Cancer at Oxford

What made you focus your research on cancer?

When I first started in medicine 30 years ago, cancer was still a devastating diagnosis. The vast majority of patients diagnosed would have a very limited life expectancy.

I feel very privileged and proud to have been able to actively contribute to major improvements for cancer patients spanning from improvements in supportive and palliative care all the way to actually curing or controlling many cancers including those of the blood system with simple tablet treatments, when only a few years ago we performed bone marrow transplantation or gave very intensive chemotherapies that had a lot of side-effects.

What has your research focused on so far?

In the clinic, my main focus was on testing these new 'targeted bullet' treatments in patients looking for side-effects, how they compared against the best available standard treatment and how affordable they would be for the NHS.

In the laboratory, we then also tried to see whether we could identify patients who might respond better than others to certain treatments by directly analysing the cancer cells and looking for changes in the genetic make-up of those abnormal cells.

This led me to understand that further improvement in cancer outlook will critically depend on detecting and treating cancer earlier before the cells can accumulate too many changes.

Through a partnership with cancer doctors and scientists in Tanzania and Uganda, I realised that early diagnosis is also key to solving the global cancer pandemic.

We need to work much closer with our colleagues from around the world if we want to solve the problem of inclusion and diversity back home.

So, currently, my research interest in the UK and also in East Africa focusses on identifying traces of cancer really early from a simple blood test and on helping to evaluate the new treatments in patients of African descent. 

What is different about Oxford's approach to researching cancer?

Oxford is a great place to work as there are so many opportunities for local collaboration.

Oxford also nourishes academic freedom, so for as long as the science is excellent and the funding has been identified, researchers are pretty independent to get on with testing their hypotheses and ideas.

Increasingly, outputs are also measured with regards to impact.

This is great for someone like myself who is mostly interested in improving the outlook for patients and not so much in writing clever research papers.

What do you think the future holds for cancer research?

The future of research generally in the UK is difficult due to loss of funding and collaboration opportunities with Brexit and then also because of the pandemic.

Specifically for cancer research, the pandemic used up a lot of funding, existing research infrastructure and human resources both for routine care and also for clinical research.

As a result, unfortunately, patients with cancer were diagnosed really late during lockdown and some of the root causes of this have still not been resolved.

This means that recruitment into clinical trials of cancer treatments is still lacking behind a lot. We really need to make a lot of changes. One of them is to conduct research closer to home as patients are afraid to attend hospital.

We also need to engage people much more into cancer screening programmes and to test new ways of screening for cancer for example by using simple blood tests. I have been involved in this type of research and there are a number of firm plans to roll out studies in this area over the next couple of years.

So, overall, I believe that the UK with its unique health system and excellent research institutions offers a lot of opportunities, but we cannot do it alone and need international partnerships across the entire globe.

What made you focus your research on cancer?

I actually do research using large scale linked electronic health records, across multiple areas, of which cancer is a significant one.

I think the motivation is the potential to generate new knowledge which has the potential to improve patient care as well as make the NHS more efficient.

Compared to similar economically developed countries, the UK has a poor record for diagnosing cancers with many diagnosed at a late stage, when curative treatment is not possible.

For example, the UK has one of the lowest survival rates for colorectal cancer in Europe which is thought to be partly related to late presentation, delays in diagnosis and delays in treatment. 

The five-year survival for early-stage colorectal cancer is greater than 90% compared with 10% for widespread cancer at diagnosis.

Evidence suggests that increased awareness of symptoms and earlier diagnosis could help improve treatment options and improve five-year survival. It has been estimated that such an approach might save 5,000 lives even without any new medical advances.

So there are huge opportunities to improve the early diagnosis of cancer by helping raise public awareness of symptoms but also by providing GPs with interactive evidence based tools and utilities to help flag the people most likely to have an undiagnosed cancer for further investigation and hopefully earlier detection.

Similarly we can improve early diagnosis of cancer through a more nuanced approach to cancer screening which takes account of people’s prior risk of cancer (for example, risk factors such as age, smoking, family history) to help prioritise those at highest risk for targeted screening or more frequent screening.

What has your research focused on so far?

Before joining the University of Oxford in 2019, I was Professor of Clinical Epidemiology and General Practice at the University of Nottingham and medical director of a medical software start up company (ClinRisk Ltd) which for a number of years.

During this time, we undertook research to help identify early symptoms of a range of different cancers. These algorithms were then developed into software tools used in GP surgeries (collectively known as the ‘qcancer tools’ (www.qcancer.org )).

We have also been working on a more systematic and individualised approach to cancer screening by developing risk stratification tools. These tools have the potential, in time, to replace the relatively crude approach to screening which is often only based on age.

Finally we have been looking at outcomes for patients once diagnosed with cancer to help better predict these, again taking account of more individualised factors and also enable the predictions to be updated over time.

What is different about Oxford's approach to researching cancer?

The unique thing (about Oxford's approach to cancer research) is the combination of curiosity driven original research questions, excellent research staff, the University being home to some of the worlds largest and best clinical databases for research, and the ability to be able to translate results of research into impactful real world benefits for patients.

What do you think the future holds for cancer research?

The more we can personalise risk at various key points in the pathway (from screening, to early detection to information on prognosis) then the more we can target interventions to help improve patient outcomes AND the better we can communicate with patients about the options to help them make informed decisions about next steps AND help the efficient use of scarce NHS resources.

What made you focus your research on cancer?

At the beginning of my career as a clinician I came face to face with the limitations of cancer treatment.

It's these patients and their stories that inspired me to become a cancer researcher and still motivate me to this day. We’ve seen terrific progress in the last 25 years, but there are still millions of patients dying from cancer every year who need us to do better.

What has your research focused on so far?

I've been involved in the development of new drugs to treat cancer. At first these were targeted agents but latterly I’ve focused on immunotherapies.

They are really exciting because they’re the first treatments that can cure metastatic cancers.

They are not magic bullets however and more work needs to be done to understand why only a minority of people respond that well, and why severe side effects happen to some patients. 

What is different about Oxford's approach to researching cancer?

The challenges of cancer can’t be tackled by individuals, however gifted.

Progress needs multidisciplinary teams working together, bouncing ideas off one other. If you make a novel observation, there is almost always an expert somewhere in the city who can help you make sense of it and take it further.

There is so much exciting work going on in Oxford. Bringing this to patients in the clinic means we can to deliver better care really quickly.  

What do you think the future holds for cancer research?

We have never known more about our patients and their cancers than we do today.

When I started out we didn’t have the tools to gather this sort of detailed information, whereas in future progress will be about making sense of the data we generate.

Creating new tools to integrate and analyse different data sets to obtain insights relevant to patients represents the greatest challenge for cancer researchers.

For clinicians like me, translating these insights to inform the decisions taken with a patient about their treatment is always the goal.

What made you focus your research on cancer?

My interest in cancer medicine started in the early 1990s when my grandmother was diagnosed with colorectal cancer.

I was a medical student at the time so the experience was formative. Initial surgery was unsuccessful, chemotherapy was deemed futile and she was left to die without treatment.

That personal tragedy and the sight of many overcrowded and underfunded cancer wards taught me that, in terms of innovation, cancer was the underdog.

Cancer treatment has massively improved since then but we still have such a long way to go.

My interest in basic research was peaked in Cambridge when I conducted a project with fruit flies. Despite their physical differences to the human species, they share 40% of their genes with us and are fascinating research tools.

It was during this time that the human genome was sequenced and I had a whiff of just how thrilling research could be.

What has your research focused on so far?

Since those fruit fly days my research has been on messenger RNA (mRNA) and the proteins that stick to it called RNA binding proteins (RBPs).

We assume that mRNAs are reliable middle men, taking a genetic message and ensuring it is accurately converted into protein. But in cancer cells the mRNAs are led astray by RBPs and are amplified or destroyed.

We have gone from thinking there were only 30 RBPs in the cell to realising there are over 2,000 and that they are menacing contributors to cancer behaviour.

Even before the COVID-19 mRNA vaccines came into existence, RNA research has been strong in the UK, and RNA biologists from around the country are currently working collectively with CRUK and pharmaceutical companies to develop treatments directed against RBPs that will enter clinical trials soon.

What is different about Oxford's approach to researching cancer?

Simple, its approach to a problem.

I have worked in many hospitals and research centres during my career but Oxford is unique in its imaginative and innovative approach to challenges.

This was exemplified during the pandemic when teams from many different areas of research came together to prevent and treat COVID-19.

Similarly, you can get a collection of scientists together around a cancer conundrum and the ideas just fly!

But it doesn’t stop at the ideas stage, Oxford has a tradition of delivering these innovative concepts into the clinic.

As a researcher in Oxford, this means I can realistically expect to translate my work into clinical practice during my career.

As director of Oxford’s cancer trials unit OCTO, I also oversee the translation of innovations from other scientists, inside and outside Oxford.

Academic trials units like OCTO are vital assets for UK innovation as they support concepts that are perhaps not yet commercial or sit at the interface between the lab and big pharma.

A particularly rewarding aspect of my job is supporting these projects to become future cornerstones of anticancer treatment.

What do you think the future holds for cancer research?

Where do I start?

I believe the future will be one of information ownership with the power shifting to patients who will have an intimate knowledge of their genetics and their risk of many diseases including cancer.

Treatments will be tailored so that the empirical trial-and-error approach will become redundant. People with a strong risk of a particular cancer will be vaccinated to prevent it and vaccine programs will replace screening.

This sounds futuristic but is perfectly achievable.  Much of this approach requires “big” data collection and interpretation, but also closer working between scientists and patient groups to ensure trust is maintained.

At a molecular level, we still need a better understanding of how normal cells turn into cancer. It is clear that some cells in our bodies hover in a ‘precancerous’ stage for decades before becoming cancers.

During this time, these rogue cells are invisible to classical detection methods (e.g. CT scans or blood tests), respond differently to treatment and do not display the traditional ‘hallmarks’ we associate with cancer cells.

However, unlike cancer cells, these precancers have an “off switch” and can return to normal under certain circumstances. The challenge for cancer researchers is knowing how to flick this switch. As one aspect of it involves RNA binding proteins, this subject is keeping my lab occupied.

With the cancer research that is currently underway in Oxford, as well as nationally and internationally, I am optimistic about the future. I believe that, by the time my children reach their old age, deaths from advanced cancer that so haunted previous generations will be a thing of the past.  

What made you focus your research on cancer?

I did my PhD with Prof George Stevenson at the Tenovus Lymphoma Research Labs at the University of Southampton which was one of the one of the few labs in the world pioneering immunotherapy in the 1970s. 

This was in the days when people were talking about using anti-tumour antibodies to deliver the “magic bullet”, and George’s team – and separately - Ron Levyy’s group at Stanford had identified a “personalised” target antigen on B cell lymphomas.

We made antibodies to these and showed that you could cure cancer in guinea pigs and part of my project was to work out the mechanism of action of the antibodies with a view to engineering them using chemistry (my degree was in biochemistry). 

Unfortunately there was a general perception at the time that monoclonal antibodies (discovered ten years before I started my PhD) had failed to deliver the goods as therapeutic agents, and in the cancer field the biotech/pharmaceutical industry rather unceremoniously dumped monoclonals to focus on small molecule therapeutics. 

By 1986, though, I was hooked on the idea of harnessing the specificity inherent in our immune system to fight cancer, and felt it was time to learn about another kind of immune recognition – by T cells. 

I joined Herman Eisen’s lab at the Cancer Center at MIT to join a growing number of scientists throughout the world who were trying to fathom the basis for T cell specificity, then set up my own lab in Oxford in the early 1990’s without much thought for cancer as a disease yet hungry to know how killer T cells recognised virus infected cells with such exquisite specificity. 

I eventually got a chance to re-unite my interest in cancer immunotherapy with T cells when I was appointed Professor of Experimental Oncology at the University of Southampton in 2000 where I worked with oncologists, scientists and mathematicians to investigate cancer-specific killer T cells and to bring some of this basic knowledge closer to the clinic.

What has your research focused on so far?

I’ve spent most of my time investigating a pathway called antigen processing and presentation which is how cancer cells alert the immune system to the fact that they are abnormal.  Understanding this pathway is a route to devising new therapeutics, like vaccines or receptor-based therapies such as CAR-TcR. 

It is also becoming increasingly important for understanding how cancers can evade immune detection, and what the hallmarks of an effective immune response to cancer are. 

When we know this – we will be in a good position to select the right immunotherapy at the right time for individual patients. 

I am interested in ways of predicting how an individual will respond to a particular immunological treatment, be it vaccination or other kinds of immunotherapy and I have worked closely with mathematicians and computational biologists over the years to develop tools to simulate immune responses. 

Hopefully these are going to help us to tailor cancer treatments to individual patients better in the future.

What is different about Oxford's approach to researching cancer?

Oxford's cancer research community is huge (about 900 researchers at the last count) and spans all disciplines. 

I’m a firm believer that transformational insight into a problem usually comes from bringing together experts from different disciplines who can look at it from different angles and reflect together to give it three dimensions, and the collaborative ethos in Oxford means that this kind of multidisciplinary approach is the norm. 

This is coupled with a strong desire (and a track record to go with it) to use new knowledge and innovative approaches to improve global health and wellbeing. 

Oxford Cancer is our way of helping this large world-leading research community to focus on major challenges facing prevention, detection and treatment of cancer to bring about rapid change for the better.

What do you think the future holds for cancer research?

I’m very optimistic about the future – particularly about using immunological approaches to treating and, who knows, even preventing cancer – at least for individuals who are at very high risk. 

As I said, I began my research career at a time when immunotherapy was futuristic, and it has been very rewarding to see it become reality.

For example, in the field of targeting cancer with monoclonal antibodies, we have seen the leukaemia antigen CD20 go from discovery in Stu Schlozman’s lab at the Dana-Farber Cancer Institute in 1980 to the first ever monoclonal to receive Food and Drug Administration (FDA) approval in oncology as Rituximab in 1997 and then become one of the most successful anti-cancer treatments ever. 

Other immunotherapies are on the same trajectory, and with more research, I expect to see most cancer types become amenable to some kind of immunology-based treatment in my lifetime.

What made you focus your research on cancer?

I chose to study science at University and have been passionate about the subject ever since.

I am fascinated by the fine-tuning of cellular processes that control cell growth and division and how these are disrupted in diseases such as cancer.

I believe that fundamental cell biology research is crucial for understanding how cancers initiate and progress, so that we and others can innovate new solutions for cancer prevention, early detection and treatment.

What has your research focused on so far?

I am a cancer biologist and my research has focussed on tumour suppression. If we can achieve a detailed understanding of this process, this will help us to develop strategies for cancer prevention, early cancer detection and new therapeutics. The tumour suppressor p53 is the most mutated gene in human cancer and is mutated in nearly half of all cancers. Understanding how p53 can prevent tumour development and how to exploit its tumour suppressive function to kill cancer cells are key questions in cancer research.

We discovered the ASPP family of proteins that regulate p53’s tumour suppressor function. Further studies from us and others have now shown that the ASPPs are key regulators of cellular plasticity – the ability of a cell to change from one state to the other. Cellular plasticity is fundamental to cancer initiation and progression and a greater understanding is vital for improving patients' responses to therapy by preventing cancer cells from escaping immune surveillance and acquiring drug resistance.

I'm particularly interested in upper gastrointestinal cancers since these are highly plastic cancers with pre-cancerous conditions such as Barrett's Oesophagus, gastritis, Epstein Barr virus and H. pylori infection, making them ideal for exploring the steps needed for cancer initiation. Learning more about this process will present opportunities for detecting these cancers earlier and preventing cancer progression.

What is different about Oxford's approach to researching cancer?

We are lucky in Oxford to have so many researchers from different fields who can come together to research cancer. This allows us to benefit from the unanticipated impacts of what might traditionally be seen as “non-cancer” research.

Especially in early detection, where we are challenging ourselves to develop new highly sensitive technologies to detect even smaller, earlier cancers, it is crucial for engineers, physicists and chemists, with their advances in detection technology, to work together with fundamental cell biologists identifying specific biomarkers indicative of cancer and clinicians who are coordinating trials of patients.

With each discipline approaching the research from different angles and open minds to embrace new ideas, we have great opportunities to develop innovative solutions to some of the key challenges in cancer research and patient care.

What do you think the future holds for cancer research?

I think early detection and preventing cancer progression are key for improving the outcomes of people with cancer.

I am excited by the potential of new technologies and their application to both discovery research and healthcare settings. We are understanding in greater depth about how cancers initiate, which creates new opportunities for early cancer detection.

We are also able to gain a much more detailed picture of the molecular basis of each patient’s cancer, which will enable more targeted treatments of primary cancers, to prevent them from progressing further.