopausal women, higher levels of testosterone, whether freely circulating or in total, were associated with a greater chance of endometrial and breast cancer.

Dr Eleanor Watts, the first author of the research from the University of Oxford, says:

“There has been indirect evidence for testosterone and melanoma before, but this is the first time we have been able to look directly at the hormones in the blood

“Although we have seen associations of prostate, breast and endometrial cancer with testosterone before, this is the first time we have seen an association with risk of melanoma in men.”

 

About Eleanor

Eleanor is an Early Career Research Fellow in the Cancer Epidemiology Unit (CEU), part of the Nuffield Department of Population Health. Her research examines the role of endogenous hormones on prostate cancer risk using UK Biobank.

New funding for early diagnosis research using platelets

It is known that the earlier a cancer is detected, the more likely a cancer patient is to have better outcomes. One of the challenges for achieving early detection is to develop a minimally invasive test to detect the signs of early cancer in the body.

Because blood tests are simple to carry out in the clinic, a lot of effort has been focused on detecting molecules released from cancer cells in blood samples – so-called ‘liquid biopsies’. However, the majority of techniques that are used currently have a low sensitivity for early-stage cancers, due to low levels of cancer cell-derived molecules being present in blood plasma.

Dr Bethan Psaila, Cancer Research UK (CRUK) Advanced Clinician Scientist, Group Leader at the Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM) and principal investigator at the Radcliffe Department of Medicine at Oxford University, is pioneering an approach that might be able to enrich for cancer-derived molecules in the blood. Working with Professor Chris Gregory (University of Edinburgh), Professor Paul Rees (University of Swansea) and Dr Henkjan Gersen (University of Bristol), Beth is leading a multi-disciplinary team that brings together cancer cell biologists, and imaging and engineering expertise to explore the use of platelets for early cancer diagnosis.

Platelets perfuse tumours and take up cancer cell-derived biomolecules. Isolating platelets from the blood and analysing their contents will hopefully be a more sensitive method for detecting cancer-specific molecules in the blood.

In this newly funded project, the team will use state-of-the-art pre-clinical models as well as samples from patients with colorectal cancer, pancreatic cancer and oesophageal cancer as exemplar cancers to assess the utility of ‘tumour-educated’ platelets (TEPs) for early cancer diagnosis. They will use detailed imaging and biomechanical techniques to assess whether TEPs can be reliably distinguished from platelets in healthy people or those with non-malignant disorders.

This multi-institutional project is funded by a Cancer Research UK Early Detection and Diagnosis Project Award and builds on a successful CRUK Innovation Award the team received after a workshop on liquid biopsy technologies in 2018. The ~£650,000 award will run for four years and will support two DPhil studentships, a postdoctoral research scientist and a research assistant.

Novel imaging device enters first round of development funding programme

Proton-beam-therapy (PBT) is becoming increasingly important for treating cancer, with projected increases of up to 50% more patients per year being treated with the technology in the UK and worldwide by 2025.

Although the precision of PBT has many advantages over traditional radiotherapy, there some uncertainty over the range of delivery the beam provides. There is risk of potential overdose to normal tissues or underdose to tumour, resulting in reduced tumour-control and long-term side-effects due to treatment of healthy tissue. This can be detrimental to patients and a burden on healthcare systems if side-effects become apparent later in a patient’s life.

Therefore, a method to verify the range of treatment beams when using PBT on patients is crucial to increase the treatment accuracy. Dr Anna Vella, Postdoctoral with the Radiation Therapy Medical Physics Group, led by Prof. Frank Van Den Heuvel, at the University of Oxford’s Department of Oncology, is investigating the efficacy of a device with this purpose.

Anna is leading CAPULET (Coded Aperture Prompt-gamma Ultra-Light imaging detector), an imaging device for quality assurance assessment of radiotherapy plan efficacy, designed for daily use in clinical practice. CAPULET could be installed onto a variety of PBT devices, and used to verify and fine-tune the dose between fractions in particle-beam radiotherapy. It does this through collecting 3D images of the particle beam penetrating soft-tissue, with the ultimate goal to fine-tune planning doses and improving the efficacy of the overall radiotherapy treatment.

This novel and unique technology is faster & more compact than current devices, increases the field-of-view, and improves the signal-to-noise ratio. The impact on patients will be to improve cancer-control, fewer complications, and improved quality-of-life following treatment.

CAPULET has recently been selected as one of 35 projects in the Pre-Development Phase of the Alderley Park Oncology Development Programme – a national programme designed to develop and progress start-up oncology projects. Funded by Innovate UK and Cancer Research UK. It will now be work-shopped, and potentially be chosen to join the full development programme with grant funding.

Proof-of-concept experiments will be performed in collaboration with the CRUK-funded ART-NET. The long-term plan of CAPULET is to develop a large-area detector to fully image the beam delivery range within lungs, liver, H&N and other large sites in the human body to overcome limited field-of-view found in other existing devices on the market.

Oxford spin out influencing patient care world wide

Optellum, a lung health company aiming to redefine early diagnosis and treatment of lung disease, today announced it received FDA clearance for its “Virtual Nodule Clinic”.

Optellum was co-founded by Oxford cancer researcher Prof. Sir Michael Brady with the mission of seeing every lung disease patient diagnosed and treated at the earliest possible stage, and cured.

Optellum’s initial product is the Virtual Nodule Clinic, the first AI-powered Clinical Decision Support software for lung cancer management. Their platform helps clinicians identify and track at-risk patients and speed up decisions for those with cancer while reducing unnecessary procedures.

Lung cancer kills more people than any other cancer. The current five-year survival rate is an abysmal 20%, primarily due to the majority of patients being diagnosed after symptoms have appeared and the disease has progressed to an advanced stage. This much-needed platform is the first such application of AI decision support for early lung cancer diagnosis cleared by the FDA.

Physician use of Virtual Nodule Clinic is shown to improve diagnostic accuracy and clinical decision-making. A clinical study, which underpinned the FDA clearance for the Virtual Nodule Clinic, engaged pulmonologists and radiologists to assess the accuracy for diagnosing lung nodules when using the Optellum software.

Dr Václav Potěšil, co-founder and CEO of Optellum says:

“This clearance will ensure clinicians have the clinical decision support they need to diagnose and treat lung cancer at the earliest possible stage, harnessing the power of physicians and AI working together – to the benefit of patients.

Our goal at Optellum is to redefine early diagnosis and treatment of lung cancer, and this FDA clearance is the first step on that journey. We look forward to empowering clinicians in every hospital, from our current customers at academic medical centers to local community hospitals, to offer patients with lung cancer and other deadly lung diseases the most optimal diagnosis and treatment.”

Funding to improve childhood, teenage and young adult cancer detection

Cancer is the commonest cause of death among children and young people in the UK and is associated with significant long-term morbidity. Unfortunately, the UK lags behind other high-income countries in the time it takes to diagnose childhood, teenage and young adult (TYA) cancer and this delay worsens patient outcomes.

One of the challenges in diagnosing childhood and TYA cancer is its relative rarity and non-specific presentation, and awareness campaigns have been run in an effort to improve recognition of cancer signs among health professionals. Although this resulted in improvements for certain types of cancers in children and TYA, the national time-to-diagnosis targets have still not been reached in all cancers for all age groups.

Dr Defne Saatci and Professor Julia Hippisley-Cox (Nuffield Department of Primary Care Health Sciences) have successfully applied for a Cancer Research UK Early Detection and Diagnosis Project Award to accelerate diagnosis of childhood and TYA cancer. They will use the QResearch database, the UK’s largest GP electronic health record database, covering 20% of the UK population and linked to national cancer, hospital and mortality registries. QResearch data will be explored to identify the early symptoms and signs associated with a subsequent diagnosis of the commonest childhood and TYA cancers (acute lymphoblastic leukaemia, lymphomas and central nervous system tumours) and this information will be used to develop a risk prediction tool for GP use.

By increasing the understanding about the clinical features associated with childhood and TYA cancers and developing this risk prediction tool for use in primary care, this study aims to make significant advancements in childhood and TYA cancer diagnosis and outcomes.

If you are an Oxford-based researcher thinking of applying for external early detection funding, please get in touch with the OxCODE Scientific Coordinator who can help to coordinate your application.

 

New partnership enables access to state-of-the-art radiotherapy machine

The first NHS patient has received treatment on the cutting-edge ViewRay MRIdian technology, thanks to a new partnership between the University of Oxford, Oxford University Hospitals (OUH) NHS Foundation Trust and GenesisCare.

The partners, with the support of the John Black Charitable Foundation, have collaborated to establish a ten-year programme of clinical treatment for NHS patients, with further research into improving cancer treatment using the Viewray MRIdian.

Due to the natural, unavoidable movement of soft tissue inside the body, normal tissue around the cancer can be exposed to radiotherapy treatment, particularly when targeting soft-tissue tumours deep within the body. It can be challenging to visualise these organs during radiotherapy with routine radiotherapy delivery.

The ViewRay MRIdian machine is the only one of its kind in the UK, with only 41 machines worldwide. It allows doctors to see the normal soft tissue and the tumour in real time by combining MRI scanning with targeted radiotherapy. Incorporating MRI scans will allow doctors to then tailor doses in real time to the specific internal anatomy of the patient on the day of treatment.

MRIdian technology also minimises the damage to surrounding healthy tissues by switching off when tumour tissue moves outside of the targeted beam. This could mean less side effects for patients and increased dosage of treatment delivered directly to the tumour.

GenesisCare, the University of Oxford and OUH will also partner in research collaborations to develop real-world evidence which will inform future utilisation of the MRIdian technology in hard-to-reach tumours, such as pancreatic cancers. The research partnership will assess the benefits of the MRIdian technology in terms of improved cancer outcomes and reduced toxicity.

Elizabeth Rapple, from South Oxfordshire, is the first patient to use the machine to treat her renal cancer, as part of the new partnership. She says:

“I feel very fortunate to be able to access this machine as part of a new Oxford-wide partnership. Any operation to remove my tumour would have been highly invasive, so it’s lucky that my cancer was suitable for MRIdian radiotherapy. I am so grateful that this unique machine has been made accessible through the NHS, and that I can be the first of many to benefit from this partnership going forward.”

Project leader Professor Tim Maughan, from the University of Oxford, said:

“Treating patients on the MRIdian is like a surgeon putting on their spectacles for an operation – for the first time we can see exactly what the cancer is doing during treatment and adapt to change accordingly.  This accuracy allows us to reduce side effects and we hope to improve cancer outcomes in hard-to-treat cancers.”

Dr James Good, Clinical Oncologist at GenesisCare, said:

“The MRIdian machine is at the cutting-edge of what is possible in radiotherapy technology. The ability to visualise the tumour more accurately, to follow it while it’s being treated and to adapt the plan every day means we can deliver the best possible outcomes.

“This collaboration with the University of Oxford and Oxford University Hospitals will be truly beneficial for cancer patients in the UK. Not only will it provide patients who otherwise would have limited, or sadly, no options with a really viable treatment option, but we can also help demonstrate the effectiveness of this treatment, with the ambition to make it available for all NHS patients in the future.”

Carol Scott, Lead Therapeutic Radiographer & Deputy Clinical Director at Oxford University Hospitals , said:

“OUH are excited to be part of this collaboration offering NHS patients the opportunity to take part in these clinical trials. The use of daily advanced imaging that clearly shows us the tumour and normal soft tissue around it will enable us to take the next step in making our treatments even more personalised and effective”

DeLIVER clinical research study underway as recruitment opens

DeLIVER is a five-year Cancer Research UK-funded research programme led by Professor Ellie Barnes (Nuffield Department of Medicine) that aims to detect liver cancer earlier. Liver cancer is the fastest rising cause of cancer death in the UK, with more than 5,000 deaths per year. To improve survival, it is crucial to diagnose liver cancer earlier, when current treatments are more likely to be successful. However, this is challenging because symptoms are vague and late-presenting, and are frequently masked by co-occurring liver disease, such as cirrhosis.

A major goal of the DeLIVER programme is to learn more about the biology of liver cancer development and to use this information to design more sensitive detection tests. Because many people being tested for liver cancer have the high-risk condition cirrhosis, these tests need to be specific enough to detect liver cancer on top of other changes in the liver caused by cirrhosis. In order to identify the defining characteristics of early liver cancer, researchers need to perform a detailed molecular analysis of tissue from tumours and the background liver in people with liver cancer and cirrhosis and compare this to liver tissue from people with cirrhosis alone.

The DELPHI (Deep Liver Phenotyping and Immunology) study will recruit 100 participants at Oxford University Hospitals NHS Trust. 80 of these recruited participants will have cirrhosis (caused by hepatitis virus B or C, fatty liver disease or alcohol) and 20-30 participants will have liver cancer in addition to cirrhosis. After giving consent, the participants will undergo fine-needle aspiration to collect tissue from the liver. This is a safe technique established in Oxford as one of only a few centres in the UK. Blood samples will also be taken.

Cancer Research UK Clinical Research Fellow Dr Rory Peters is leading the study. He said,

“We are very pleased to have started the recruitment for the DELPHI study. The in-depth analysis of samples from the DELPHI participants will be critical for increasing our understanding of how liver cancer develops and will give insights into how this cancer can be detected earlier.”

The researchers will look at individual cells to understand the cellular make-up of the tumour and surrounding tissue, including infiltrating immune cells, and how this may influence cancer development. By comparing the tissue from participants with and without cancer, they will also look for changes in protein or metabolite levels and alterations in the levels of chemical modification of DNA by methylation using the TAPS assay developed in Oxford by Dr Chunxiao Song. They will investigate whether the changes that they observe from the tissue analysis can also be detected in the blood, which would provide evidence that a blood-based assay could be developed as a less invasive diagnostic test.

Professor Ellie Barnes, Chief Investigator for DeLIVER said,

“The DELPHI study is one of three clinical projects within the DeLIVER programme. Together, these studies will inform us which of our diagnostic technologies perform best at detecting liver cancer at the earliest stages. We hope this work will lead to a step-change in earlier liver cancer diagnosis and improved patient survival.”

 

Read more about the DeLIVER programme in the OxCODE liver cancer early detection research showcase.

Prof Andi Roy receives new award for immune-cell research

Co-funded by Cancer Research UK and Children with Cancer UK, Andi is one of 5 to receive £1 million each to investigate children’s and young people’s cancers.

Registration open for Cancer Early Detection and Epigenetics Symposium

Join us and our co-hosts for this free virtual event on 28-29th April 2021 to hear the latest developments from international leaders in these fields

Improving immunotherapy through epigenetics

Immunotherapy has shown remarkable efficacy against a range of cancers. One approach, termed immune checkpoint blockade therapy, blocks an inhibitory immune receptor called PD-1 to take the brakes off the immune system and allow it to kill cancer cells. However, despite this success, anti-PD-1 therapy is ineffective in the majority of cancer patients.

Research is underway to discover strategies that can overcome tumour resistance to immunotherapy. A promising avenue for further investigation is the manipulation of epigenetic regulators. Epigenetic regulators influence the expression of genes without changing the underlying DNA sequence. They can dampen the response of the immune system and their inhibition has been shown to enhance the response to anti-PD-1 treatment. However, because epigenetic regulators are involved in several aspects of the anti-tumour immune response, inhibiting them can result in potentially opposing effects, with the result of little or no overall benefit.

In this paper published in the journal Cancer Discovery, Professor Yang Shi and his laboratory explore the opposing effects of inhibiting one such epigenetic regulator, LSD1. Using mouse and tumour cell models, they show that when LSD1 is repressed, there is a greater immune cell infiltration into the tumour but this is counteracted by the increased production of a cell regulatory protein called TGF-β that suppresses the ability of these infiltrating immune cells to kill cancer cells.

To tackle these conflicting effects, the team experimentally depleted both LSD1 and TGF-β during anti-PD-1 therapy and demonstrated a significant increase in immune cell infiltration, cytotoxicity and cancer cell killing. This combination treatment led to eradication of these previously resistant tumours and long-lasting protection from tumour re-challenge, making it a promising future strategy for increasing the efficacy of this important class of cancer treatment.