Cancer research often makes the biggest headlines at the point when it begins to benefit patients – through the success, for example, of molecularly targeted drugs or the new immunotherapies.
The Institute of Cancer Research, London, is very well known for this kind of ‘translational research’ – where we move new research ideas and approaches out of the laboratory and into the clinic for the first time. This in turn leads on to later-stage clinical research, where the benefit for large numbers of people with cancer is eventually demonstrated in larger trials.
In recent weeks, we’ve published a couple of major translational and clinical research achievements with our hospital partner, The Royal Marsden – setting out how targeted therapies could be used in advanced prostate cancer, and how viral therapy can benefit patients with malignant melanoma.
These types of translational and clinical research are incredibly important – but they are only part of the picture.
In order to come up with innovative approaches to cancer treatment, we need first to have made exciting new scientific discoveries that illuminate our understanding of the molecular basis of cancer – answering fundamental questions such as what molecules control how cells behave?; how do these molecules change to cause the disease?; and how exactly do such changes convert a normal cell into a cancerous one?
First understand – then translate
It’s only through understanding the fundamental mechanisms underlying cancer that we can figure out how to intervene very specifically by developing a new targeted treatment. Otherwise we are shooting in the dark.
This earlier stage of research goes by a number of names – basic research, fundamental research, discovery research, exploratory research, or sometimes ‘pure’ or ‘blue skies’ research.
Basic research generates and tests new ideas, principles and theories about the world. The research findings can often be surprising and unexpected.
Some scientific research institutions specialise more on basic research while others focus to a greater degree on the translational or clinical phases. And they can be very effective at what they do.
But here at the ICR, we have always believed that to defeat cancer it’s essential that we carry out basic research on this disease in tandem with translational and clinical research. What’s more, we believe that all of our research needs to be integrated closely with the care of cancer patients.
This is why the ICR’s partnership with The Royal Marsden is so important.
Being comprehensive – the value of integration
The close integration of basic, translational and clinical research with cancer care allows us to be what is known as a ‘comprehensive cancer centre’ – a term initially used in the US where the definition given by the National Cancer Institute (NCI) is: “a cancer research center that gets support from the … NCI to do cancer research and provide services directly to cancer patients. Scientists and doctors at these centers do basic laboratory research and clinical trials, and they study the patterns, causes and control of cancer in groups of people.”
So why is it that basic cancer research – perhaps a misleading term since the science is in fact often highly complex and sophisticated – so very important? And why does it need to be integrated with more applied cancer research, and indeed with cancer care?
Fundamental cancer research is crucial because it leads to incremental and sometimes spectacular advances in our understanding of the molecular basis of malignant disease – explaining how tumours grow, invade, spread and evolve.
And it’s important to embed such basic research alongside more applied research because the fundamental insights into cancer that we obtain are in turn critical for the rational design and delivery of innovative and effective new strategies for diagnosis, prevention and treatment.
Furthermore by embedding our basic, translational and clinical research with the care of cancer patients we can ensure not only that the earlier-stage research is connected and channelled to clinical need, but also that we achieve the most rapid possible progression of new ideas and treatments into routine clinical practice.
Unravelling cancer’s secrets – in model organisms and humans
There is in fact another important reason for closely integrating basic investigations with research involving patients. In the past the fundamental breakthroughs in cancer biology have often arisen from research in the laboratory using a range of apparently strange organisms – viruses, bacteria, slime moulds, flies, worms, fish, mice and rats among others. These provide a ‘model’ for humans – a simpler system – in which fundamental principles of biology and disease can be defined.
Such approaches are still very valuable to us. But today, breakthrough discoveries in cancer research are frequently also now made through research carried out directly on human tissue and through the linkage of the molecular findings to, for example, disease outcomes in human patients.
This change owes much to the sequencing of the human genome and other technological developments – in fact powerful advances in technology are often critically important in opening up the new research approaches that lead to amazing breakthroughs in understanding.
Of course it goes without saying that all such research on human subjects and human tissue is carried according to the appropriate ethical and legal safeguards.
In his Nobel prize lecture, the iconic molecular biologist Sydney Brenner – who received his 2002 award in Physiology or Medicine (shared with Robert Horvitz and John Sulston) for his pioneering studies on the nervous system of a worm called Caenorhabditis elegans (and went on to sequence the genome of the pufferfish) – predicted a future of research in which: “I am convinced that we will make our significant discoveries in humans”.
Although we often talk about moving research from the lab to the clinic, or from bench to bedside, there is in fact no one, simple, linear pathway. Basic discoveries can be made in model organisms or in humans, and research moves very rapidly between the bench and the bedside and back again in what is more of an iterative process.
Our ability to integrate all the basic and applied phases of research allows the ICR and The Royal Marsden to operate very efficiently in this iterative way and to progress from fundamental discoveries to clinical translation and beyond with a real sense of urgency.
In the past it has taken decades to exploit a new discovery for the benefit of patients – now we can often initiate this translation in a few weeks or months.
My own passion for understanding and translating
I originally started my career in cancer research because I was intensely interested in the chemical machinery and signalling switches that control the cells in our bodies. I was driven by a passionate curiosity about how cells function and reproduce – and equally by how, when the chemical signals go wrong, this leads to disease.
At the same time, I was equally passionate in my determination to use this knowledge to fight diseases, especially cancer, with drugs.
Since then I have always sought to bridge basic and applied research and I find the interface between the two – and especially multidisciplinary team science – especially exciting and rewarding.
I’ve done this interconnected research in universities and research institutes, and also in a big pharmaceutical company and in biotechnology companies I’ve founded. My own experience is that true integration of the different phases of cancer research works best in a comprehensive cancer centre.
And it has certainly paid off for myself and my colleagues in the number of drugs we have discovered at the ICR – based on knowledge from fundamental research – and which have progressed into the clinic. Drugs like PI3 kinase inhibitors that block the action of one of the most common oncogenes in human cancer.
Over the 40 years I’ve been working in cancer research, we have learned an incredible amount about the fundamental basis of cancer – especially about cancer genes, and now whole cancer genomes, and the signalling switches and complex networks through which they work. And this work by researchers around the world has undoubtedly resulted in better and more targeted treatments.
I am convinced that making basic scientific discoveries about cancer remains crucial. We know a lot more than we ever did but there is much more still to learn.
The biggest breakthroughs in therapy come through innovative, discovery research – rather than simply producing variations on the treatments that what we already have.
If we want to make real advances in treating the cancers that aren’t currently treatable and to make the biggest differences to the lives of people with cancer, then it’s essential that we continue invest in early-phase, blue skies discovery research.
Probably the most powerful example is the extraordinary eventual impact of the discovery of the double helix structure of DNA by Watson and Crick in 1953 (the year after I was born) – forming the basis for modern genetics, the Human Genome Project, the biotechnology industry and much of biomedical research today.
Basic, translational and clinical research at the ICR
Further proof of the importance of basic cancer research discoveries can be found in the ICR’s history.
In the early 1960s, research at the ICR by Peter Brookes and Phil Lawley provided the first conclusive evidence that the basic cause of cancer is damage to our DNA. It was a discovery that changed scientific opinion dramatically – since up until that point, proteins had widely been thought to be the site of action for cancer-causing chemicals.
This paradigm shift paved the way for the ICR and others to discover, at first one by one, the particular genes that undergo cancer-causing changes in their DNA code – such as many genes that increase the risk of cancers that run in families.
That in turn led to the proposal by ICR scientists Mike Stratton and Richard Wooster, along with Andy Futreal, to sequence the entire genomes of cancers to find cancer genes – subsequently carried out at the Sanger Centre, then in large consortia around the world and now in many individual patients, as in our Tumour Profiling Unit at the ICR.
The subsequent advances we have seen in molecularly targeted therapies owe a huge amount to the findings of this initial basic cancer research as well to the elucidation of the signalling switch functions of the proteins encoded by cancer-causing genes.
Before the discovery of cancer genes the emergence of cancer drugs had to rely on a ‘black box’ approach. While this led to the discovery of many effective cancer drugs (such as melphalan, chlorambucil and carboplatin at the ICR) these acted more like a shotgun blast compared with the rapier-like action of targeted therapies – which accounts for the severe side-effects associated with chemotherapy.
It was an ICR team that discovered the BRCA2 gene – mutations in which dramatically increase the risk of developing breast cancer, and of several other cancer types.
As a result, families with a history of breast, ovarian and prostate cancer can now be assessed for future risk, and where necessary offered preventative measures or close monitoring. And the ICR’s Alan Ashworth and colleagues then built on the discovery of the gene by devising a brand new approach for treating women with inherited BRCA mutations – by using a new type of drugs called PARP inhibitors that specifically kill cancer cells with these BRCA defects.
We also played a major part in uncovering the role played by mutations in the BRAF gene in cancers such as malignant melanoma. This built on pioneering basic research by Chris Marshall, Richard Marais and David Barford and colleagues at the ICR to understand the signalling switches that are turned on in the pathway in which BRAF and other cancer genes operate.
Those basic research discoveries allowed others to make drugs to block the signals from the faulty cancer-causing versions of BRAF, giving us the new cancer drugs vemurafenib and dabrafenib. These are the first drugs in decades to be approved for lethal melanoma, and both have been recommended for use on the NHS by NICE. Other research originating at the ICR has produced new panRAF drugs that could be even more effective.
The drug abiraterone – discovered by Mike Jarman’s team at the ICR, trialled in the clinic by researchers at the ICR and The Royal Marsden and now benefiting thousands of men around the world with advanced prostate cancer – is an excellent example of integrated basic, translational and clinical research.
It was at the ICR too that Jacques Miller made the basic discovery that explained the function of a then poorly understood organ called the thymus – and its critical role in the immune system. That discovery underpinned all of modern immunology, and paved the way for the breakthrough immunotherapies which are now, 50 years later, producing such powerful anti-cancer effects in cancer patients.
The new immunology drugs have only emerged because of Miller’s original discovery and decades of research from many others that have elucidated exactly how the immune system recognises cancers.
The ICR’s basic research has also played a leading role in meeting what I believe to be the biggest challenge we face in treating cancer today – the genetic diversity of tumours, and their ability to become drug resistant.
The problem is that cancers evolve and develop resistance to treatment in a kind of Darwinian survival of the fittest – which I like to describe as the ‘survival of the nastiest’.
One of the ICR’s leading scientists, Mel Greaves, was a pioneer in what is known as 'clonal evolution' in cancer. This basic research provided a fundamentally new insight that changes the way we think about how cancers develop and behave, and is now beginning to shape the way we design and implement new treatments.
As Chief Executive and President of the ICR, a high priority for me is to foster an organisational culture which allows basic cancer research to thrive alongside the translational and clinical research that is essential to our mission.
It’s true that basic research can be unpredictable – in the discoveries made, and in where they lead. That’s in the nature of this kind of research. We can though make sure that the basic cancer research we do is integrated very effectively with the more applied work we carry out at the ICR.
We need to embrace the unpredictability of basic cancer research and continue to invest in it. Otherwise, we will deny ourselves the opportunities to make those unexpected scientific discoveries that can, eventually, have a huge impact on people with cancer.
Without basic cancer research we have nothing to translate to the clinic.
Finding the right balance and making everything connect is crucial for success.
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