The Enemy Within – 50 years of fighting cancer

Cancer has always been with us, affecting our species for many thousands of years. For most of that time there was little we could do in the face of such a powerful adversary, and it wasn’t until the 20th century that scientists made any significant inroads into understanding and treating the disease.

Arguably, the real progress we’ve made has only been over the past few decades.

To see how things have changed over the past 50 years, make yourself a cuppa and settle down to watch this hour-long documentary which we helped to put together, presented by leading science broadcaster Vivienne Parry.

And if you prefer words to pictures, read on for the incredible journey we’ve taken in the fight against cancer.

In search of the ‘magic bullet’ – the 50s and 60s

The story of our fight back against cancer really starts in the 1950s and 60s – an era that had well and truly shaken off the shadow of World War II and was forging ahead in all aspects of science and technology, culminating in man stepping onto the moon for the first time in 1969.

Researchers were buoyed by Sidney Farber’s discovery that combinations of certain drugs could treat childhood leukaemia and lymphoma with some degree of success. A type of cancer had just been cured with a single drug for the first time. So enterprising chemists and doctors in the US threw themselves into chemical warfare against the disease.

Sustained by the myth of the ‘magic bullet’, chemotherapy was hailed as the future of cancer treatment. Meanwhile in the UK, methodical radiotherapists and their carefully-rationed radium formed the backbone of cancer treatment in the NHS.

But outside the clinic, the mood was less optimistic. Cancer was a disease to be feared or mentioned only in whispers, and a diagnosis was tantamount to a death sentence. Surgery and radiotherapy – along with their damaging side effects – were the mainstays of treatment, as they had been since the turn of the century.

There was no screening, no prevention, and no cure. It wasn’t even clear what actually caused cancer – was it viruses, lifestyle, the environment, something in our own bodies or a combination of all four?

Something Had To Be Done.

That Something was the US War on Cancer. Goaded by rich and influential voices, such as Farber and his patron Mary Lasker, President Richard Nixon signed the National Cancer Act in 1971, committing large amounts of money and political will towards finding a cure, optimistically within the next decade. While other organisations around the world were also engaged in the same fight, this flamboyant gesture served to put cancer well and truly on the map.

At the same time, awareness of cancer was rising thanks to the work of advocates and activists, particularly breast cancer survivors. In the US, this was in no small part due to First Lady Betty Ford, who went public with her diagnosis of breast cancer.

Fighting the ‘War on Cancer’ – the 70s

Scientists threw themselves into this new river of research. Their endeavours led them to the discovery that cancer is the ‘enemy within’, driven by corrupted messages from our own genes and caused by a range of factors.

Researchers pinned down some of the external causes, namely the newly-identified viral culprits human papillomavirus, Epstein-Barr virus and hepatitis B. There was also growing evidence and anxiety about the link between cancer and smoking – although the tobacco companies did their best to downplay it and keep the Marlboro Man high on his horse.

In hospitals around the world, the doctors of the 1970s seized on newcomers tamoxifen and cisplatin. They also refined the toxic drug combinations of the 50s and 60s with impressive results, and started testing the benefits of chemotherapy alongside surgery and radiotherapy – a multi-pronged approach that now forms the mainstay of modern oncology.

They could spy on cancer within the body in greater detail than ever before, thanks to shiny new MRI, PET and CT scanners, improving on the two-dimensional world of diagnostic X-rays. And as the 70s rolled into the 80s, surgeons moved away from the radical techniques perpetuated for decades and refined their skills, aiming to preserve as many nerves and muscles as possible while still removing the cancer.

But as Reagan took the reins in the White House, and Thatcher asserted herself in Downing Street, the mood changed. Despite all the money poured into cancer and all the apparent advances of the past decades, the footsoldiers in the War on Cancer seemed to be fighting a losing battle.

Cancer was turning out to be a much tougher opponent than had been previously believed. Rather than one cause and one cure, every cancer type was maddeningly different and the ‘magic bullet’ was nothing more than a fantasy.

In a damning report published in 1986, John Bailar declared the War to be “judged a qualified failure”. Although there were pockets of progress, the vast majority of tumours remained stubbornly incurable, and any gains were blown away by the alarming rise in lung cancer thanks to smoking. At least the tobacco industry was starting to look a little less confident by this point, after a series of bruising legal challenges.

Unlocking cancer’s genetic secrets – the 80s and 90s

Away from the disillusioned doctors, scientists were opening an exciting new front in the conflict – one that would change the face of treatment in the years to come. The molecular biology revolution had arrived, revealing the true identity of the enemy (or rather, enemies) within us.

The truncated acronyms of oncogenes and tumour suppressors – the ‘accelerators’ and ‘brakes’ of cancer cells – and other genes danced across the pages of scientific journals. Ras, Myc, p53, Rb, VEGF, EGFR and many more double-agents yielded their secrets as lab techniques became ever more sophisticated. Researchers were also creating entirely new weapons in the form of monoclonal antibodies, based on the molecules produced by our own immune systems to seek out and destroy infections.

These efforts began to bear fruit in the 1990s, as the first wave of molecularly targeted treatments – specifically designed to home in on faulty molecules in cancer cells – reached clinical trials and then arrived in cancer clinics around the world. The antibody drugs rituximab (Mabthera), trastuzumab (Herceptin) and bevacizumab (Avastin) led the charge, and have brought benefits to many thousands of patients.

At the same time, large clinical trials were consolidating the use of chemotherapy and hormone therapy – step-by-step progress adding up to big survival benefits over the long term, particularly for breast cancer drugs such as tamoxifen.

The 90s also saw another shift in public perception of cancer, as the new-fangled “information superhighway” brought reliable information – along with an abundance of quackery and scaremongering – direct to people’s desktops. There was an increasing interest in what caused cancer and what we could do to prevent it.

From yoga to vitamin supplements, power lines to pesticides, the media caught on to the cancer craze. Ironically, they failed to point the finger at what was still the leading preventable cause of the disease – tobacco. When Bailar revisited his analysis of the War on Cancer in 1997, he found that any gains in survival were yet again overwhelmed by the looming shadow of lung cancer, although survival rates have climbed consistently – albeit slowly – in many countries since the mid-1990s.

From genes to drugs

If the 90s gave birth to the ‘-abs’ – antibody-based drugs – the next decade spawned the ‘-ibs’ – potent little chemical inhibitors that specifically targeted faulty molecules in cancer cells. Unlike the early chemotherapy drugs, which were often stumbled upon more by luck than judgement, these drugs were rationally designed, based on intimate knowledge of the biology of cancer.

The first, and probably still the greatest, example of these is imatinib (Glivec), which locks on to a faulty protein made by certain types of leukaemia.

Imatinib has effectively cured many patients whose cancers are driven by this rogue molecule, and has also proved useful in other forms of the disease fuelled by the same fault. And although they haven’t yet had the same profound effect as imatinib, other similar drugs – such as erlotinib (Tarceva), lapatinib (Tykerb), gefitinib (Iressa) and vemurafenib (Zelboraf) have followed, along with genetic tests to identify which patients will benefit from them, although they’re yet to replicate Glivec’s success.

Back in the lab, the main feeling during the 90s was one of frustration. Scientists were still making steady progress in understanding the biology of cancer and exposing its molecular weaknesses. In particular, the discovery of the breast cancer genes BRCA1 and BRCA2, and genes for hereditary bowel cancer had whetted researchers’ appetites for hunting cancer genes, but their tools were now hopelessly outdated.

They knew that the key to understanding the disease lay in the genome – the tens of thousands of genes that tell our cells what to do, when to grow, and when to die – but they could only study a handful at once. The ‘noughties’ brought the second genetic revolution in the form of speedy DNA sequencers, microarray readers and powerful computers to analyse the gigabytes of data these machines generate.

By 2003, the entire human genome had been sequenced, and as the decade progressed, researchers were analysing tiny differences in the DNA from thousands of cancer patients and their healthy counterparts. They could now pinpoint the gene variations that influenced not only the risk of the disease but how an individual might respond to treatment.

Along with the new targeted drugs, the stage was set for the advent of personalised medicine – tailoring treatment to the genetic makeup of a patient’s tumour rather than the traditional one-size-fits-all treatments of the past. Instead of talking about “bowel cancer”, “melanoma” or “breast cancer”, doctors can now divide patients according to the rogue molecules that are driving their disease.

Where are we now?

As new treatments come through and survival rates continue their slow but steady climb, increasing focus has been turned on the concept of survivorship – of living with, rather than dying from, cancer. And with it has come a greater interest in quality of life, making sure that we aren’t just buying some extra time at any cost  – but that they are months or years worth living. And if treatment is not successful, there are still more benefits that could be gained from improved palliative care at the end of life.

So how have things changed since those hopeful days of the 60s? And how will they change in the future?

Cynics still rant about the “cut, poison and burn” approach to treatment, yet today’s therapies are a world away from the brutal days of the early to mid-20^th century, and are changing year on year.

Despite the multitude of drugs in an oncologist’s arsenal today, the knife still cures more cancers than any other treatment and, thanks to keyhole surgery, it is less debilitating than ever. Although the radium of the early years has been replaced by more accurate linacs and proton beams, radiotherapy still cures more people than chemotherapy.

And while diligent clinical trials over the years have added up to huge survival benefits for some patients – notably in breast and childhood cancers, and early-stage disease – tackling cancer once it has spread and developed resistance to treatment remains a huge challenge.

Where are we going?

Scientifically speaking, cancer is complicated. Every new discovery throws up more unanswered questions, and tumours evolve and evade treatment faster than we can currently stop them. But we are narrowing down the ‘known unknowns’ and homing in on the gaps in our knowledge.

The imminent arrival of the thousand dollar genome and the ability to decipher the molecular signature of an individual’s own tumour has the potential to completely change the way the disease is routinely diagnosed and treated in the future. There is also hope that immunotherapy – turning the power of the immune system on cancer – will finally live up to its promise, after more than a decade of false starts.

As everyone knows, prevention is better than cure, and preventable causes of cancer still continue to claim a huge toll around the world. Smoking remains the chief villain, and though the introduction of smoke-free legislation in many countries has loosened the grip of the tobacco industry in the West, they have taken their trade elsewhere. China and Africa are their main targets, priming a tobacco timebomb that will explode into millions of lung cancer cases over the coming decades.

One in five cancers globally is caused by viruses and bacteria, which could be prevented by vaccination and antibiotics, respectively. The modern plagues of obesity and excessive alcohol consumption are having a significant impact on cancer rates in developed countries, posing the challenge of balancing personal responsibility with public policy.

Screening also has a vital role to play in reducing cancer deaths in the future, and has already saved many thousands of lives here in the UK through the bowel, cervical and breast screening programmes. Research is ongoing to develop effective screening tests for other types of cancer and refining the tests we already have, as well as making sure that patients have access to accurate information so they can make the right decision on their treatment.

There are millions of people around the world who are alive today after hearing the words “You have cancer” – in some cases many decades after their diagnosis. We are moving towards cancer being a chronic rather than fatal disease although there’s still a long way to go, particularly in lung, pancreatic and oesophageal cancers and in brain tumours. And although we’ve made huge strides in curing many types of cancer in children, we still need to find ways to minimise long-term side effects among those who are struck by the disease at a tragically young age, as well as tackling harder-to-treat childhood cancers such as brain tumours.

The challenge facing cancer researchers around the world is to work smarter, not harder. Their servers are bursting with data about the intricate genetic and molecular changes in cancer cells, but this has to be turned into more effective treatments. New initiatives to speed up analysis can help here, such as ‘gamifying’ data for the public to crunch, or borrowing techniques from astronomers.

The need for cross-disciplinary collaboration is also clear. Cancer research touches virtually all fields of science, from physics (radiotherapy) and chemistry (drug design) to mathematics (modelling tumour growth and analysing trial data) and, of course, biology. The upcoming Francis Crick Institute in central London is a prime example of this ‘melting pot’ approach, throwing together scientists across the whole gamut of fields to work on heart disease, infection, dementia, cancer and more.

The road from the lab to the clinic is long and tortuous, and the majority of new agents fall by the wayside, while the costs of drug development spiral ever higher. Speeding up this journey and developing smarter, faster clinical trials will be essential.

Thanks to advances in public health, infectious diseases and heart disease, many people are living longer. But, because cancer is mainly a disease of old age, this is a prime driver of rising incidence rates. At the same time, healthcare costs are increasing year on year. Policymakers and healthcare providers must ensure that they are prepared to fight cancer in the 21st-century and take advantage of the benefits that research continues to bring.

Based on the trend of the past half a century, sooner or later we will beat cancer. Let’s all join together to make sure it happens sooner.

Kat

• Read more about how our scientists have contributed to this progress in this blog series

Image credits

• 1950s scientist by University of Iowa Libraries, via Flickr under CC BY-NC 2.0
• Poppy field by Tony Hisgett under CC BY 2.0, via Wikimedia Commons
• HPV image by Unknown photographer [Public domain], via Wikimedia Commons
• Herceptin image by RedAndr under CC-BY-SA-3.0, via Wikimedia Commons