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Drug target potential for myelofibrosis

A new paper led by Dr Bethan Psaila, from the Weatherall Institute of Molecular Medicine (WIMM) of the Radcliffe Department of Medicine, has revealed a potential new immunotherapy drug target in the treatment of myelofibrosis.

Myelofibrosis is an uncommon type of bone marrow cancer characterised by gene mutations acquired in blood stem cells that lead to over-production of bone marrow cells called megakaryocytes, development of scarring or ‘fibrosis’ that stops the bone marrow being able to produce blood cells in adequate numbers, low blood counts and a large spleen.

At present, bone marrow transplant is the only potentially curative treatment for myelofibrosis, but this procedure carries high risks and only a small proportion of patients are suitable candidates for this. While drug therapies including JAK inhibitors can improve symptoms and quality of life, none are curative and these do not improve the bone marrow fibrosis. Therefore, there is a need to identify new targets for therapeutic development.

In a paper recently published in Molecular Cell, Beth Psaila and her team investigated a specific aspect of myelofibrosis, which is an increased frequency of bone marrow megakaryocyte (MK) cells. MKs are the bone marrow cell responsible for the production of platelets. While they are rare cells in healthy bone marrow, a pathogenomic feature of myelofibrosis is that they are observed in high numbers, and they are recognised as the key cellular drivers of fibrosis.

In order to better understand the cellular and molecular pathways leading to over-production of Mks and their dysfunction, the team used single-cell analyses, studying over 120,000 blood stem/progenitor cells individually.

This led to two key observations: firstly, that the proportion of blood stem cells that were genetically ‘primed’ to give rise to MKs was 11-fold higher in myelofibrosis patients than in healthy donors, and secondly that MK genes were being switched on even in the most primitive stem cells in myelofibrosis, suggesting massive expansion of a ‘direct’ route for MKs to develop from stem cells in myelofibrosis, a phenomenon that was almost undetectable in healthy bone marrow.

They found that the myelofibrosis stem/progenitor cells, but not the wild-type or normal stem cells, expressed a high level of G6B, a immunoglobulin cell-surface receptor protein. They validated G6B as an exciting potential immunotherapy target that might be utilised to specifically ablate both the cancer stem cell clone and the fibrosis-driving MK cells.

Dr Beth Psaila commented:

“The finding that G6B is markedly increased in the cancer stem cells is very important, as it suggests that targeting G6B in combination with a stem cell marker may be a way of selectively targeting the cancer-driving stem cells while sparing healthy stem cells.

“Identifying ways to knock out the disease-initiating cells is crucial to make progress in this disease, as currently there are no curative treatments available to offer the majority of our patients.”

Going forward, Beth and her team will be working on further validating their targeting strategy to see if it might be translated to the clinic.

About Beth

Beth is a CRUK Advanced Clinician Scientist at the MRC Weatherall Institute of Molecular Medicine. The primary focus of her group is on megakaryocyte and platelet biology in cancer, and the application of single-cell approaches to clarify the cellular pathways by which megakaryocytes arise from haematopoietic stem cells.

She trained at Clare College, Cambridge, Imperial College London/The Hammersmith Hospital, Cornell, New York, and the National Institutes of Health, Bethesda USA, Beth is also an Honorary Consultant in Haematology in Oxford and a Senior Fellow in Medicine of New College, Oxford.

This research was conducted in collaboration with Prof Adam Mead and Dr Supat Thongjuea in the WIMM, including using data that was generated by Dr Alba Rodriguez-Meira. The work was partially funded by a Cancer Research UK Advanced Clinician Scientist Fellowship, a CRUK Innovation Award; a Wellcome Career Development Fellowship and a Medical Research Council (MRC) Senior Clinical Fellowship.

Tackling oesophageal cancer early detection challenges through AI

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What is a clinical trial? – new video series

Discover what it means to take part in a cancer treatment clinical trial with this new video series

The Early Phase Clinical Trials Unit (EPCTU) is a specialist unit that supports the transition of cancer research findings into clinical applications for helping treat cancer.

The unit integrates oncology and haematology findings and applies them through clinical trials, with around 150 patients per year recruited into novel cancer therapies. By taking part in the clinical trials, the patients help to contribute to discovering new, more efficient or patient-focused treatments for their type of cancer in the future.

What should I expect?

When a patient is referred to EPCTU, they are often given a lot of information about what it means to be involved in the clinical trial process. This information can often be over-whelming, and in response to a patient satisfaction survey, the EPCTU created the following video series so that patients can better understand the process and how clinical trials effect their daily lives.

Video 1 – before the trial

The first video below touches on the aspects that influence a patient’s consideration in taking part in a clinical trial. Clinical trials deal with new, innovative treatments, and as such, are part of a clinical learning curve.

The video below touches on topics such as time frames and how you can expect to receive information. It’s important to give clinical trials proper consideration and understand what will happen at every stage, before reaching the later screening and eligibility process.

 

 

Video 2 – taking part

The second video is about what to expect after the screening process, once a patient has been recruited onto the trial.

Clinical trials can take a long time, both in the treatment process and the requirements later down the line after treatment. The second video in the series, seen below, outlines what to expect once you are on a trial and the benefits of seeing the trial to the very end.

 

Video 3 – trials at the EPCTU

The final video of the series, coming soon, will explain further about the EPCTU and the facilities in the centre.

It is designed for new patients to find the unit’s location and know where to find everything that they will need during the trial process.

Be sure to check back to our website homepage or this news article to see the final video in the series.

Metabolic profiles of breast cancer linked to response to metformin treatment

 

(B)(extract): Static PET-CT images in coronal plane pre- and post-metformin are from an individual with an

increase in KFDG-2cpt following metformin;note increased uptake in axillary lymph nodes (circled).

 

 

An international collaborative team of medical oncologists, radiologists, cell biologists and bioinformaticians led from Oxford by Simon Lord and Adrian Harris, have identified different metabolic response to metformin in breast tumours that link to change in a transcriptomic proliferation signature.

Published last week in Cell Metabolism, the team integrated tumour metabolomic and transcriptomic signatures with dynamic FDG PET imaging to profile the bioactivity of metformin in primary breast cancer.

Simon Lord stated: “This study shows how the integrated study of dynamic response to a short window of treatment can inform our understanding of drug bioactivity including mechanism of action and resistance. Further work will look to identify how mutations in mitochondria may define the metabolic response of tumours.”

The group demonstrated that metformin reduces the levels of several mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumours.

The paper “Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer” defines two distinct metabolic signatures after metformin treatment, linked to mitochondrial metabolism. These differential metabolic signatures apparent in tumour biopsy samples, did not link to changes in systemic metabolic blood markers including insulin and glucose, suggesting metformin has a predominant direct effect on tumour cells. Analysis of the dynamic FDG-PET-CT data showed that this novel imaging technique may have potential to identify early response to treatment that is not apparent using standard static clinical FDG-PET-CT.

 

 

Key point summary of the study:

  • There is great interest in repurposing metformin, a diabetes drug, as a cancer treatment
  • Two distinct metabolic responses to metformin seen in primary breast cancer
  • Increased 18-FDG flux, a surrogate marker of glucose uptake, observed in primary breast tumours following metformin treatment
  • Multiple pathways associated with mitochondrial metabolism activated at the transcriptomic level
  • Further evidence that metformin’s predominant effects in breast cancer are driven by direct interaction with tumour mitochondria rather than its effects on ‘host’ glucose/insulin metabolism

 

The study has been funded by Cancer Research UK, the Engineering and Physical Sciences Research Council, the Medical Research Council, and the Breast Cancer Research Foundation.

 

The published paper can be found at:

https://www.cell.com/cell-metabolism/home

 

Content adapted from the original paper by Simon Lord et al.

Oxford researchers discover DNA repair protein complex important in drug resistance in cancers driven by BRCA mutations.

A team of Cancer Centre researchers lead by Associate Professor Ross Chapman have discovered a novel DNA repair protein complex called ‘Shieldin’.

Published in Nature, the paper describes the identification of ‘Shieldin’, which was shown to be essential for generating genetic diversity in antibodies produced during immune responses.

When activated following an infection or immunisation, B cells activate the expression of enzymes that induce multiple breaks in the genes encoding the different antibody fragments. Highly specialised DNA repair proteins are essential for the generation of the deletions and mutations required to generate new antibody genes, which enables the production of antibodies with different or improved specificities towards an antigen. Researchers found Shieldin binds to specific DNA structures present at the ends of DNA breaks formed during these processes, and was essential for their repair.

Shieldin was found to link the adaptive immune system to a mutagenic DNA repair process associated with the progression of hereditary breast and ovarian cancers caused by BRCA1 mutations.

Commenting on the link between DNA, the immune system and cancer, Associate Professor Ross Chapman, lead author of the study and group leader at the Wellcome Centre for Human Genetics remarked “For some time, my lab has been puzzled over why a DNA repair pathway that normally only functions in the immune system, is also the primary pathway responsible for cancers driven by BRCA1 gene mutations. In finding Shieldin, we have taken a major step in answering this question. DNA breaks generated during antibody class-switch recombination are known to have single stranded DNA tails at their ends. The fact that Shieldin binds these structures and promotes their repair, also suggests that the recognition and repair of similar DNA structures by Shieldin when the BRCA1 protein is no longer functional, may be what leads to the mutations that cause cancer.”

The group’s findings also provide new insights into how cancer cells can become resistant to anti-cancer drugs: “PARP inhibitors are proving to be an extremely powerful drugs to treat cancers driven by BRCA mutations, however a lot of these cancers are known to then go on to develop resistance. Our work shows mutations that effect any of the four Shieldin proteins will render these cancers completely resistant to PARP inhibitors. By working out exactly how Shieldin works, we hope to identify secondary vulnerabilities in these resistant cancers, which can be exploited in anti-cancer therapies to counteract the threat of this resistance.”

Sarah Blagden Associate Professor of Experimental Cancer Medicine & Consultant Medical Oncologist, and Director of Early Phase Cancer Trials Unit & Oxford ECMC lead, emphasises the importance of the new findings: “In this paper, Ross Chapman and his team have unpicked the main method of DNA damage repair in patients with BRCA1 mutations called non-homologous end joining (NHEJ). By comparing NHEJ in different cellular processes they have shown that, in cells lacking BRCA1, NHEJ is reliant on the four-protein complex Shieldin. Not only do they indicate Shieldin is responsible for the cancers that develop in patients with BRCA1 mutations, but also that Shieldin drives resistance to PARP inhibitors. Chapman’s findings are important in our understanding of why it is that patients with BRCA1 mutations that are taking PARP inhibitors like olaparib, rucaparib or niraparib eventually become resistant to them. By providing these new insights into BRCA1 biology, they open future avenues for tackling PARP resistance and improving outcomes for BRCA1-cancer patients in the future.”

This project was funded by Medical Research Council (MRC) Grant (MR/ M009971/1) and Cancer Research UK Career Development Fellowship (C52690/A19270) awarded to J.R.C.

https://www.nature.com/articles/s41586-018-0362-1

 

 

Oxford University scientist developing new treatments to tackle breast cancer that has spread to the brain

Oxford University scientist developing new treatments to tackle breast cancer that has spread to the brain
Professor Nicola Sibson of the Department of Oncology has been awarded a grant worth almost £200,000 by research charity Breast Cancer Now to fund cutting-edge research to uncover novel treatment combinations to control breast cancer that has spread to the brain.
The news comes on Secondary Breast Cancer Awareness Day (Friday 13th October 2017), as leading charity Breast Cancer Now announces more than £700,000 of funding across the UK for research specifically targeting secondary (or metastatic) breast cancer – where the disease has spread to another part of the body.
When breast cancer spreads, known as secondary or metastatic breast cancer, it becomes incurable. While metastatic breast cancer can sometimes be controlled using different combinations of treatments, it cannot be cured, and almost all of the 11,500 women that die as a result of breast cancer each year in the UK will have seen their cancer spread. Nearly 600 women in Oxfordshire are diagnosed with breast cancer every year, and over 100 women in the region die from the disease each year.1
The brain is protected by its own security system, a structure called the blood-brain barrier (BBB). The BBB acts as a filter, preventing harmful substances from reaching the brain. However the virtually impenetrable nature of the BBB makes delivery of drugs to the brain extremely difficult, meaning there are few effective treatments for breast tumours that have spread to the brain (brain metastases).
Up to a third of patients with secondary breast cancer have seen their cancer spread to the brain. This can cause varying problems with brain function depending on which areas the breast cancer cells have spread to, and can often severely affect a patient’s quality of life, with debilitating symptoms such as changes in mood or behaviour, seizures, headaches, vomiting and uncoordinated movement.
Professor Sibson, Professor of Imaging Neuroscience at the CRUK/MRC Oxford Institute for Radiation Oncology has previously found that one element of the immune system, the inflammatory response, is important in the spread of breast cancer to the brain. Her team has previously found that certain inflammatory molecules are present at higher levels in brain metastases, and may be key drivers of tumour growth.
With funding from Breast Cancer Now, Professor Sibson and her team will undertake a three-year project to pinpoint which combinations of anti-inflammatory drugs, which are able to cross the BBB, reduce the growth of breast tumours in the brain most effectively, and whether these could also be given alongside radiotherapy with greater effect.
Professor Sibson said “We urgently need to find ways to treat brain metastases more effectively and improve survival rates. With this funding from Breast Cancer Now our aim is to increase treatment options for patients suffering metastatic spread to the brain. We hope that by targeting the innate immune system we can halt or reduce tumour growth, and enhance the effectiveness of radiotherapy.”
The scientists will first implant breast tumours into the brains of mice, before testing a range of anti-inflammatory drugs and examining the effect on tumour growth. The team will then combine the most effective anti-inflammatories with radiotherapy in mice to identify which combinations best control tumour growth in the brain. The researchers hope to identify new ways to predict which patients are most likely to benefit from anti-inflammatory drugs and radiotherapy. In addition, the team will explore how another component of the inflammatory response, adhesion molecules, are involved in tumour growth, and whether targeting these directly could also be an effective treatment strategy.
Dr Richard Berks, Senior Research Communications Officer at Breast Cancer Now said “Professor Sibson’s research could pave the way for new treatment combinations that could halt tumour growth in men and women whose breast cancers have sadly spread to the brain. Anti-inflammatory drugs are already used to treat arthritis – and if these new combinations are found to be effective, these drugs could be made available for treating patients with brain metastases much more quickly.
“It is essential that we find new ways to treat secondary breast cancer in the brain – to improve quality of life and chances of survival for those living with this debilitating disease.
“Our ambition is that by 2050, everyone who develops breast cancer will live. But if we are to achieve this, we desperately need to raise funds for research to find ways to stop the disease spreading. Professor Sibson’s project could help bring us one step closer to our 2050 vision and we’d like to thank our supporters across Oxford who continue to help make our world-class research possible.” 
Fiona Leslie, 49 from Aylesbury, is living with incurable metastatic breast cancer. Having first been diagnosed with breast cancer in 2013, Fiona underwent a mastectomy, radiotherapy and chemotherapy, before learning that her breast cancer had unfortunately spread to her lungs and her spine.
In April 2015, Fiona began receiving revolutionary drug Kadcyla, which kept her disease at bay for over two years, and enabled her to live a relatively normal life in the meantime. However in June 2017, scans showed that Fiona’s breast cancer had spread to her brain.
1. Local incidence and mortality survival statistics were provided on request by Public Health England, April 2017.

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