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.

AstraZeneca – Oxford Cancer Symposium (AZOCS), Thursday 13th September 2018 | Keble College, Oxford

 

AstraZeneca – Oxford Cancer Symposium (AZOCS)

Thursday 13th September 2018 | Keble College, Oxford

 

On Thursday 13th June, Keble College in Oxford hosted the
inaugural AstraZeneca – Oxford Cancer Symposium (AZOCS).

 

Over 125 researchers from Oxford and 90 cancer scientists from AstraZeneca and MedImmune attended to develop and establish a series of collaborative cancer research projects.

 

Almost 100 posters and 27 presentations showcased current
projects across all organisations, covering DNA Damage
Response
, Early-Phase Clinical Trials, Enabling Technologies,
Epigenetics, Immuno-Oncology, and Radiation Oncology.

 

 

David Andrews from AstraZeneca in Cambridge commented:

“The feedback I have had from AstraZeneca and Medimmune colleagues has been overwhelmingly positive and it is clear there are many opportunities for us to collaborate – from target identification and validation all the way through to patient studies. We are very excited by the prospect of deploying our disease know-how, target knowledge and
portfolio of drugs in development alongside Oxford’s excellent
access to patients and patient-derived models.
Oxford’s specific disease and biological knowledge should also
enable us to more deeply understand biological targets

and bring benefit to patients.”
 

 

Chris Schofield from the Department of Chemistry in Oxford
emphasised: “The AZ-Oxford meeting showcased brilliant
science from both organisations aimed at enabling breakthrough treatments for cancer. The truly impressive research ranged from fundamental work on the origins of tumorigenesis to clinical studies. There is clearly enormous potential for industry and academic to work synergistically to cement the UK’s leading position in cancer research.”

 

 

Poster winners for the AZOCS Poster Prizes 2018 are:

 

A Fluorescent Reporter of Base Editing

Activity Reveals Editing Characteristics of APOBEC3A
and APOBEC3B

– Matthew Coelho, AstraZeneca

A gene signature associated with PTEN activation defines good outcomes in intermediate-risk prostate cancer cases

– Chee Wee Ong, University of Oxford

 

 

If you attended the Symposium and would like to find out any more information about any of the presentations you saw, any of the posters, or further information on the CRUK Oxford Centre or AstraZeneca/MedImmune then please contact cancercentre@oncology.ox.ac.uk .

 

If you would like further information on how to download the Networking Meeting App ATTENDIFY, please contact cancercentre@oncology.ox.ac.uk .

 

Pioneering Combination Therapy Approach to Treating Colorectal Cancer

Celleron Therapeutics, the UK-based company and Oxford University spin-out developing personalised medicine for cancer patients, has today announced the initiation and first patient enrolment of its clinical study that will evaluate the effect of a novel combination therapy approach for colorectal cancer.

Professor Mark Middleton, Consultant Medical Oncologist and Professor of Experimental Cancer Medicine at the University of Oxford commented: “We are delighted to be part of this important trial, which has the potential to bring immunotherapy to patients who hitherto have not benefitted from this approach. It is also very satisfying to see CXD101, a drug first given to patients at the Experimental Cancer Medicine Centre here in Oxford, developed further in the clinic based upon scientific insights made here in the city.

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Celleron Therapeutics Clinical Trial Authorisation to conduct a Phase Ib/II clinical trial with CXD101, a highly potent class 1 histone deacetylase inhibitor, in combination with an immune oncology (IO) agent, nivolumab. Celleron appointed Syneos Health as the CRO to support the trial which is investigating the clinical activity of CXD101 in combination with nivolumab, measuring the anti-tumour effect on a type of colorectal cancer (microsatellite stable) which typically does not respond to IO agents alone. The clinical trial strategy rests on compelling pre-clinical results which provide novel insights into how CXD101 and IO drugs work together to re-engage recognition of tumours by the immune system. The trial will also allow exploration of a range of new biomarkers to help select those patients likely to benefit most from combination therapy.

Professor Nick La Thangue, Founder and Chief Executive of Celleron Therapeutics, and Professor of Cancer Biology in the Department of Oncology at Oxford University, commented: “CXD101 is a very interesting drug with great clinical potential. The new trial is a major step forward in understanding its therapeutic application. We have observed striking effects on late stage cancer patients in previous studies. This trial exploits our deep scientific understanding of how CXD101 exerts anti-cancer activity, which underpins the hypothesis being tested in the novel combination approach.”

CXD101 is Celleron Therapeutics’ next generation epigenetic immune-regulator representing a class of drug that kills cancer cells by blocking certain vital functions involved in gene expression and reactivates the patient’s immune system so that cancer cells can no longer evade immune recognition.

Professor David Kerr CBE, Founder and Chief Medical Officer, Celleron Therapeutics and Professor of Cancer Medicine, University of Oxford commented: “There is a very significant unmet need for novel therapy for patients with advanced colorectal cancer. As colorectal tumours progress, they find a variety of ways to avoid recognition and destruction by the immune system, increasing their potential to grow and spread. We have discovered that CXD101 can reverse this process of “immune silencing” making it, potentially, an ideal partner for existing immune oncology agents.”

 

Content adapted from Celleron Therapeutics website.

 

 

 

 

 

 

 

www.cellerontherapeutics.com

Rare cancer could be caught early using simple blood tests

A pioneering study into myeloma, a rare cancer, could lead to GPs using simple blood tests to improve early diagnosis.

CRUK Centre members, in collaboration with the University of Exeter and Chiddenbrook Surgery, Crediton, found that a simple combination of blood tests, which are routinely conduced in GP surgeries, could improve early diagnosis of myeloma.

Dr Brian D Nicholson, clinical researcher at the Nuffield Department of Primary Care in Oxford, and co-author of the study stated: “We wanted to develop a simple rule based on existing commonly used blood tests to help GPs identify which patients  should be investigated further for Myeloma. By achieving this we offer guidance that can be implemented immediately in routine primary care to benefit all patients.

Researchers investigated how useful a number of different measures were for indicating the presence of the disease, and suggested what combinations of these tests were sufficient to rule out the disease, and to diagnose it, saving the patient from the worry of specialist referral.

Blood tests of 2703 cases taken up to five years prior to diagnosis were analysed and compared with those of 12,157 patients without the cancer, matching cases with control patients of similar age amongst other relevant parameters.

They demonstrated that a simple combination of two blood parameters could be enough to diagnose patients. Such blood tests are routinely conducted in GP surgeries.

Constantinos Koshiaris, lead author of the study, from Oxford University, said: “The combination of levels of haemoglobin, the oxygen carrier in the blood, and one of two inflammatory markers (erythrocyte sedimentation rate or plasma viscosity) are a sufficient test rule out myeloma. If abnormalities are detected in this test, it should lead to urgent urine protein tests which can help speed up diagnosis.”

Each year approximately 5,700 people are diagnosed with myeloma in the UK alone. It can lead to symptoms such as bone pain, fatigue and kidney failure. It has the longest diagnosis process of all common cancers, and a large number of patients are diagnosed after emergency care, over a third of which having had at least three primary care consultations.

Professor Willie Hamilton, of the University of Exeter Medical School, is principal investigator on the study. He said: “Ordinarily a GP will see a patient with myeloma every five years – and early diagnosis matters. More timely treatment could significantly improve survival rates for this disease. We report a simple way a GP can check patients presenting symptoms such as back, rib and chest pain, or recurrent chest infections, and determine whether they have myeloma or not.

The authors also suggest the possibility of integrating a system in the electronic health record to alert clinicians to relevant symptoms or changes in blood parameters related to myeloma.

 

The case-control study was led by Constantinos Koshiaris (Oxford University) and published in the British Journal of General Practice. https://bjgp.org/content/early/2018/08/13/bjgp18X698357

This project was funded through a DPhil scholarship awarded to Constantinos Koshiaris by the University of Oxford, the Primary Care Research Trust, and the National Institute for Health Research (NIHR) Oxford CLAHRC.

Content adapted from University of Oxford news site.

 

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

 

 

Focussed ultrasound and nanomedicine offer new hope for improving effects of cancer drugs

Researchers have made a breakthrough in more precisely targeting drugs to cancers.

A number of Centre members were part of a multi-disciplinary team of biomedical engineers, oncologists, radiologists and anaesthetists that have used ultrasound and lipid drug carriers (liposomes) to improve the targeting of cancer drugs to a tumour. The new technology has been used in humans for the very first time, with ultrasound remotely triggering and enhancing the delivery of a cancer drug to the tumour.

“Reaching therapeutic levels of cancer drugs within a tumour, while avoiding side effects for the rest of the body is a challenge for all cancer drugs, including small molecules, antibodies and viruses” says Professor Constantin Coussios, Director of the Oxford Centre for Drug Delivery Devices and of the Institute of Biomedical Engineering at the University of Oxford. “Our study is the first to trial this new technique in humans, and finds that it is possible to safely trigger and target the delivery of chemotherapy deep within the body from outside the body using focussed ultrasound. Once inside the tumour, the drug is released from the carrier, supplying a higher dose of chemotherapy directly to the tumour, which may help to treat tumours more effectively for the same or a lower systemic dose of the drug.”

The 10-patient phase 1 clinical trial, supported by the Oncology Clinical Trials Office, used focused ultrasound from outside the body to selectively heat liver tumours and trigger drug release from heat-sensitive carriers, known as thermosensitive liposomes. Building on over a decade of preclinical studies, the study demonstrated the ultrasound technique to be feasible, safe, and capable of increasing drug delivery to the tumour between two-fold and ten-fold in the majority of patients. Ongoing research worldwide is investigating the applicability of this technique to other tumour types, and future research could explore the combination of ultrasound with other drugs.

All 10 patients treated had inoperable primary or secondary tumours in the liver and had previously received chemotherapy. The procedure was carried out under general anaesthesia and patients received a single intravenous dose of 50 mg/m2 of doxorubicin encapsulated within low-temperature-sensitive liposomes (ThermoDox®, Celsion Corporation, USA). The target tumour was selectively heated to over 39.5° C using an approved ultrasound-guided focussed ultrasound device (JC200, Chongqing HAIFU, China) at the Churchill Hospital in Oxford. In six out of ten patients, the temperature at the target tumour was monitored using a temporarily implanted probe, whilst in the remaining four patients ultrasonic heating was carried out non-invasively.

Before ultrasound exposure, the amount of drug reaching the tumour passively was low and estimated to be below therapeutic levels. In seven out of 10 patients, chemotherapy concentrations within the liver tumour following focussed ultrasound were between two and ten times higher, with an average increase of 3.7 times across all patients.

“Only low levels of chemotherapy entered the tumour passively. The combined thermal and mechanical effects of ultrasound not only significantly enhanced the amount of doxorubicin that enters the tumour, but also greatly improved its distribution, enabling increased intercalation of the drug with the nucleus of cancer cells ” says Dr Paul Lyon, lead author of the study.

“This trial offers strong evidence of the rapidly evolving role of radiology in not only diagnosing disease but also guiding and monitoring therapy. The treatment was delivered under ultrasound guidance and patients were subsequently followed up by CT, MRI and PET-CT, evidencing local changes in tumours exposed to focussed ultrasound” commented Professor Fergus Gleeson, radiology lead co-investigator for the trial.

“A key finding of the trial is that the tumour response to the same drug was different in regions treated with ultrasound compared to those treated without, including in tumours that do not conventionally respond to doxorubicin” adds Professor Mark Middleton, principal investigator of the study. “The ability of ultrasound to increase the dose and distribution of drug within those regions raises the possibility of eliciting a response in several difficult-to-treat solid tumours in the liver. This opens the way not only to making more of current drugs, but also targeting new agents where they need to be most effective”.

The study was published in The Lancet Oncology journal.

Prognostic biomarkers discovered for patients with malignant pleural effusion

In a collaboration spanning multiple departments within Oxford and beyond, Centre members led by Dr Ioannis Psallidas have developed a new risk score (PROMISE score) that can provide important information on patient prognosis, and guide the selection of appropriate management strategies for patients with malignant pleural effusion.

Malignant pleural effusion is defined as the accumulation of a significant amount of fluid in the pleural space, accompanied by the presence of malignant cells or tumour tissue. It is commonly associated with breast and lung metastases, but the majority of late stage cancer could develop this type of metastasis. Currently, patients suffering from malignant pleural effusion have poor prognosis, with median survival ranging from 3 to 12 months. Additionally, the incidence of this condition is on the rise due to the increase in cancer prevalence and therapy improvements that allow patients to live for longer.

The most common treatment of malignant pleural effusion is pleudodesis, which involves the induction of pleural inflammation and fibrosis to prevent fluid accumulation. To improve the stratification of treatment for patients and to aid the understanding of the mechanisms underlying disease progression, prognostic biomarkers need to be identified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion.

Researchers discovered four proteins associated with patient survival that were independent of the cancer type. The data from one protein named tissue inhibitor of metalloproteinases 1 was combined with seven clinical biomarkers to build a score that predicts risk of death within 3 months. These four proteins that were associated with predicting survival also have potential as targets for novel treatments.

Ioannis remarked ‘The PROMISE score provides a valuable tool for clinicians to help stratify patients with malignant pleural effusion. Those of which have good prognosis can be identified for clinical trials of novel treatments. The patients with poorer prognosis can be treated symptomatically, reducing the number of hospital visits and procedures, such as pleudodesis, which may result in mortality. In the future we will be to aiming to secure funding to set up trials to investigate the effects of targeting the proteins identified in this study’.

The PROMISE study results have been published in Lancet Oncology.

Aspirin and acid reflux medication reduce the likelihood of patients with Barrett’s oesophagus developing oesophageal cancer.

Results of the AspECT clinical trial, coordinated by the CRUK Oxford Centre supported Oncology Clinical Trials Office, have shown the important role aspirin and acid reflux treatment can have in preventing those at high risk of oesophageal cancer from going on to develop the disease.

The trial led by Professor Janusz Jankowski had results presented last week at the American Society of Clinical Oncology conference. The trial investigated the chemo preventative effects of different doses of the antacid medication esomeprazole, with and without low dose aspirin in patients with Barrett’s oesophagus. Since acid reflux is involved in causing Barrett’s oesophagus it had been suggested that reduction of acid to very low levels might prevent progression to cancer.

The randomised phase III trial involved over 2500 patients who were followed for 7.9 years. Patients who followed a seven year course of high dose of esomeprazole with low dose aspirin, followed by high dose esomeprazole, were 20% less likely to develop oesophageal cancer than if they had been untreated.

Professor Janusz Jankowski, who completed an MSc in clinical trial research at Oxford University in 2009 and is currently Professor of Medicine at the University of Central Lancashire said: “Our results are very exciting. Oesophageal cancer is hard to diagnose and hard to treat. So, we’re pleased that such a cheap and well-established medicine can prevent and/or delay development of cancer for these patients. Our hope is that this may also offer an opportunity to prevent oesophageal cancer in wider populations.”

AstraZeneca – Oxford collaborative Symposium September 2018 – Registration now closed

We are delighted to announce a partnership symposium between AstraZeneca and the Cancer Research UK Oxford Centre, which will take place on September 13th 2018 at Keble College.

The primary aim of the event is to provide an opportunity for researchers from both organisations to get a better understanding of the research activities of the other, in order to establish a series of collaborative cancer research projects. Through the Centre Development Fund, financial support for projects emerging from the event will be available.

The event will include presentations on 4 core topics, DNA damage repair, radiation oncology, epigenetics and immunoncology and posters covering target identification and validation, CRISPR capabilities, early phase clinical trials, biophysics, structural biology, biochemistry/cellular assays and chemical probes.

There will be a range of speakers from both Oxford and AstraZeneca (see draft schedule below), and numerous opportunities for individual networking during breaks and at the drinks reception. We will be opening our next round of development funding at the event in order to support collaborations emerging from the event.

If you are interested in attending this free event, (open to group leaders, and post-doc’s across the University and Trust) and presenting a poster to showcase your research to AZ (and making yourself eligible for the poster prize) please register your interest here by Tuesday June 19th. Places are limited to 150 attendees and will be prioritised to those researchers presenting posters and those who register sooner.

Please note, all information included in the above application and presented at the conference will be considered pre-competitive, so bear this in mind when choosing which details to disclose.

Chris Holmes appointed Programme Director for Health Data in a partnership between Health Data Research UK and the Alan Turing Institute

We are delighted to congratulate Professor Chris Holmes, member of the Centre Management Group, on his new joint role for the Alan Turing Institute and Health Data Research UK (HDR UK).

Chris, who is Professor in Biostatistics at the University of Oxford, has considerable expertise in data science and artificial intelligence methodologies, specifically statistics and machine learning and its application to health and biomedical science problems. He has been employing computational statistics and machine learning approaches to integrate the multi-omics data (DNA sequence, methylation, transcriptome and patient records) generated by the S-CORT consortium to provide a greater biological understanding of colorectal cancer.

In his new role, Chris will facilitate direct scientific collaboration and leadership between the two national centres. He will develop and coordinate a programme of research involving collaboration across The Alan Turing Institute’s growing university network, creating opportunities with HDR UK’s six substantive sites and the broader health and data science sector. His programme will build on an already established set of health projects underway at the Turing, including partnerships with Cystic Fibrosis Trust applying machine learning to improve treatment plans, a set of interdisciplinary projects awarded jointly with the British Heart Foundation through the BHF-Turing Cardiovascular Data Science Awards and cross-cutting foundational research looking into data security and privacy.

Commenting on his appointment, Chris remarked:
“Already we are seeing data science and AI innovation bear fruit in the health sector; with areas like medical imaging now opening up to machine learning algorithms. There are many other areas of opportunity; including using data to inform adaptive clinical drug trials, personalised medicine, addressing operational challenges within the health service and using theoretical mathematics and statistics to help connect and understand the algorithms that can extract information from large datasets.”

“I am delighted to join with the Turing and HDR UK and look forward to working with these two national centres to improve human health and the scientific understanding of biomedical systems.”