A round up of Pancreatic Cancer Awareness Month at the University of Oxford
The discovery of pancreatic cancer biomarkers (naturally occurring molecules, genes or characteristics which can be used to confirm the presence or predict the outcome of a cancer) is vital in understanding patient outcomes and finding new therapeutic targets. In recent years, improved understanding of the biology of pancreatic cancers has resulted in new combination therapies being developed, including the development of the first successful biomarker-guided therapy in pancreatic cancer known as the POLO trial.
A recent paper from the SCALOP-1 trial team, led by Prof. Somnath Mukherjee, was published in BJC Nature, which has identified proteins that could act as a new biomarker to predict a patient’s outcome from pancreatic cancer. The chemokine protein known as CCL5, found circulating in patient blood, was found in low quantities in patients with better overall pancreatic cancer survival (around 18.5 months, rather than less than a year).
It is already known that CCL5 is involved in tumour invasion, tumour metastasis and the creation of an immune-system-suppressing micro-environment that allows pancreatic cancer to develop quickly. Its identification as a biomarker makes CCL5 a perfect new target for potential drug treatments. For example, blockade therapies that target the CCL5-CCR5 pathway and reduce the presence of CCL5, may produce new opportunities to improve the outcome of other immunotherapies that pancreatic cancer patients are undergoing.
Co-lead of this study, Prof Eric O’Neil from the Department of Oncology, is now investigating combination of CCL5 antagonist drugs with immunotherapy and radiotherapy drugs in animal models, which he hopes will lead to the development of new, more-effective pancreatic treatments in the future.
Next steps for the SCALOP trials
When pancreatic cancer has developed beyond a stage where it is operable, the only option for patients is often chemotherapy or chemoradiotherapy (the combination of chemo and radio therapy). The creation of new combination drugs used in the chemotherapy process has led to some improvement in overall length of patient survival of pancreatic cancer, which remains one of the highest causes of cancer death in the UK, however the use of these drugs is limited by the toxic effect on the body.
Following on from the SCALOP-1 trial, the SCALOP-2 trial, has been run from the University of Oxford, hosted through the Oncology Clinical Trials Office and lead by Prof Somnath Mukherjee. It has completed recruitment earlier in the year and final results are awaited.
Currently in the UK, chemoradiotherapy for locally advanced pancreatic cancer consists of 28 daily treatments of radiotherapy. Although this treatment is effective in controlling local symptoms and slowing down local cancer progression, in most cases it is unable to remove the cancer or shrink it well enough to make it operable. There is a need to find more efficient treatment combinations to improve patient outcomes.
The SCALOP-2 clinical trial compared different ways of combining chemotherapy and chemoradiotherapy to see which combination provides the most benefit to patients who have inoperable pancreatic tumours. This includes testing radiotherapy dose escalation and the use of nelfinavir as a radiosensitizer drug – something that makes tumour cells more sensitive to the effects of radiation therapy. In doing so, it is hoped that researchers can uncover more efficient drug combinations for patients with pancreatic tumours that are inoperable.
Blood and biopsy samples have been collected as a part of SCALOP-2 trial, in order to allow the team to take a more detailed look at proteins, DNA and cells involved in the cancer and how they are affected by treatment. This will tell researchers much more about how a patient’s type of cancer behaves and how it has responded to various treatments, allowing for the discovery of biomarkers just like CCL5 from the SCALOP-1 trial.
More information about the SCALOP-2 trial can be found on the Pancreatic Cancer UK website here.
Cancers detected at an earlier stage have a much higher chance of being treated successfully. The main method for diagnosing cancers of the gastrointestinal tract is endoscopy, when a long flexible tube with a camera at the end is inserted into the body, such as the oesophagus, stomach or colon, to observe any changes in the organ lining. Endoscopic methods such as radiofrequency ablation can also be used to prevent pre-cancerous regions from progressing to cancer if they are detected in time.
Unfortunately, during conventional endoscopy, the more easily treated pre-cancerous conditions and early stage cancers are harder to spot and often missed, especially by less experienced endoscopists. Cancer detection is made even more challenging by artefacts in the endoscopy video such as bubbles, debris, overexposure, light reflection and blurring, which can obscure key features and hinder efforts to automatically analyse endoscopy videos.
In an effort to improve the quality of video endoscopy, a team of researchers from the Institute for Biomedical Engineering (Sharib Ali and Jens Rittscher), the Translational Gastroenterology Unit (Barbara Braden, Adam Bailey and James East) and the Ludwig Institute for Cancer Research (Felix Zhou and Xin Lu) have developed a deep-learning framework for quality assessment of endoscopy videos in near real-time. This framework, published in the journal Medical Image Analysis, is able to reliably identify six different types of artefacts in the video, generate a quality score for each frame and restore mildly corrupted frames. Frame restoration can help in building visually coherent 2D or 3D maps for further analysis. In addition, providing quality scores can help trainees to assess and improve their endoscopy screening performance.
Future work aims to employ real-time computer algorithm-aided analysis of endoscopic images and videos, which will enable earlier identification of potentially cancerous changes automatically during endoscopy.
This work was supported by the NIHR Oxford Biomedical Research Centre, the EPSRC, the Ludwig Institute for Cancer Research and Health Data Research UK.
Previous phase 1 and 2 clinical trials have been conducted into Tebentafusp, a new anti-tumour immune response drug for patients with metastatic melanoma. The results from Immunocore and the University of Oxford, found that this first-of-its-kind treatment showed great promise in helping the immune system fight off melanoma cancers of both the eye and skin. The phase 3 clinical trial for this drug is the first for an affinity optimised T-cell receptor drug, making it the first of its kind.
Today, Immunocore the company behind the drug have announced trial results showing tebentafusp works better for patients with untreated metastatic uveal melanoma, when compared to other treatment choices.
“A positive survival benefit for tebentafusp represents a major step towards bringing a potential new treatment for cancer patients with a high unmet need. If approved, it would be the first new therapy to improve the overall survival in 40 years and to be specifically used in the treatment of metastatic uveal melanoma, a disease with poor survival where new therapies are urgently needed”
– Bahija Jallal, CEO of Immunocore
Tebentafusp comes out of clinical trials led by Prof Mark Middleton (Department of Oncology). Now, we see the potential for this drug coming into the clinic, subject to regulatory approval, as early as next year.
“It is very exciting that our observations in the first trial of tebentafusp, that it could make some uveal melanomas shrink, have now been borne out in larger studies. There’s still a way to go but there is every hope that this will prove an option for the treatment of this difficult cancer quite soon.”
– Prof Mark Middleton, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre.
Uveal melanoma is a rare and aggressive form of cancer that affects the eye, and typically has a poor prognosis and has no accepted optimal treatment and management. After the cancer metastases, 50% of patients have life expectancy of less than a year. Tebentafusp has the potential to be the first new therapy to improve the life expectancy of patients in over 40 years.
About the researchers
This research was funded by Immunocore.
Prof Mark Middleton is the Head of the Department of Oncology at the University of Oxford. He has overseen the development of internationally leading melanoma and upper GI clinical research groups and establishment of portfolios of early phase radiotherapy and haemato-oncology trials in Oxford. He is involved in the evaluation of novel immunotherapeutics, including pre-clinical development, trial design, proof of mechanism and proof of concept.
Immunocore, is a pioneering, clinical-stage T cell receptor biotechnology company working to develop and commercialise a new generation of transformative medicines to address unmet needs in cancer, infection and autoimmune diseases. The Company’s most advanced programs are in oncology and it has a rich pipeline of programs in infectious and autoimmune diseases. Immunocore’s lead program, tebentafusp (IMCgp100), has entered pivotal clinical studies as a treatment for patients with metastatic uveal melanoma. Collaboration partners across the Immunocore pipeline include Genentech, GlaxoSmithKline, AstraZeneca, Eli Lilly and Company, and the Bill and Melinda Gates Foundation. Immunocore is headquartered at Milton Park, Oxfordshire, UK, with offices in Conshohocken, Pennsylvania and Rockville, Maryland in the US. For more information, please visit www.immunocore.com.
The National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) is based at the Oxford University Hospitals NHS Foundation Trust and run in partnership with the University of Oxford.
The NIHR is the nation’s largest funder of health and care research. The NIHR:
- Funds, supports and delivers high quality research that benefits the NHS, public health and social care
- Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
- Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
- Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
- Partners with other public funders, charities and industry to maximise the value of research to patients and the economy
The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.
This work uses data provided by patients and collected by the NHS as part of their care and support and would not have been possible without access to this data. The NIHR recognises and values the role of patient data, securely accessed and stored, both in underpinning and leading to improvements in research and care. www.nihr.ac.uk/patientdata
Pancreatic cancer has the lowest survival rate of any cancer in the UK, due in part to the limited ability to diagnose it at an early stage. Earlier detection of pancreatic cancer is a major priority of cancer researchers, in order to identify tumours at an earlier stage when they are more easily treatable.
Identifiable biomarkers (naturally occurring molecules which can be related to the presence of a cancer) is one method that can be used to predict or diagnose pancreatic cancer. Currently, the previously-identified biomarkers available have a limited ability to accurately diagnose pancreatic cancer. There is a need to identify new biomarkers that more accurately predict the presence of pancreatic cancer for improved earlier diagnosis.
Dr Christiana Kartsonaki, a senior scientist at the MRC Population Health Research Unit in the Nuffield Department of Population Health, is leading investigations on the potential of protein biomarkers in blood, using data from the China Kadoorie Biobank. Blood samples from over 500,000 Chinese adults have been collected as part of this data set, allowing researchers to identify circulating proteins in the blood and see which individuals went on to develop pancreatic cancer.
During 9 years of follow-up, 700 individuals from the ~500,000 went on to develop pancreatic cancer. From their blood samples, Dr Christiana Kartsonaki and her colleagues will be able to identify a number of protein biomarkers that are associated with a future risk of pancreatic cancer. This study builds on their previous work on the associations of metabolic and lifestyle factors with risk of pancreatic cancer.
Identification of biomarkers may prove very useful in the establishment of strategies to utilise these proteins in predicting the development of pancreatic cancer and help with its diagnosis.
Results from this research will likely be published next year. Once biomarkers are identified, this work may help researchers understand the role that individual proteins play in the development and progression of pancreatic cancer, and whether they may have therapeutic potential as drug targets in its treatment.
About the study
This study is funded by the Nuffield Department of Population Health, Pancreatic Cancer UK and the CRUK Oxford Centre. It was co-led by Associate Professor Michael Holmes, Professor Zhengming Chen, Dr Yuanjie Pang and Dr Christiana Kartsonaki.
Understanding how an individual survives cancer, and why they respond well to therapy, can be vital in identifying new therapeutic targets. A new project seeks to see why some advanced pancreatic cancer patients overcome the odds and respond positively to treatment.
Pancreatic cancer is the 11th most common cancer in the UK. However, the mortality rate remains the highest among all cancers, due to diagnosis at late stages. As a result, less than 20% of patients diagnosed with pancreatic cancer are suitable for surgery with curable intent, and only 16% of patients are likely to live longer than a year after diagnosis.
The survival rate is much higher when the cancer is found at an earlier stage. However, there is no national screening programme or reliable tests for pancreatic cancer. Most symptoms reported to be associated with pancreatic cancer are vague and non-specific, which increases the difficulty of general practitioners (GPs) recognising early signs of pancreatic cancer in the community.
Identifying red flag symptoms
To address this research gap, the ADEPTS study was set up, using linked data from GP records, hospital records, ONS mortality data, and cancer registry data from the QResearch database, with the aim to better understand the symptom profile of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PNEN, a rarer type of pancreatic cancer). The ADEPTS study is run by researchers from the Nuffield Department of Primary Care Health Sciences.
This is a case-control study. The team identified about 23600 patients diagnosed with PDAC and 600 patients with PNEN from the QResearch database in the last 20 years.
Up to 10 patients without cancer (controls) with the same age, sex, calendar year registered in the same general practice were identified and matched with each case (patient diagnosed with PDAC/PNEN). The team also identified a list of potential symptoms that may be associated with PDAC and/or PNEN through literature review, leading research charities like Cancer Research UK and Pancreatic Cancer UK, NICE guidelines, and patient representatives. The team explored the presentation of symptoms in different time windows (e.g. within 3 months, 6 months, 1 year, and 2 years before diagnosis) and the association with the diagnosis of PDAC and PNEN.
Through this analysis, a profile of symptoms that are associated with PNEN and PDAC can be determined, which can be used to update the QCancer (Pancreas) prediction model. The model can be used in primary care settings to help GP identify patients who are at high risk and investigate these patients in a timely manner.
So far, the team have already identified a number of red flag symptoms. The results will be published next year. They have also identified certain ethnic groups that are less likely to develop PDAC, along with certain co-morbidities (other health conditions beside pancreatic cancer) that could also be used to predict cancer risk.
Increasing public awareness and GP pathways
After publishing their study findings, the research team hope to engage with relevant stakeholders, to increase public awareness of symptoms that are associated with pancreatic cancer, such as weight loss, abdominal pain, jaundice, etc.
In conjunction with this, the ADEPTS study is working with GPs to improve better direct access to diagnostic investigation resources, such as ultrasound, CT scans and MRIs. This way, when a patient presents to their GP with symptoms, they can be quickly and accurately diagnosed in the hopes of identifying PDAC earlier.
Improved GP assessment tools are being developed as part of the study. By improving the identification and quantification of red flag symptoms associated with pancreatic cancer, the ADEPTS study will help GPs ensure that right patients are sent for the right investigatory methods, making efficient use of scarce or expensive resources such as MRI scans. By communicating its findings with GPs and patients, the ADEPTS study will increase public awareness of symptoms and prompt earlier diagnosis through investigation. Look out for the published findings next year.
About this study
The QResearch database is founded and directed by Prof Julia Hippisley-Cox, who is the Principal Investigator of the ADEPTS project. External collaborators include Prof Carol Coupland (Medical Statistics) from the University of Nottingham, and Prof Stephen Pereira (Hepatology & Gastroenterology) from University College London.
Scenic Biotech was founded in March 2017 as a spin-out of the University of Oxford and the Netherlands Cancer Institute. The company is based on the Cell-seq technology developed by co-founders Sebastian Nijman and Thijn Brummelkamp in their academic labs.
Cell-seq is a large-scale genetic screening platform that allows the identification of genetic modifiers – or disease suppressors – that act to decrease the severity of a disease. These disease-specific genetic modifiers are difficult to identify by more traditional population genetics approaches, especially in the case of rare genetic diseases. By mapping all the genetic modifiers that can influence the severity of a particular disease, Cell-seq unveils a new class of potential drug targets that can be taken forward for drug development.
In a deal worth $375m, Scenic Biotech has recently entered into a strategic collaboration with Genentech, a member of the Roche Group. This will enable discovery, development and commercialisation of novel therapeutics that target genetic modifiers.
Pancreatic ductal adenocarcinoma (PDAC) makes up 95% of all pancreatic cancer cases and has the lowest survival rate, and early diagnostic methods have yet to be developed. As a result, diagnosis often comes at a later stage when treatment options are limited and prognosis is poor.
Diagnosis at this stage often comes from imaging techniques followed by tissue biopsies, which are not appropriate options to use as standardised, early screening methods. New ways to diagnose PDAC at an earlier stage are needed, without the use of invasive procedures.
Liquid biopsies are becoming a more popular option to fill this demand. Taking a blood sample is minimally invasive, quick, and can tell us a lot of information about a person from their cfDNA (cell free DNA). cfDNA is released from cells and circulates in the blood, containing information about the cell they come from.
Methylation on cfDNA often appears in cancer patients, making it an effective biomarker that can be used to diagnose the presence of cancer with high accuracy and specificity about the cancer (such as location). The concept has many applications, including in the earlier diagnosis of PDAC.
The identification of these biomarkers in blood is often limited to the technology used, with DNA being damaged by the harsh chemicals that are used in the processing. The recent development of TAPS technology at the University of Oxford has helped to overcome this, using a bisulphate-free method, and making it a perfect method for PDAC biomarker identification.
DPhil students Paulina Siejka-Zielinska and Felix Jackson and Postdoctoral Researcher Jingfei Chang from Dr Chunxiao Song’s lab in collaboration with Dr Shivan Sivakumar (consultant medical oncologist) have been investigating TAPS as a method to identify PDAC biomarkers. Using blood samples from PDAC patients and healthy individuals, they are applying TAPS technology to prove that it can be used to accurately detect pancreatic cancer biomarkers in cfDNA.
Preliminary results from this study suggest that cfDNA methylation can be used for the identification of PDAC, as well as being able to accurately distinguish between pancreatic cancer and other pancreatic disorders that effect the DNA, such as pancreatitis.
If this is the case, then the results from this study will make for solid grounds for the application of TAPS in the earlier screening for pancreatic cancer.
About the Song Lab
The Song Lab combine various chemical biology and genome technologies to develop novel tools to analyse the epigenome. The lab apply these tools to two main research areas: the use of epigenetic modifications in circulating cell-free DNA from the blood for non-invasive disease diagnostics including early detection of cancer, and understanding the contribution of epigenetic heterogeneity in cancer development.
Most recently, the TAPS technology developed at the Song Lab has led to the creation of the start up Base Genomics, which has been launched to set a new gold standard in DNA methylation detection using this TAPS technology. Base Genomics will initially focus on developing a blood test for early-stage cancer and minimal residual disease. You can read more about it here.
Pancreatic cancer has a limited response to chemotherapy treatment, due to the movement of anti-cancer drugs from the blood into tumour cells being limited by cellular mechanisms such as poor perfusion, high stromal content and raised interstitial pressure. One way to overcome these challenges and increase the toxic effect of chemotherapy treatment on a tumour would be to increase drug dosage. However, this would result in the damage of healthy non-tumour cells, and would likely result in unacceptable toxicity to patients.
The aim of Professor Constantin Coussios and his team in the Institute Biomedical Engineering is to develop of drug delivery system capable of enhancing drug penetration into and around a tumour, whilst minimising toxicity to the patient. The team has so far found a successful approach, by increasing drug uptake into tumours through warming of the body, which causes vasodilation.
By using focused ultrasound (FUS) to generate heat, only defined areas (approximately the size of a grain of rice) are targeted for treatment. In combination, chemotherapy drugs such as doxorubicin can be encapsulated in a heat-sensitive lipids (ThermoDox®), so that the active drug is only released when a specific temperature is reached at a specified location, as defined by the position of the FUS beam.
Research fellows Dr Michael Gray (Dept of Engineering) and Dr Laura Spiers (Dept of Oncology) have been working with the Department of Pathology in the Oxford University Hospitals NHS Foundation Trust, to help characterise the efficacy of this approach, by assessing thermal and acoustic ultrasound properties of the ex vivo pancreas.
This new knowledge will be directly applied to patients in the new early phase clinical trial, PanDox (targeting pancreatic cancers with focused ultrasound and doxorubicin chemotherapy). This builds on the successful TarDox trial, which already demonstrated FUS-induced heating resulted in improved delivery of the ThermoDox® encapsulated chemotherapy drugs to liver metastases from various primary cancers.
The effect in the TarDox trial was such that a positive response to therapy from the tumour was seen after only a single treatment cycle in 4 out of 7 patients, even in cancers as colorectal adenocarcinoma (which is not known to respond to conventionally administered doxorubicin). These results suggest that if the cytotoxic threshold needed to successfully treat a tumour can be reached, then a positive response may be achieved without unacceptable toxic consequences on the patient.
The upcoming PanDox trial translates this approach to patients with non-resectable pancreatic adenocarcinomas. It will combine focused ultrasound to generate heat with ThermoDox® delivered into the blood.
The main aim of PanDox is to determine whether this novel approach to treating pancreatic cancer can enhance the amount of drug delivered to tumours that cannot be surgically removed. Secondary aims will assess tumour response and procedural safety. The first patients will be recruited from early 2021.
About the PanDox Team
Prof Constantin Coussios, PanDox Priniciple Investigator, is the Director of the Institute of Biomedical Engineering. His area of interest is in the study of drug delivery systems and improvement of delivery into tumours. He founded and heads the Biomedical Ultrasonics, Biotherapy and Biopharmaceuticals Laboratory (BUBBL), a research group of 4 faculty and some 45 researchers working on a wide array of therapeutic applications. He is also serves as the Director of the Oxford Centre for Drug Delivery Devices.
Dr Laura Spiers is a doctor of Medical Oncology. She is currently undertaking a DPhil in Oncology with the Institute of Biomedical Engineering, investigating ultrasound-enhanced drug delivery.
Dr Michael Gray is a Senior Research Fellow, interested in the clinical therapeutic potential of ultrasound.