A lab at the Imperial Cancer Research Fund in the 1960’s
“Abiraterone gave me a lifeline. In my case, it’s been hugely successful at treating my cancer.” Alfred Samuels is one of the thousands of people with cancer around the UK every year who receive drugs as part of their cancer treatment.
Drugs can be given for different reasons, not just with the aim of eliminating the tumour. Sometimes they’re used to keep advanced disease like Alfred’s at bay. In other cases, it’s to prevent cancer coming back after surgery, to shrink tumours prior to surgery or radiotherapy, or make radiotherapy more effective.
To add to the complexity, there are different types of drug which work in different ways.
Some – generally called chemotherapies – target fast-dividing cells like cancer cells. Others, called immunotherapies, can be used to galvanise the body’s own immune system to treat the disease.
Yet more – so-called targeted therapies – are designed to target specific molecules on or inside cancer cells. And hormone therapies – like the abiraterone used to treat Alfred’s prostate cancer – work by disrupting a tumour’s reliance on certain hormones.
In all, there are hundreds of drugs available to treat the disease. And they all have one thing in common: they’re all the product of a painstaking global research effort.
To mark 20 years since Cancer Research UK was formed, from a merger between the Cancer Research Campaign (CRC) and the Imperial Cancer Research Fund (ICRF), we’ve delved into the research that led to many of the drugs in use today, and mapped these charities’ contributing role.
We’ve focused on 3 main steps in a drug’s journey to the clinic: discovery research, drug development and clinical testing. And we’ve identified more than 50 drugs where the hard work of scientists and doctors we’ve funded has helped hasten these drugs’ journey to patients.
It all starts with ‘why?’
Whether it’s understanding how ‘mustard gas’ chemicals used in World Wars kill cells, or working out how growth signals are transmitted to a cell’s nucleus, the first step in a drug’s journey usually starts with the question ‘why’? Why does a particular gene or molecule encourage cells to grow? Or, conversely, why does a chemical affect growing cells in a particular way?
In the case of early chemotherapy, it was pioneering work in the 40s and 50s that helped opened the door to the chemotherapy drugs in use today. CRC-funded chemists and biologists at the Chester Beatty Laboratories in London (now known as the Institute of Cancer Research) discovered exactly how the nitrogen mustard chemotherapy molecules damaged a cell’s DNA. And in doing so, they developed 3 new drugs – melphalan, busulfan and chlorambucil.
Scientists around the world have since built on their insights, developing drugs such as carmustine and lomustine. All of these drugs are still in use today and play a key role in the treatment of a range of cancers, including leukaemias, lymphomas and brain tumours.
Thirty years later, a humble PhD student at ICRF’s London Research Institute (now part of the Francis Crick Institute) uncovered something fascinating about a relatively unknown protein made by our cells, known as epidermal growth factor receptor, or EGFR for short.
“I’d had to wait for the evening for the one of the few computers in the lab to be free before I could begin to look at the data from my experiments. That night the computer came up with a match – EGFR was almost identical to a protein produced by a virus that causes cancer in chickens. It really was a ‘Eureka!’ moment – our own cells contained molecules that accelerated cancer growth.”
Professor Julian Downward’s observation overturned widely held ideas on the causes of cancer, which many had thought was caused by infection. It triggered a wave of research around the world that ultimately led to the development of drugs that target the EGFR protein – drugs that US data suggests are playing a role in reducing deaths from lung cancer
“It may have taken years for our findings to be translated into drugs to treat people with cancer, but even then we knew it was significant – my supervisor even came back into the office late that night to see what I was seeing.”
There are many more drugs built from the fundamental insights of laboratory research funded by Cancer Research UK and its predecessors.
For example, we supported work on yeast and sea urchins that’s led to new drugs for breast cancer, careful genetic studies that have opened the door to effective melanoma drugs, and painstaking unravelling of cells’ DNA repair mechanisms that’s led to drugs for ovarian, prostate, breast and pancreatic cancers.
Turning ideas into drugs
The next stage in getting drugs from the lab to the clinic is harnessing scientific insights to develop molecules that can be given to people as drugs – a process collectively called drug discovery. And we’ve played an important role here too.
Take abiraterone, for example – the hormone-disrupting drug currently holding Alfred’s cancer at bay. Abiraterone emerged from a quest to shut down a key step in testosterone production, and so slow or even halt cancer growth in prostate cancer.
In the early 1990s, researchers at our Centre for Cancer Therapeutics at the Institute of Cancer Research in Surrey were studying existing anti-fungal drug that could do this. But there was a problem: the body broke it down too quickly to be effective. Some clever chemistry led to a molecule they simply called ‘3’, which was able completely shut off testosterone production in mice. Taken to our Strathclyde formulation unit in Scotland, the prototype was developed into a tablet, opening the door to clinical trials. The rest is history.
There are many more drugs whose existence has been underpinned by researchers we’ve supported. In the 1930s, our researchers created a synthetic form of oestrogen called stilboestrol, which became a mainstay of prostate cancer therapy for decades, and opened the door to modern hormone-blocking drugs.
Carboplatin – a widely used chemotherapy drug – arose from our researchers’ work to improve platinum-based chemotherapy in the 1970s. More recently, our researchers in Newcastle and Cambridge have helped develop targeted drugs called PARP inhibitors.
Into the clinic
Once a drug has been discovered it needs to be tested in clinical trials, which are critical to ensure that the drugs are safe, effective and better than what’s currently available.
It’s a difficult path for a drug to walk, and it’s estimated that just 1 in 10 drugs entering first-in-human clinical trials end up making it all the way to approval.
Over 120 years Cancer Research UK and its predecessors have run thousands of clinical trials, from early, first-in-human studies that look at a drug’s safety and toxicity through to larger ‘phase 3’ studies that compare them to other treatments.
At the beginning of the clinical trial pathway sits our Centre for Drug Development, the world’s only charity-funded drug development facility. A similar size to a medium sized pharmaceutical company, it’s responsible for running the first-in-human clinical trials, including for 6 drugs widely available today – with 21 more in the pipeline.
One of these drugs, temozolomide, is now used worldwide as the frontline drug for people with glioblastoma, a type of brain tumour.
And beyond the vital work in bringing new treatments to patients for the first time, our research has led to the refinement of their use in later phase clinical trials.
Our Glasgow clinical trials unit, working as part of an international consortium, led the way in showing docetaxel could benefit women with ovarian cancer. Other trials we’ve funded have shown the best way to use drugs like fluorouracil for liver cancer, mitoxantrone for acute leukaemia and capecitabine in stomach cancer.
Alfred received abiraterone thanks to a clinical trial called STAMPEDE, which has been testing new combinations of drugs to see which may improve prostate cancer survival.
In the last 17 or so years since the study began, STAMPEDE has already changed clinical practice 29 times. In 2015 it showed giving men docetaxel in addition to standard treatment was beneficial – this led to change in NHS guidelines and transformed clinical guidelines across the world.
A few years later it showed that adding abiraterone and the steroid prednisolone to standard hormone therapy extended survival by a similar amount.
Around 10 years after his initial diagnosis, Alfred says STAMPEDE was an opportunity for him to not let statistics rule his life. “So far, the treatment has been working and my cancer is being managed well. While I’ll be on the treatment for the foreseeable future, it’s given me the chance to live life. I see the world differently now and I take stock of what I’m seeing.”
The (even) bigger picture
This long and winding road a new drug travels to reach people with cancer spans so many research areas, making it unsurprising that there’s rarely a single research group or organisation responsible for an individual drug. Drugs come about through collaboration, competition and a collective effort.
Through careful work – combing historic research papers, searching our archives and interviewing researchers – we’ve built a picture of how funding from Cancer Research UK and our predecessors has contributed to more than 50 cancer drugs in use today.
These drugs have had an extraordinary impact, offering options to millions. Thanks to data collected by the National Cancer Registration and Analysis Service, we’ve been able to calculate that the drugs that CRUK research has contributed towards, are used to treat 3 in 4 people with cancer who receive cancer drugs in England every year.
These drugs’ impact extends well beyond the UK. More than 20 appear on the World Health Organisation’s drugs list of ‘Essential Medicines’, meeting the most pressing needs of a country’s health system.
It’s a legacy we’re extremely proud of. But it means even more to people like Alfred. “I don’t think I’d be here today if it wasn’t for the trial, abiraterone and Cancer Research UK scientists who helped develop the drug,” says Alfred.
“I like Cancer Research UK’s approach and I see the value of what they’re doing. It’s real. It’s keeping people affected with cancer at the heart of what they do, and making a real difference for people like me.”
Catherine Pickworth is a research information manager at Cancer Research UK
About the project: We investigated the contribution of CRUK/CRC/ICRF funding to more than 80 individual cancer drugs in 3 separate research areas (underpinning research, discovery and development and clinical trials) through a comprehensive literature review and interviews with the research community. We identified more 56 drugs where contributing research was CRC/ICRF/CRC funded. We then used NHS Digital’s SACT database, which captures prescribing information of SACT drugs, to calculate the proportion of patients who are prescribed one of these 56 drugs, and therefore the proportion who have received at least one drug built on CRUK’s research.