Despite big improvements in survival, cancer is still one of the world’s biggest killers. Leading Cancer Research UK-funded scientists explain why it presents such a challenge – and look at how far we’ve come
Written by Natalie Grover for Guardian Labs
Part of a pancreatic tumour seen down a microscope, with tumour cells labelled in green, and different types of immune cell in pink, yellow, red, and turquoise. Image credit: Silvia Cusumano, Assya Legrini, Leah Officer-Jones, Dr Nigel Jamison and Prof John La Quesne
This entry is part 4 of 5 in the series Cancer Revolutionaries
Recent decades have yielded extraordinary progress in cancer survival, but many cancers remain deadly, with half of people diagnosed dying within 10 years. So why hasn’t science found a way to cure more people yet?
A major challenge is that scientists aren’t in fact targeting a single disease but a constellation of hundreds of diseases that are lumped together under the umbrella classification of cancer. This came about because all cancers start in the same way, with mutations in genes that control cell function.
Such mutations can fuel the unfettered replication of a single cell. If conditions are right, the cell grows and divides, escalating to millions of cells that may clump together to form a tumour – in which no two tumour cells are identical in a single tumour.
“I might have been pessimistic that we would ever be able to control these rapidly multiplying clumps of cells,” says Prof Sir Mike Stratton, director of the Wellcome Sanger Institute and a genetics expert.
“But time and again, the achievements of cancer research have mitigated that pessimism and converted it to optimism. It isn’t that one drug will wipe the whole lot [of cancers] off the map, but bit by bit we are eroding the mortality rates of many cancers.”
Stratton, leader of the Cancer Grand Challenges Mutographs team, which is working on a £20m project to look for unknown causes of cancer, adds: “We’re learning that research – finding out what is actually going on in cancer cells – is the route to new strategies for undermining the ability of cancer cells to behave in the way that they do.”
How many types of cancer are there?
While cancers may start in the same way, decades of research have shown that they evolve into very different diseases requiring a panoply of treatments. So far, scientists have classified more than 200 types of cancer, and found a myriad of genetic mutations underlying them.
Out of around 20,000 genes in the human genome, between 500 and 1,000 have been identified as contributing, when mutated, to a cell becoming cancerous. There is, however, a set of cancers for which the genes are still unclear, says Stratton, who is credited with identifying the breast cancer susceptibility gene BRCA2 among others.
It’s tempting to think that the way forward is to target all the genes known to be implicated in cancer by launching 500-plus drug development programmes.
But not only is this a huge task, it’s by no means certain that the drugs developed would be the answer to “curing” the different cancers. This is because tumours develop considerable genetic diversity as they evolve, and often become resistant to treatments as more mutations occur in cells.
Targeted therapies have been approved for a range of cancers including breast, liver and lung cancers, and are helping more people to live longer. For now, though, the search for more “precision” treatments goes on. “There is a set of cancer genes … that are switched off by their own mutations,” Stratton says. “So how do we use those genes in order to develop new therapies?”
What are we doing to cure more people?
Drug resistance is one of the biggest challenges in cancer – that’s why it’s so important to diagnose cancers early when treatment is more likely to be successful, says our chief clinician Prof Charles Swanton, group leader at the Francis Crick Institute, co-director of the charity’s Lung Cancer Centre of Excellence and a consultant at University College London Hospitals (UCLH).
Early diagnosis isn’t always possible, for a range of reasons. For example, there are very few techniques that can detect small, early tumours, and some cancers simply don’t trigger symptoms early enough until they have already spread (or metastasised) – and it is at this stage that the oncologist’s toolkit of drugs often falls short.
Each cancer has a different suite of signals which it’s responding to
Robert Insall, professor of mathematical and computational biology
To help uncover the tricks that tumours deploy to evolve, spread and develop drug resistance, we are supporting the TRACERx clinical study for which Swanton is chief investigator. By following the progress of hundreds of patients with the most common form of lung cancer from the point of diagnosis onwards, the study views cancer through an evolutionary lens, and uses a vast array of cutting-edge techniques to monitor participants’ disease.
According to Swanton, the lessons already learned from tracking these patients are applicable to many types of cancer. For instance, the study has shown that tumours with a high level of genetic diversity have the worst clinical outcomes, and that tumours use an assortment of ploys to elude the immune system, including losing the “flags” on their cell surface that enable them to be recognised as problematic.
Overall, says Swanton, the major barriers to successfully treating metastatic cancer are the genetic diversity within tumours, the evolutionary fitness of cancer cells that allows them to adapt, and – of increasing focus – the ways tumours modify their local microenvironment to support their survival.
A ‘rogue organ’?
The tumour microenvironment is composed of non-malignant cells that have been hijacked by cancer cells to support and nourish the tumour. This allows the cancer to smother the body’s immune defence.
Typically, half of the cells that make up a tumour are non-cancerous, and include fibroblasts (for structural support), fat cells and endothelial cells (which can form blood vessels that deliver oxygen and nutrients, and eliminate waste), says Prof Fran Balkwill, whose work at the Barts Cancer Institute in London centres on the links between cancer and inflammation.
Better understanding of this microenvironment – and potentially “reprogramming” it – could restrict nourishment of this cancerous “rogue organ” and reawaken the body’s immune cells to recognise and destroy it.
Already this ecosystem of hijacked normal cells within tumours is being targeted by cancer treatments, whether immunotherapy or chemotherapy, says Balkwill, noting that it is likely that treatments in the future will be combinations of drugs that target malignant cells and this microenvironment.
What makes cancer ultimately so dangerous, however, is the suite of signals that induce it to move beyond its primary site into the blood, lymphatic system or other tissues.
Typically, chemical signals steer a cancer cell to move in a particular direction, but in many cases we don’t know what they are, says Robert Insall, professor of mathematical and computational cell biology at the our Beatson Institute in Glasgow. “So, if you’re looking at this theme of why isn’t cancer cured yet, it’s because each cancer has a different suite of signals which it’s responding to.”
In the case of melanoma, a serious form of skin cancer, Insall’s research suggests that the cancer cells themselves make their own spreading signals, creating the local instructions that direct them to spread.
“Other kinds of skin cancer are not nearly as scary because they either don’t, or rarely, spread. And one of the reasons is that they are not primed to drive themselves outwards in the same way,” he says. “My suspicion is that the most metastatic, the most deadly, cancers have this same property [as melanoma].”
Reprogramming a tumour’s microenvironment could reawaken the body’s immune cell’s to destroy it
Professor Fran Balkwill
What progress are we making?
Insights such as Insall’s continue to inform research into the biology of cancer, building on the decades of endeavour that have gone before. This burgeoning knowledge has transformed the way doctors diagnose and treat cancers – in the UK, for instance, survival rates have doubled in the past 40 years for all cancers combined. “On this journey to cure patients with cancer,” says Swanton, “I think we’re about half way there.”
The second half of this odyssey demands further research. Research that will not just benefit the cancer patients of tomorrow, but is keeping hope alive for people affected by cancer now who may have limited or no treatment options if their cancer progresses.
Eileen Rapley, a participant in the TRACERx study who is being treated at UCLH, and who has also been receiving an immunotherapy drug that has so far kept her cancer at bay, says: “When you’re diagnosed with cancer and you’re suddenly very dependent on other people, being able to contribute something makes it a little more palatable. You feel that at least this cancer is having a positive effect rather than a negative one.”
But funding for this type of lifesaving research has come under considerable strain, in large part due to the pandemic, with CRUK needing to reduce its planned spending for 2022-23 from £400m to £300m.
“Maintaining investment in cancer research and getting back to where we were in 2017, 2018 and 2019 is going to be absolutely crucial,” says Swanton.
“We are now getting to the point of being able to personalise medicines given to patients upon the genetic basis of their disease,” he says. “But we need new medicines to circumvent and overcome drug resistance in cancers that have spread, and new approaches to detect small, early stage tumours, and treat them before they become malignant – that’s where some of the major advances are going to come from over the next five decades.”
This article was originally published on theguardian.com as part of the Cancer Research UK and Guardian Labs Cancer revolutionaries campaign.
To dig deeper into why we haven’t cured cancer, we heard from Dr Alanna Skuse, Dr Mariam Jamal-Hanjani and Sir Leszek Borysiewicz in the latest episode of our podcast That Cancer Conversation.
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