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3rd October 2019
A classic boxing move, the ‘one-two punch’, could also be effective against cancer: a left jab knocks cancer cells senseless, quickly followed by a right hook that knocks them out altogether.
Researchers at the Netherlands Cancer Institute have shown that cancer cells are vulnerable to this kind of approach.
Many combinations of cancer medicines could theoretically work very well together, but in practice these combinations are too toxic for the body to withstand. The researcher René Bernards has devised a possible alternative: the ‘one-two punch’, named after the effective combination of two quick successive punches in boxing. “The first medicine creates a weakness in the cancer cell and the second deals a merciless blow to the weakened cell. So while the two medicines are not given simultaneously, you still get the benefit of their synergetic effect.”
Sleeping cells
At the Netherlands Cancer Institute, Bernards and his colleagues investigated whether this worked. As the cancer cell’s weak spot they chose a well-known cell reaction to stress: senescence. Under stressful circumstances ordinary body cells can put themselves into a kind of sleep mode. They do so, for instance, if their DNA is damaged. This is useful, because they then stop proliferating and the body’s own immune system can clear them up.
In the laboratory Bernards and his colleagues found a way to bring this about in liver cancer cells. This was doubly useful: the cells stopped proliferating, and they had a vulnerability that could be exploited, since the researchers also discovered a way to knock out the ‘sleeping’ cells. Working with liver cancer cells, the researchers finally identified a combination of medicines that had good results in mice. On 2 October the results of their experiments were published in Nature.
Exploiting a weakness
“The great thing about this approach is that it could work for a wide range of tumour types,” says Bernards. “In principle, senescence can be induced in all kinds of tumours.” Provided you know how, and how you then deal the sleeping cells a death blow. Bernards recently founded a company, Oncosence, which is entirely devoted to identifying substances that induce senescence in cancer cells and other substances that kill these specific cells. The second ‘punch’ is essential. “It seems that senescent cancer cells can actually encourage tumour growth and metastasis if the immune system, or a therapy, does not remove them.”
The idea of the ‘one-two punch’ arose out of earlier research in which researchers at the Netherlands Cancer Institute exploited a weak point in resistant skin cancer cells in order to destroy them. “The principle of exploiting a weakness was one we wanted to apply more widely, and we identified senescence as a universal response that could be used in this way.” Having been awarded a substantial grant by the European Research Council, the research group is now searching for different ways to induce senescence in cancer cells.
What did the researchers investigate?
With a large-scale genetic screen the researchers identified a protein whose inhibition induces senescence in liver cancer cells: CDC7 kinase. By subjecting senescent cancer cells to a great many chemical substances, they discovered that the common antidepressant sertraline could kill the senescent cells. Once they had identified how the drug had this effect (through the cell’s mTOR signal route), they could start searching for drugs that performed this even more effectively. In laboratory mice they then combined a CDC7-inhibitor with an mTOR-inhibitor, both of which are already used in research and which have been individually tested on cancer patients. The result: twice as many mice survived in comparison with those receiving current standard treatment.
This research was partly funded by the Dutch Cancer Society through Oncode Institute and by the European Research Council.
The University of Birmingham’s Centre for Liver and Gastrointestinal Research and Novo Nordisk have joined forces in a collaboration supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre.
The NIHR Birmingham BRC brings together the expertise of University Hospitals Birmingham NHS Foundation Trust (UHB) and the University of Birmingham, both members of Birmingham Health Partners (BHP).
Professor Philip Newsome, Director of the University of Birmingham’s Centre for Liver and Gastrointestinal Research and who leads the partnership, said: “It is estimated that up to a quarter of the adult population worldwide has a condition called non-alcoholic fatty liver disease, which occurs due to the build-up of fat in the liver and it is commonly seen in patients who are overweight or diabetic.
“What is concerning is that the incidence of fatty liver disease is rapidly increasing world-wide as we are becoming a more sedentary society consuming diets which are high in fat and sugar.
“Non-alcoholic fatty liver disease now therefore presents an enormous challenge for healthcare providers which is made worse due to the lack of approved and effective treatments.
“This exciting new partnership will see us working together with Novo Nordisk to harness our cutting edge translational research facilities and in vitro models to identify new disease mechanisms and potential targets for treatment.”
Professor David Adams, Pro Vice-Chancellor at the University of Birmingham and Director of the Birmingham NIHR BRC and Birmingham Health Partners, said: “New therapeutic candidates are needed in order to manage the complex mix of liver injury, vascular disease and cancer risk in patients with non-alcoholic fatty liver disease.
“This new collaboration is yet another example of how, through a strategic alliance, Birmingham Health Partners is harnessing research strengths between the University and NHS to deliver better treatments and care to patients. Together, we are delivering research that matters.”
The team at the University of Birmingham who will be involved in the collaboration are Professor Philip Newsome, Dr Patricia Lalor, Dr Chris Weston, Dr Matthew Armstrong, Dr Celine Hernandez, Dr Thin Luu, Dr Stuart Hunter and Dr Paul Horn.
Karin Conde-Knape, Corporate Vice President of Cardiovascular and Liver disease research at Novo Nordisk, added: “We are very excited to work with such a talented group of scientists in order to understand better key drivers of non-alcoholic fatty liver disease and find pathways and targets to deliver treatments for the patients suffering from this disease.
“This is another example of how Novo Nordisk is striving to collaborate with translational academic institutions to increase further our disease understanding.”
1st October 2019
An innovative AI-based nursing service has been introduced across Vale of York to identify patients at risk of unplanned care attendances and admissions, helping to improve quality of life and reduce emergency admissions.
The pioneering project, commissioned by NHS Vale of York CCG, tackles the NHS’ ever-increasing demand for urgent and emergency care services, as highlighted in figures released by NHS Digital recently which showed that emergency admissions have peaked nationally, increasing 28% over the last ten years.
Health Navigator is the first service of its kind in the UK to use cutting-edge, real-time AI and predictive data analytics to identify patients, often those with long-term conditions and who are potentially regular users of health services, who may benefit from health coaching.
Those patients from York Teaching Hospitals NHS Trust, a key partner in this initiative, are offered a referral to Health Navigator’s ‘Proactive Health Coaching’ service.
Delivered by registered nurses and healthcare professionals, the service is designed to support patients with complex conditions and empower them to take control of their health.
Evidence from a local randomised control trial (RCT) showed a 36% reduction in A&E attendances for those patients supported by health coaching compared to patients that had not received the intervention.
The trial also demonstrated a 30% reduction in unplanned hospital admissions and some 25% lower planned admissions for the same Vale of York CCG patients. Patient activation, a key metric for a patient’s ability to take control of their own health and healthcare, improved by more than 30%.
A wider RCT – the UK’s largest for AI-powered unplanned admission prevention – includes a total of seven NHS acute sites working with Health Navigator. Interim results from other sites are similar, in cases demonstrating up to 59% reduction in unplanned admissions for patients receiving the intervention. Results are currently being evaluated and shall be published with the NHS and the Nuffield Trust.
Chris Sherlaw‑Johnson, senior research analyst, at the Nuffield Trust, said: “RCTs are the golden standard for evidence generation in healthcare, the approach adopted for drug safety and efficiency evaluation, yet RCT-level evidence for innovative digital health interventions remains globally scarce.”
On the strength of the local results, NHS Vale of York CCG has already expanded the contract to 1800 patients.
Fiona Bell, Lead Officer for Primary Care, NHS Vale of York CCG, said: “High emergency admissions are a system problem, not just the responsibility of secondary care. A lot of people go to A&E if they are feeling anxious about their health or they need reassurance. We needed to find a way to support these patients to help them understand their conditions better, make life changes which will improve their health and know which services to access when they need support.
“From the local RCT, we found that 55% of patients felt much more engaged with their care, whilst 84% of people reported an improved quality of life and having more confidence in managing their conditions. These results are really impressive and have a huge impact on patients’ everyday lives.
David Friend, who was diagnosed with Parkinson’s disease and then suffered from cellulitis and tendonitis, said: “Last year I wasn’t too well. I was referred to the Health Navigator service and I had one person coordinating the various things that I was suffering from and defining a course of action. I have since been in better health and better spirits. It is a good service and it would be well worth it for many people in society.”
With 25-35% of urgent and emergency care being deemed avoidable and costing the NHS £6bn annually, the project, through the RCT, has demonstrated that improvements in the patient experience can lead to reduced demand for healthcare services.
Bell added: “If we can replicate the results from the RCT trial on a larger scale then we are confident that we will have a significant and positive impact on reducing growth in A&E attendances and non-elective admissions. Most importantly, we will help to support patients who receive this service to understand and manage their long-term conditions better which we’ve already seen can have a very positive impact on their quality of life.”
There are already plans for Vale of York to become the first CCG to extend this type of service into primary care to alleviate the increasing demand for GP appointments, which Bell describes as a “really exciting next step for us”.
Joachim Werr, Health Navigator CEO, said: “We know that 1% of the UK population accounts for 50% of non-elective bed days, so there is huge potential for new models of care such as this, based on scientific and real-world evidence of patient benefit, to reduce avoidable admissions and improve system performance.
“Vale of York has invested in a service that, most importantly, supports patients to lead healthier lives, but also has the potential for major service transformation and improvement” concluded Werr.
Whole genome sequencing (WGS) of tumour cells could help predict the prognosis of a patient’s cancer and offer clues to identify the most effective treatment, suggests an international study published in Nature Medicine.
To understand whether WGS might be useful in a clinical setting, Cambridge researchers teamed up with colleagues in Sweden running a population-wide project called SCAN-B, which has been recruiting all women diagnosed with breast cancer in the South of Sweden since 2010. This was critical as SCAN-B has a large amount of clinical outcome data.
This international collaboration of researchers used WGS to analyse tumours from patients who had been diagnosed as having triple negative breast cancers. These cancers are so-called because they lack three key molecules known as receptors. They account for around 9% of breast cancers and are associated with poorer outcomes. They are also more common amongst women with African and Asian ancestry.
“Whole genome sequencing gives us a complete view of the cancer genome. It reveals many things that we couldn’t see previously, because we simply did not look for them,” explains Dr Serena Nik-Zainal from the Medical Research Council Cancer Unit at the University of Cambridge, who led the study.
“Having a complete cancer genome map for each patient helps us to understand what has caused each patient’s tumour and treat each individual more effectively. Previously, it was like going on a voyage with only a limited map, but now, with whole genome sequencing we have a much better, more detailed map and know the best route to reach our destination.”
The researchers then applied a machine learning algorithm called HRDetect, which they had previously developed to identify tumours with signatures caused by mutations in the BRCA1 or BRCA2 genes. Having a variant of either of these two genes greatly increases an individual’s risk of developing breast cancer and a relatively new class of anti-cancer drug called PARP-inhibitors have been developed specifically for these tumours. HRDetect scores had previously suggested that a greater proportion of women in the general population could have tumours that are very similar to BRCA1/BRCA2-mutant cancers.
Taking the scores, the team categorised each patient as either high, intermediate or low scoring.
Patients who scored highly were those that had the best outcomes using current treatments for triple negative breast cancers – they are also most likely to respond to PARP inhibitors.
Surprisingly, those with intermediate scores had the poorest outcomes. Current triple negative breast cancer treatments had limited effectiveness suggesting that new approaches would be necessary to tackle these cancers. However, the genetic changes and signatures revealed through WGS gave clues to the mechanisms driving these tumours, which in turn may help inform the development of new drugs.
Those patients with low scores also have poor outcomes, though not as badly as those in the intermediate group. However, the WGS profile in some of these tumours suggested biological abnormalities that could potentially be targeted by existing drugs or drugs currently going through clinical trials, such as so-called checkpoint inhibitors or AKT inhibitors.
“Using whole genome sequencing, we can truly discriminate tumours that may or may not respond to current drugs among triple negative breast cancer patients, a type of breast cancer that we still struggle to treat well,” says first author Dr Johan Staaf from the Department of Clinical Sciences, Lund University, Sweden.
“But importantly, this approach also gives us clues to some of the mechanisms that are going wrong in the poor-outcome tumours, and hence how we might treat those tumours differently or how we might develop new drugs.”
The speed of sequencing technology has progressed such that WGS can be carried out in 24 hours, with another 24-48 hours for analysis of the data. In theory, therefore, it should be possible to offer whole genome screening as a matter of course to all patients, allowing a personal readout of their tumour and potential treatment options.
“The potential for whole genome sequencing to open up a personalised approach to treating cancer is huge,” says Dr Nik-Zainal. “In the past, the cost and issues with managing the huge volume of data created barriers to its widespread application. But we are moving closer to a time where it can be routinely offered to all patients, with the potential to transform the management of even difficult-to-treat cancers.”
Scientists have developed a computer method that may help improve understanding and treatment of Crohn’s disease.
The study, published in Genome Medicine, used artificial intelligence to examine genetic signatures of Crohn’s in 111 people. The method revealed previously undiscovered genes linked to the disease, and accurately predicted whether thousands of other people had the disease.
“Our method is not a clinical diagnosis tool, but it generates interesting observations that need to be followed up,” said senior author Yana Bromberg, an associate professor in the Department of Biochemistry and Microbiology at Rutgers University-New Brunswick. “Further experimental work could reveal the molecular reasons behind some forms of Crohn’s disease and, potentially, lead to better treatments of the disease.”
The scientists evaluated genetic variants in the 111 people, including 64 with Crohn’s disease, and used artificial intelligence techniques to pinpoint genes whose functions changed more in Crohn’s patients than in healthy people, and vice versa. While the model’s accuracy may improve by including more people, it could help reveal the origins of Crohn’s and improve early diagnosis and accuracy, the study says.
“We believe that we can use the knowledge gained from this study to similarly model other genetically linked diseases,” said Bromberg.
New data have shown for the first time that targeted therapy can improve the outcome of patients diagnosed with advanced cholangiocarcinoma.
Cholangiocarcinoma is a subtype of bile duct cancer with aggressive behaviour and poor prognosis. Despite the low incidence, most patients die from the disease and therefore new effective therapies are urgently needed.
The data reported at the ESMO Congress 2019 are the first to show clinical benefit with targeted therapy in cholangiocarcinoma. Results of the ClarIDHy Phase III trial have shown that ivosidenib, an oral drug targeting the isocitrate dehydrogenase 1 (IDH1) mutation, expected in around 15% of advanced cholagiocarcinoma patients, significantly improved progression-free survival with a trend to improved overall survival compared to placebo.
“The ClarIDHy study demonstrates for the first time the feasibility and clinical benefit of targeting a molecularly defined subgroup in cholangiocarcinoma. It shows that targeting mutated IDH1 with ivosidenib significantly improves progression-free survival and gives a favourable trend in overall survival in patients with advanced IDH1-mutated cholangiocarcinoma,” said study author Dr Ghassan Abou-Alfa, Memorial Sloan-Kettering Cancer Center, New York, USA.
“The findings mean all patients with cholangiocarcinoma should be tested for IDH-1 mutation. Tumour mutation profiling should be a new standard for the care for patients with this heterogeneous tumour type,” he said. He considered that future studies should investigate ivosidenib as first-line treatment for IDH1-mutated cholangiocarcinoma in addition to its use in combination therapy and as adjuvant therapy.
Commenting on the relevance of the new data, Dr Chris Verslype, University Hospital Leuven, Belgium, said, “What we see in this study is really unprecedented. We previously had no options for patients with cholangiocarcinoma who failed systemic therapy, and they had very limited survival. These are important data. There is a gain in progression free survival with ivosidenib that is clinically relevant for this patient population,” he said.
Dr Angela Lamarca, Christie NHS Foundation Trust, Manchester, UK, representing the ESMO Press & Media Affairs Committee, agreed, “The reported median progression-free survival may seem short and some people may question whether this is clinically meaningful. However, for researchers working in cholangiocarcinoma it is a breakthrough. A treatment that increases the chance of being free from progression by 30% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families.”
Verslype noted, “It’s the first time in cholangiocarcinoma that a Phase III study tests a drug targeted to a specific anomaly, and it seems to work. Importantly, you identify suitable patients by selecting them for IDH1 mutation. It’s precision medicine brought to the clinic. And it’s very likely to change clinical practice. It will, for sure, drive the further development of targeted therapy for this disease.”
Verslype considered there were few limitations. Patients selected for the study had to have good performance status after previous chemotherapy, so may not be representative of patients whose disease progresses rapidly on chemotherapy. “But it is still a strong study because of the randomisation to placebo. It showed a real effect.” The study had a high crossover rate from placebo to ivosidenib, making the overall survival endpoint difficult to assess, but he pointed out that allowing patients to crossover was important from an ethical perspective. “Additional analysis suggested a benefit in overall survival if there had been no crossover.”
Study results
The global Phase III ClarIDHy study investigated the first in a new class of targeted drugs, ivosidenib, to target a mutant IDH-1 protein. Around one in six patients with cholangiocarcinoma have IDH1 mutations. These result in the production of a metabolite (D-2-hydroxyglutarate) that promotes oncogenesis.
The study randomised 185 patients with advanced cholangiocarcinoma and IDH1 mutations to ivosidenib or matched placebo. Patients could crossover from placebo to ivosidenib when their disease progressed.
Median progression-free survival was 2.7 months for patients treated with ivosidenib compared to 1.4 months with placebo (hazard ratio [HR] 0.37; 95% confidence interval [CI]: 0.25, 0.54, p<0.001). The median progression-free survival rate at six months was 32.0% with ivosidenib, while no patients randomised to placebo were free from progression at this timepoint.
Results showed a favourable trend in overall survival with ivosidenib. Median overall survival was 10.8 months for ivosidenib and 9.7 months for placebo (HR 0.69, one-sided p=0.06). Adjusting the overall survival results to take account of 57% of placebo patients crossing over to ivosidenib gave an adjusted overall survival of 6 months for placebo, which was significantly shorter than with ivosidenib (HR 0.46, p=0.0008).
Ivosidenib was generally well tolerated, with Grade 3 or higher adverse events reported in 46% of patients on the targeted agent and 36% of those on placebo. There were no treatment-related deaths.
30th September 2019
Novartis has announced that investigational, once-daily, fixed-dose inhaled QMF149 (indacaterol acetate and mometasone furoate or IND/MF) was superior to mometasone furoate (MF) in improving trough forced expiratory volume in one second (FEV1) after 26 weeks, meeting the primary endpoint of the Phase III PALLADIUM clinical trial.
This superior improvement in lung function was achieved in patients with asthma who remain uncontrolled on treatment with inhaled corticosteroid (ICS) at medium or high dose, or long-acting beta agonist (LABA)/ICS at low dose. IND/MF was generally well tolerated, and safety was comparable across treatment arms.
The key secondary endpoint, improvement in Asthma Control Questionnaire (ACQ-7), was also met for combined doses of IND/MF when compared to combined doses of MF, with a statistically significant improvement of asthma control achieved from baseline at Week 261. The PALLADIUM study was conducted to evaluate the efficacy and safety of medium and high doses of QMF149 (150/160μg and 150/320μg) delivered via the dose-confirming Breezhaler® device versus two respective medium and high doses of MF (400 μg and 800μg) delivered via Twisthaler® in patients with asthma who were uncontrolled on medium or high dose ICS or low dose LABA/ICS (as determined by pulmonary function testing and effects on asthma control). The PALLADIUM study also included an additional secondary comparison of high dose IND/MF delivered via the dose-confirming Breezhaler® device with twice daily salmeterol xinafoate/fluticasone propionate (50/500μg) delivered via the Accuhaler®.
“Nearly half of all patients with moderate-to-severe asthma remain uncontrolled and continue to suffer with regular symptoms and exacerbations,” said Dr Richard van Zyl-Smit, Associate Professor, Head of the Lung Clinical Research Unit, University of Cape Town Lung Institute, and Consultant Pulmonologist, Groote Schuur Hospital, Cape Town, South Africa. “Promising results from PALLADIUM in both doses of the indacaterol and mometasone furoate combination provide evidence for the efficacy and safety profile of QMF149 for the treatment of asthma. If approved, the easy-to-use, dose-confirming, once-daily device adds an additional and important option for clinicians treating asthma. I believe that this new fixed-dose combination has the potential to improve and simplify the lives of many patients with uncontrolled asthma.”
“We are very pleased that PALLADIUM demonstrated the efficacy and safety of medium and high doses of QMF149, delivered via our dose-confirming Breezhaler® device,” said Linda Armstrong, MD, Respiratory Development Unit Head, Novartis Pharmaceuticals. “These results complement the findings of the Phase III QUARTZ study for a lower dose of QMF149 and provide additional evidence of the benefits of this combination treatment across the full dose range. We look forward to announcing more data from the PLATINUM clinical development program.”
The overall incidence of adverse events (AEs) and serious AEs in PALLADIUM was comparable among treatment groups and consistent with the known safety profile of the monocomponents.
The detailed results from the PALLADIUM trial will be presented at upcoming medical congresses. As previously announced, the regulatory submission for QMF149 was accepted for review by the European Medicines Agency earlier this year.
27th September 2019
26th September 2019
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