Behind the science: Dr Dan Carter

Behind the science: Dr Dan Carter

When they find a gene that can produce a poor prognosis in patients, but can’t be treated with drugs, researchers target its partners in crime.

Because of its range of clinical outcomes, neuroblastoma, which typically appears in children under the age of five, has been described as an enigmatic type of cancer. Sometimes its tumours completely disappear after treatment and other times they grow at a furious, lethal rate.

Dr Dan Carter, whose research has been funded by The Kids’ Cancer Project, has been concentrating his focus on the patients who do poorly in order to understand specific risk factors, and to develop a drug or a combination of therapies to help mitigate those factors.

“There are several risk factors, such as simple clinical traits like patient age and observation of metastasis, which is where the cancer spreads around the body,” Carter, who works at UTS Sydney and Children’s Cancer Institute, says. “These can be indicators of poor outcome.”

“But there are also genetic indicators that allow the tumour to gain advantage, to stay alive, continue to grow and not respond to therapy. These genetic markers are our interest because they’re ultimately the reason these tumours are lethal. From a molecular point of view, understanding how those genetics relate to the cell biology of the cancer, that’s our goal. We’re figuring out the mechanism that a particular genetic pathway leads to aggressive tumour growth.”

In particular, Carter has been interested in a gene called MYCN which can encourage uncontrolled cell growth. Such genes typically become the focus of researchers who design drugs to target that gene, disrupting its chain of behaviour while also avoiding side-effects related to such treatments as chemotherapy. The treatment is commonly referred to as ‘targeted therapy’.

Read more: Targeting FACT To Inhibit MYCN-Driven Transcription In Neuroblastoma

Unfortunately, researchers are beginning to believe that the MYCN gene is not able to be targeted by current drugs. This fact simply created a new and more interesting challenge for Carter and his team.

Destroy its partners

Carter’s research, funded by The Kids’ Cancer Project, established the mechanistic link between MYCN and another gene known as FACT.

“MYCN starts a molecular signalling cascade in the cell that allows the cell to keep dividing,” Carter explains. “But in itself, this is just signalling. It needs other genes to do their job once they receive the signals.

This part of the process, the expression of a signal into an action, is known as ‘transcription’. FACT is crucial for the transcription of MYCN’s signals. So just as one army might gain a massive advantage if they’re able to disrupt the signals of their enemy, so too the battle against neuroblastoma can have a greater chance of victory if FACT is taken down.

“Our idea was that we could target FACT with a drug called CBL0137, and therefore overcome MYCN’s pro-cancer effects,” he says.

This drug, in fact, is already in early-phase clinical trial in adults in the US and Russia. It’s being tested for safe-dose administration, rather than its effects on cancer.

“A nuance of the clinical trial system is that you always test a drug in adults first, before you proceed even to an early-phase clinical trial in children,” he continues. “And so, based on the success of that trial, we will do a similar, early-phase trial in children, which would include neuroblastoma patients.

Carter’s work over the last few years has contributed vital knowledge that is essential to offer such a clinical trial the greatest chances of success.

Is this a cancer cure?

While this drug may show some benefit in the treatment of neuroblastoma, Carter says, the more recent strategy of his team is to combine it with other drugs to create a new combination therapy. Essentially, his aim is to choose drugs that, when combined together, are more potent in killing cancer cells.

“What we’re looking at is the development of a targeted therapy,” he says. “You find a genetic alteration for which you then design a drug, and that drug targets a gene and takes away the cancer’s ability to grow.”

“Chemotherapy, which is a blanket term for a lot of the older drugs used for treatment of cancer, is currently nowhere near as specific as a targeted therapy. As a result, an issue with chemotherapy is that while it’s very effective at killing cancer, it also kills normal cells.”

“This means you get a huge amount of side effects in the patient, and those side effects limit the amount of chemotherapy a medical professional can give to a patient. The cancer can survive as a by-product of that.

Instead, targeted therapies are all about specificity. They are solutions that do not hurt normal cells but do great damage to cancer cells.

If researchers are able to find more pathways and discover more about the mechanisms of genetic actions within cells, numerous targeted therapies can be developed. They can then be used in unison, as essential ingredients of sorts, in the recipe for treatment of cancers in specific individuals.

“We want to find all of these pathways that relate to this particular gene and drug, so we can combine it with other drugs to develop a therapy that is far more potent for an individual than current treatments,” he says.

“Over the last three or four years we’ve done a lot of work in this area and have had some very promising results.” 

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