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About a decade after World War II, an unexplained phenomenon hit US sheep farmers in Southern Idaho.

In the affected area up to a quarter of new born lambs had underdeveloped brains and a single, central eye like a cyclops.

This, unsurprisingly, puzzled and seriously alarmed farmers, the US Department of Agriculture, and scientists.

A decade later, researchers discovered the root of the problem. Pregnant sheep grazing at higher altitudes were eating a plant called corn lily, which contained a harmful molecule that caused the birth defects.

That molecule is called cyclopamine, and its effects are intimately tied to one of the earliest ‘targeted’ cancer drugs: vismodegib (Erivedge), which is used to treat a common type of skin cancer – basal cell carcinoma – that has spread.

While the one-eyed sheep led to the discovery of cyclopamine, the development of vismodegib as a cancer treatment largely stemmed from research into gene defects in a very different animal: the fruit fly, Drosophila.

And now, 20 years after the key discoveries by our scientists that led to the drug, a missing part of the puzzle revealing how the drug works has been put into place.

A team of our scientists from the University of Oxford, publishing their findings in the journal Nature, have taken the first clear snapshot of the molecule targeted by vismodegib. And their discovery offers vital clues into how to tackle resistance to the drug.

But first, a little more of the drug’s history.

The birth of a medicine

In the 1980s, researchers were busy studying the ways that genes, and the molecules they provide a blueprint for, control how fruit fly embryos develop.

One such group of molecules, crucial to normal embryo development, is the ‘hedgehog signalling pathway’. They transmit messages that tell embryonic cells whether to divide and keep growing, or to stop dividing and specialise into a particular type of cell. A discovery that later won the researchers the Nobel Prize.

cyclopamine lamb

The effects of cyclopamine on a newborn lamb. Image credit: Public domain image via Wikimedia Commons

Fast-forward a decade and Professor Philip Ingham, a fruit fly biologist funded by our predecessor (the Imperial Cancer Research Fund), discovered that one of these molecules – called Smoothened – transmits the Hedgehog signal into the cell (more about their key discovery here).

And it’s at this point the stories of the one-eyed sheep and the fruit flies converge. Thanks to the work of the fruit fly biologists, researchers were able to make the link between the developmental abnormalities of the Idaho lambs and Hedgehog signalling. In 2002, they discovered that the corn lily’s devastating effects were caused by cyclopamine stopping Smoothened from working.

Next, cancer researchers were quick to draw on these discoveries too. They predicted that these developmental controls that tell a cell whether or not to divide or to specialise might be the same processes that are faulty in many cancers – and they quickly spotted that faulty Hedgehog signalling was at the root of many cases of basal cell carcinomas.

This all led to vismodegib, which was unveiled by drug company Genetech in 2012. It targets the Smoothened molecule but, as with many similar drugs, there’s a catch.

Hedgehog turns prickly

Drug resistance is a common challenge with ‘targeted’ drugs because cancers can evolve over time and escape treatment. At least one in five basal cell skin cancers become resistant to vismodegib treatment because new genetic mistakes in Smoothened stop the drug from working.

The problem is that researchers didn’t know what these faults were doing to Smoothened. And that’s because nobody had ever been able to work out its shape.

Producing a detailed picture of Smoothened eluded scientists for several reasons. The molecule is relatively large, and it’s covered in a thick layer of sugar molecules. It also has parts that will only dissolve in water mixed with parts that will only dissolve in oil.

It’s a tricky customer to work with.

But this is where one of our researchers, Professor Christian Siebold, and his team at the University of Oxford has stepped in. And, crucially, the fruits of their labour reveal how drug resistance emerges, potentially offering a way to stop it.

Smoothly changing shape

Because molecules are extremely small, one of the best ways to reveal their shape is to make it into a crystal before using X-rays to pick out the details.

“We started this project to determine the exact structure of Smoothened back in 2012”, says Siebold. “But it took us three years to find the exact technique and conditions to get this protein to form crystals we could study.”

But once they cracked it, the structure revealed new, crucial information about Smoothened and vismodegib.

Cells are enveloped in an outer layer of fat, called the cell membrane. And Smoothened is wedged inside this layer. It has a portion inside the cell, a portion that sits in the fatty cell membrane, and a portion that pokes outside of the cell, says Siebold.

“Vismodegib works by sticking to Smoothened in the part of the protein that crosses the cell membrane,” he adds.

Smoothened is like an antenna, picking up a signal from outside a cell and transmitting the information inside. But before it can transmit its signal, cholesterol needs to be added to the part of the protein sticking out of the cell.

“When vismodegib sticks to Smoothened, it stabilises the protein in a certain shape that means cholesterol can’t help switch it on anymore,” says Siebold. “And that’s how vismodegib stops cancer cells receiving the signals that tell them to keep growing.”

But resistance to vismodegib is a growing problem. And Siebold and his team have figured out how cancers are escaping treatment.

“In these cases, newly acquired DNA mistakes affect the part of the Smoothened where the drug sticks, physically blocking the interaction and stopping vismodegib working,” he says.

Pushing cancer back into hibernation

According to Siebold, this means new approaches are needed to tackle vismodegib-resistant skin cancers.

We discovered that cholesterol sticks to another part of Smoothened than vismodegib does – they’re not competing for the same space. And this opens a new avenue to fight drug resistance

– Professor Christian Siebold

“We discovered that cholesterol sticks to another part of Smoothened than vismodegib does – they’re not competing for the same space. And this opens a new avenue to fight drug resistance”, he says.

Their findings open up an opportunity to develop a second line of attack – a drug that stops cholesterol attaching to Smoothened another way, turning off cancer’s faulty instructions to grow.

This discovery could be the first step towards developing a new treatment for people with an advanced type of skin cancer that’s stopped responding to vismodegib.

Or giving people a ‘double whammy’ – a combination of vismodegib with a second drug that blocks Smoothened another way – could be more effective at stopping cancer from escaping treatment and coming back.

And it could be important for people with other types of cancer in the future, too.

Vismodegib is still being tested in clinical trials for other types of cancer driven by faulty Hedgehog signalling, including some types of bowel, lung, stomach and pancreatic cancers, and a type of brain tumour called medulloblastoma.

So understanding how resistance develops and finding ways to stop cancer escaping could have an impact on even more patients in the future.

Emma

Reference

Byrne, E., et al. (2016). Structural basis of Smoothened regulation by its extracellular domains. Nature. DOI: 10.1038/nature18934

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