Imatinib – the dawn of targeted treatments

Mary Bacon was treated with imatinib for two years after she was diagnosed with CML in 2008

Thirty years ago, we published research that was a key early step in the journey towards the first genetically tailored cancer drug, imatinib (also known as Glivec, or Gleevec in the United States).

This drug changed the landscape, not just for those for whom it was designed – people with chronic myeloid leukaemia – but for cancer treatment as a whole.

Imatinib is unlike the conventional chemotherapy drugs that came before it. Such ‘cytotoxic’ chemo indiscriminately kills rapidly dividing cells. These include the intended target – cancer cells – but also some healthy cells like those lining the gut and mouth and hair follicle cells. Imatinib on the other hand, is specific to a molecule produced by certain cancer cells.

Imatinib featured on the front cover of Time magazine and was hailed as a “magic bullet”.  It was indeed a revolution of its time – after it was approved in 2001, bed-ridden patients who’d been given just months to live were up on their feet and re-energised, thanks to their cancer being eradicated by imatinib.

The story of imatinib – outlined in more detail below – is proof that if you understand the precise abnormality that is driving the cancer, there is hope for a cure. And we are proud that our early laboratory work provided a crucial stepping stone on the road to its development.

Early work

In the early 1980s, in the lab of our then Director General Sir Walter Bodmer, Cancer Research UK scientists were hard at work examining the DNA in cells. Imatinib was yet to be dreamt up, but these scientists were carrying out crucial early lab research that would increase our understanding of the genetic causes of chronic myeloid leukaemia and lay the foundations for this remarkable drug.

Nigel Spurr, Peter Goodfellow, Ellen Solomon and Walter Bodmer from the charity were working with colleagues from the National Cancer Institute in America and Galton Laboratories. They discovered that the ABL cancer gene was located on chromosome 9.

On the surface, this may not be the most exciting-sounding finding. But at the time, it was like finding a needle in the proverbial haystack – it was already known that nearly all (95 per cent) people with chronic myeloid leukaemia had a major fault in this chromosome. In these people, part of chromosome 9 breaks off and sticks to chromosome 22, forming what is known as the Philadelphia chromosome – a major discovery made a decade earlier by Janet Rowley at the University of Chicago.

Our scientists’ work opened up the question – was the newly located ABL cancer gene involved in this crucial disease-causing rearrangement?

A few months later, Cancer Research UK-funded scientist Nigel Spurr was part of the Dutch and American collaboration that answered the question. They demonstrated that this was indeed the case. The ABL cancer gene was definitely involved – it broke off from chromosome 9 and joined with part of chromosome 22.

A few years later, in 1985, the gene to which ABL joins on chromosome 22 was identified as BCR. And after further research, it became clear that it was the ABL-BCR ‘fusion gene’ that was fuelling the cancer – by making the cell produce a molecule (called a tyrosine kinase) that encourages white blood cells to incessantly grow and multiply.

Finding a drug

Imatinib (red) blocking part of ABL (green)

With the crucial molecular players identified, the hunt was on to find a drug that could stop them.

Biochemist Nicholas Lyndon then working for Ciba-Geigy (now Novartis) and Brian Druker who was training to be a cancer doctor at the Dana-Farber Institute in America, were inspired by the prospect. They had realised that if you could block ABL-BCR, you could potentially stop CML in its tracks.

Lyndon and his team set about screening hundreds of chemicals to come up with a drug that would block the tyrosine kinase. Together with Brian Druker, he tested some likely candidates on cells grown in the lab and hit upon one that worked – they tweaked it to develop imatinib.

Astonishing results

The drug worked in cells and mice, but would it work in patients? In the mid-1990s, Brian Druker led the team which carried out the clinical trials. The results were nothing short of astonishing. The drug worked quickly and effectively in patients for whom there had previously been no hope, and imatinib became the fastest drug to be approved in history.

Before imatinib, the only real option for CML patients had been debilitating treatment with interferon or a stem cell transplant. Now, the patients could take a tablet, once a day in the comfort of their own home, and there was no need to go to hospital for treatment. And because the drug was so targeted, the side effects were limited. As Brian Druker who led the trials sums it up, “In short, it is a simple, effective treatment that disables the cancer without disabling the patient.”

It is no surprise, then that in 2009, Lyndon, Druker and another colleague Charles Sawyers, were awarded the Lasker–DeBaker Clinical Medical Research Award for “converting a fatal cancer into a manageable condition”. And earlier this year, Druker, Lyndon and Rowley were given yet another prestigious award: the Japan Prize for their part in “the “development of a new therapeutic drug targeting cancer-specific molecules”.

What about other cancers?

Encouraged by the success imatinib had seen in treating CML patients, scientists then started to turn their attention elsewhere. Could imatinib produce a similar miracle effect in other cancers where tyrosine kinases were overproduced?

In 1998, some Japanese scientists found a possible candidate – gastrointestinal stromal tumours. These tumours develop from the cells of the connective tissues that support the organs of the digestive system – the gastrointestinal tract – and generally don’t respond well to chemotherapy or radiotherapy.

They found that gastrointestinal stromal tumours may be caused by faulty KIT genes. And faulty KIT genes were already known to make the cell overproduce tyrosine kinase – which meant that imatinib could work in these patients.

Soon, international trials were underway to test whether imatinib could indeed be used to treat gastrointestinal stromal tumours.

From lab to clinic

Having been involved in very early lab work twenty years earlier that had led to imatinib’s development, we were then involved at the other end of the spectrum – helping to test the drug in clinical trials for people with gastrointestinal stromal tumours.

Professor Ian Judson led these early trials at the Cancer Research UK Centre for Cancer Therapeutics at the ICR, in collaboration with EORTC Soft Tissue and Bone Sarcoma Group.

It was this important work that led to imatinib being approved to treat people with advanced gastrointestinal stromal tumours.  Today, a sample of a patient’s tumour needs to be tested first to see if it has a faulty KIT gene before they are prescribed imatinib.

And that’s just the beginning…

Imatinib set the stage for tailored cancer treatments. Today, there are many more targeted cancer therapies in use or in trials, several of which are underpinned by our work – erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), trastuzumab (Herceptin) and vismodegib (Erivedge), to name but a few.

Our part in the story of imatinib was small but significant, and something that we’re tremendously proud of. Nobody could have known at the time how far-reaching the consequences of our research on the ABL gene would be, but that is the way of laboratory science. We don’t always know where our research today will lead, but we do know that funding work to unravel the inner workings of cancer is crucial to find the cures of tomorrow.

Around 40 per cent of our research is on fundamental biology, and there are countless examples of biological insights in the lab that have laid the foundations for new cancer treatments. Where will discoveries made in our labs today lead to in the future? Time will tell, but there’s no doubt that more ingenious ways to beat cancer are around the corner.

Josephine

Reference

Heisterkamp, N. et al. (1982). Chromosomal localization of human cellular homologues of two viral oncogenes, Nature, 299 (5885) 749. DOI: 10.1038/299747a0