The story of vismodegib and skin cancer

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The course of drug development never did run smooth. Drug development pipelines – like the X-Factor – are littered with thousands of ‘hopefuls’ who fail to make the cut.

Very few drugs survive the arduous journey from bench to bedside, and those that do often emerge ten to twenty years later, bearing little resemblance to their former selves.

In fact, only about one in ten drugs initially tested in patients make it through to routine use. So it’s always good news when an experimental drug makes it all the way through the difficult journey  of tests and clinical trials.

As we reported in 2012, vismodegib (Erivedge) – a skin cancer drug that our work helped shape – was described as “the greatest advance in therapy yet seen for this disease” in the prestigious New England Journal of Medicine. And in 2013, the drug was approved by the European Medicines Agency and will be available in England for NHS patients through the Cancer Drugs Fund.

So in the latest of Our Milestones series, we’d like to tell the story of Professor Phil Ingham, and how his fundamental research in fruit flies and fish evolved into a drug that could revolutionise treatment for patients with advanced basal cell carcinoma – a type of skin cancer.

Molecular GPS

Soon after sperm meets egg, we stop being a microscopic cluster of identical cells. So our developing bodies need some sort of ‘map’, to work out where the head should go, and to make sure that ten little toes appear at the ends of our feet.

Somehow, we acquire a molecular GPS, and our cells start to distinguish themselves from their neighbours. This impeccably choreographed passage from ‘amorphous blob’ to ‘person’ has fascinated and infuriated scientists for centuries.

Pretty fly for an eye guy

For many scientists, the easiest way to study this was in fruit flies (also known as Drosophila melanogaster, or just Drosophila for short).

Drosophila biologists were often viewed with a certain sense of amusement by their colleagues who simply couldn’t understand what fly development could possibly have to do with human health.

But during the 1980s, everything changed. Researchers studying the fly’s eye noticed that one of the molecules they were working on bore striking similarities to molecules with known roles in human cancers.

As they pondered their data, something struck them: The developmental pathways told a cell whether or not to divide or to specialise – weren’t they the very processes that were faulty in cancer?

Not long afterwards, others showed that a gene controlling the formation of flies’ wings was almost identical to a gene that propels bowel cancer in mice (and we now know that the same gene is equally important in human bowel cancers).

So research in Drosophila ultimately revealed that the mechanisms controlling development and cancer were one and the same, something that biologists today take for granted.

How the hedgehog got its name

Fly biologists often name new genes after what developing flies look like under the microscope when the gene is deactivated.

In 1980, two scientists from the European Molecular Biology Laboratory in Heidelberg, Germany – Eric Wieschaus and Christiane Nüsslein-Volhard – had noticed that embryos lacking a particular gene were stumpy and covered in tiny bristles, just like a well-known prickly nocturnal creature.

They called their new gene ‘hedgehog’.

Quirky name aside, researchers were intrigued by hedgehog because cells seemed ‘lost’ without it– unable to tell front from back. In effect, they’d lost their GPS. So what was going on?

A team led by Phil Ingham, then based at the Cancer Research UK laboratories in Oxford, decided to find out.

Smoothened operator

Ingham’s team figured out how hedgehog was working. The hedgehog gene isn’t active in all cells in the developing embryo; it’s only ‘on’ in thin strips of cells that run all the way along the embryo.

When it’s ‘on’, cells make and release a protein molecule (also called hedgehog). In papers published in Nature in 1989 and 1991, Ingham showed how nearby cells ‘grab’ hedgehog using a second molecule on their surface, known as ‘patched’.

And 1996, Ingham’s lab – now based at our London Research Institute, showed that a third molecule called ‘smoothened’ transmitted the ‘hedgehog’ signal inside the cell.

The diagram below shows how the pathway works.

But how does this equate to a ‘GPS’ system? The team’s key realisation was that hedgehog molecules don’t travel far, so levels aren’t the same around the whole embryo. Instead, a concentration gradient is set up, with cells closest to the central strip of cells receiving a strong signal, and those further away receiving a weak one.

This signal strength acts as the molecular GPS – telling cells where in the developing embryo they are. This helps cells decide what to become when the time comes to specialise into certain parts of the body.

These were exciting discoveries but no-one at the time, not even Ingham himself, realised how profoundly important they were soon to become.

Hedgehog and cancer

Ingham next set his team the challenge of locating hedgehog’s equivalents in vertebrates (the large group of organisms that includes us humans, as well as all other mammals, and fish and birds).

Together with colleagues in the US, his efforts were rewarded with the identification of not one, but three Hedgehog-like genes in vertebrates: they called these Desert hedgehog, Indian hedgehog and – a sign of the video-gaming times – Sonic hedgehog.

Today’s scientists would struggle to find an aspect of the vertebrate body plan that did not depend on hedgehog signalling. And we now know that inherited mutations in the hedgehog gene – or in other parts of the pathway it controls (such as patched and smoothened) – are usually lethal, or associated with serious developmental defects.

And it wasn’t long before faults in the hedgehog pathway were found in cancer.

First, faults in the human counterpart of patched were found in patients suffering from a cancer-linked condition called nevoid basal cell carcinoma syndrome (NBCCS, also called Gorlin syndrome), an inherited disorder associated with developmental abnormalities.

Next, faults in smoothened were found to underpin the formation of a type of skin cancer called basal cell carcinoma (BCC), which affects about 100,000 people a year in the UK.

Finally, faulty hedgehog signalling was later discovered in several other cancer types, notably medulloblastoma, the most common type of childhood brain tumour.

With the pathway now firmly linked to cancer, Ingham’s early discoveries in the fly suddenly had greater implications for human health than he could have imagined.

Indeed, the significance of these findings was obvious: drugs that target hedgehog signalling could help treat cancer.

Ingham is now based at the A*Star Institute of Molecular Biology in Singapore, where he’s still working on hedgehog signalling.

”We always believed that our work would have wider significance,” he told us, “but only in our wildest dreams did we imagine it could set the stage for a new cancer treatment.”

Basic research on a developmental pathway in a fruit fly had ignited a worldwide race to develop drugs to save human lives.

Vismodegib

In January this year, pharma giants Genentech won the race.

Vismodegib (also known as Erivedge), a drug that works by blocking smoothened, crossed the finish line and was approved in the US for treating BCC that can no longer be treated with surgery or radiotherapy.

The diagram below shows how the drug works.

And results published today in the New England Journal of Medicine suggest that vismodegib might represent a new “gold-standard” treatment for patients with BCC that is extremely advanced, or which has begun to spread. This is a tiny minority of patients with BCC – but they’re people for whom doctors had little left to offer.

One such doctor is Dr John Lear, a consultant dermatologist at Manchester Royal Infirmary who wrote an editorial about the new trials in today’s New England Journal of Medicine.

“Vismodegib could transform the treatment of this devastating type of skin cancer,” he told us.  Although advanced BCC is rare, the arrival of vismodegib is, in Lear’s view, “promising news for patients who would otherwise face disfiguring surgery that could, for example, result in the removal of an eye or an ear”

And that’s not all. Results from a second clinical trial – also published today – showed that vismodegib effectively prevented BCCs from forming in patients with Gorlin syndrome, so it might also prove to be a game-changer in the treatment of this condition.

And scientists are now exploring whether vismodegib might be effective in treating other cancer types – notably pancreatic and non-small cell lung cancer.

The drug isn’t yet available outside of clinical trials in the UK. But the manufacturers applied for a European License in December. We hope the drug will be made available – at a suitable price – as soon as possible.

But for us, the good news doesn’t end there. Cancer Research UK – via our technology arm, Cancer Research Technology – licensed some of Ingham’s early discoveries to the pharmaceutical industry. So we will receive a small amount of royalty from the sale of vismodegib; these funds will, of course, be ploughed straight back into our research. As well as directly helping cancer patients today, the money we raise from vismodegib could also fuel future advances against cancer.

Following the yellow brick road

Who would have thought that a cancer drug would have its origins in the humble fruit fly? Indeed, when Nüsslein-Volhard and Wiechaus (together with Edward Lewis) accepted the Nobel Prize in Physiology or Medicine in 1995, Nüsslein-Volhard expressed her surprise at how their work had evolved:

None of us expected that our work would be so successful or that our findings would ever have relevance to medicine… We want to express our sincere gratitude to the people who supported us during those years, when few people saw any future in poking thousands of tiny Drosophila embryos.

But we’re not surprised. A brilliant American screenwriter once wrote “great achievement has no roadmap” and when it comes to fundamental research, we couldn’t agree more.

For us, the hedgehog’s tale is a testament to the beauty and potential of basic biology. It’s certainly not the first time that our basic research has helped set the stage for a new drug that can help cancer patients, and – given the progress we’re continuing to make in our research centres across the country – we doubt it will be the last.

Safia

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• More information about vismodegib on CancerHelp UK

References

• Sekulic, A et al. (2012). Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma New Engl J Med, 366, 2171-2179 : 10.1056/NEJMoa1113713
• Tang, JY et al.(2012). Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome N Engl J Med, 366, 2180-2188 : 10.1056/NEJMoa1113538