Preventing aggressive prostate cancer

The way to prevent cancer could lie in a small number of people in the Middle East and remote parts of Ecuador. They have a rare condition called Laron syndrome, which means that the body doesn’t respond to growth hormone, resulting in dwarfism and almost complete protection from cancer.

The dwarfism caused by Laron syndrome is due to a genetic mutation that means they don’t produce enough of a protein called IGF (or insulin-like growth factor), and it’s low levels of this protein that could also explain why no-one with the syndrome has died of cancer.

From rare disease to chance discovery 

Growing cancer cells in the lab is a tricky process. Although they might grow out of control in the body, they need special conditions and nutrients to survive in a flask. So when Dr Val Macaulay found some cancer cells that grew without any added nutrients, she knew there was something special about them.

“I sent them to a colleague for testing, and he said ‘They’re chock-full of IGF.’” That led her to start looking into the importance of this protein in cancer.

Dr Macaulay is a medical oncologist at the Churchill hospital in Oxford, so divides her time between giving drugs to her patients at the hospital and trying to find new ways to treat cancer in the lab. “A few of my patients have asked to come and visit the lab, because it’s just next door. They come in, still attached to a drip, and they can see the scientists using the same drug on cells in the lab. This is very interesting for the patients, and also inspiring for the scientists who may not have had the opportunity to talk to people with cancer.”

Prostate Cancer UK are now funding Dr Macaulay to run a trial of an IGF blocker drug in men with prostate cancer who are about to have their prostate surgically removed. “I’ve been trying to do a clinical study based on my research for quite a while, and this grant has really given me the first opportunity,” she says.

This study is the result of over a decade of research, ever since that first discovery of those fast-growing cells in the lab. From those initial findings, we provided funding for Dr Macaulay’s lab in 2004 to study how IGF affects prostate cancer cells.

Just as every key has a lock, every hormone has a receptor. The IGF receptor is found on the surface of most cells, and it is switched on when IGF is attached to it. Research in Dr Macaulay’s lab discovered that the IGF receptor was produced in high levels in most prostate cancers, and lowering these levels could reduce the cancer’s ability to grow and spread.

However, other scientists were sceptical of this finding, and it still wasn’t clear how IGF has this effect on cancer. More research was needed.

Digging deeper

Dr Macaulay’s lab found that something strange happens when there is a lot of IGF – the receptor leaves its usual location on the surface of the cell and moves inwards, into the cell nucleus where the DNA is stored.

This unusual discovery showed that we still had a lot to learn about IGF and its receptor. We provided further funding over a series of grants from 2008 to find out what the IGF receptor was doing in the nucleus.

This series of grants from the charity helped to keep a researcher in my lab working on the project and kept it going. She did a very expensive experiment that showed how IGF drives the cancer cells to grow and spread, which we couldn’t have done without that support.

- Dr Val Macaulay

 

That experiment showed that the IGF receptor attaches itself to DNA, triggering cells to produce proteins that help the cancer to grow. This helps to explain why high levels of the receptor in the nucleus is linked to more aggressive cancers.

In theory, this could be stopped by lowering the amount of IGF in the body. This could stop slow-growing prostate cancers from becoming aggressive and fast-growing, reducing the chance of the cancer coming back after treatment or even avoiding the need for treatment entirely.

That could potentially help men on Active Surveillance, like Robin Porter: “The downside of being on Active Surveillance is that you do have the stress. You know that one day you may have to have treatment and obviously, unless you’re a very special type of person, when you go for the tests you are thinking, well is this the time when they say, ‘Sorry, Robin, you’re going to need an operation’?”

New research leads to prevent prostate cancer growth 

To see if this could work outside the lab we need to know what will happen in actual men. We have given a Research Innovation Award to Dr Macaulay to do just this through a cleverly-designed study. She will be giving an IGF blocker drug to men who have been diagnosed with localised prostate cancer and are about to have surgery. There is typically a four-week window before the surgery, where the men can take the drug with little chance of any potential long-term side effects.

Once the prostate has been removed, Dr Macaulay’s lab can analyse it to see what effect the drug had. “If this Research Innovation Award enables us to get evidence that we can stop the IGF receptor working, at the cell surface and in the nucleus, and if that makes the cancer less aggressive, it could be enough to justify a larger clinical trial. The research may also help us to understand how high IGF is linked with increased risk of cancer, which may give us new targets to block.”

IGF blocker drugs are already being tested in men with advanced prostate cancer. If this type of treatment is successful, then it could be used for men at an earlier stage, potentially to stop the cancer behaving aggressively. But what about men without cancer? Could the cancer protection of Laron syndrome dwarves be replicated through a drug, in the way we use statins for heart disease today? Dr Macaulay thinks this could be a possibility one day:

“We hope that our current research can help us to understand how IGF drives cancer growth, and provide evidence that we can stop early cancers growing. If we can do that, it does raise the possibility that we might be able in future to design a treatment to give to healthy men at high risk of prostate cancer, to stop the prostate cancer developing in the first place, and that would be amazing!”