The Kids Research Institute Australia and Perth Children’s Hospital will lead an international clinical trial of a novel drug combination they hope will increase cure rates for one of the most aggressive forms of childhood brain cancer.
The SJ-ELIOT trial, to run in Australia, Germany and the United States, will be the first to test the safety and effectiveness of the drug prexasertib in combination with chemotherapy treatments for medulloblastoma – which accounts for about 20 per cent of all childhood brain tumours.
Head of the Oncology and Haematology Department at Perth Children’s Hospital and The Kids researcher, Professor Nick Gottardo, is leading the clinical trial with fellow The Kids co-head of brain cancer research, Dr Raelene Endersby. He said approximately 30 per cent of children diagnosed with medulloblastoma died of the disease and for those that were cured, survival came at a heavy cost.
“Far too many of these children are dying of this brain cancer, and those that are saved tend to have permanent, life-changing side effects due to the intense nature of the treatment needed to save them,” Professor Gottardo said.
“Curing them requires surgery to remove the tumour, then radiotherapy to the whole brain and spinal cord, and then intensive chemotherapy.
“Some of the side effects are immediate, like losing hair, being susceptible to infections and having difficulty walking, but then there are the more long-term side effects which can affect intelligence, memory, attention, puberty and growth – there are a multitude of problems that are not reversible.
“We know we can change that with research, by finding smarter drugs and smarter treatments that are more effective on the cancer and cause less collateral damage on the body.”
Professor Gottardo and Dr Endersby hit upon prexasertib while screening thousands of drugs for their potential to kill medulloblastoma cancer cells.
In laboratory research carried out by the The Kids Cancer Centre over seven years, the pair tested the drugs on medulloblastoma cells donated by Perth Children’s Hospital patients to pinpoint those capable of killing tumour cells.
After narrowing these down to a handful of candidates, they undertook further lab work to see which of the drugs were not only effective but could be safely combined with existing treatments. Prexasertib emerged as the standout.
“The way prexasertib works is by preventing cancer cells from repairing themselves once they’ve been damaged by chemotherapy,” Dr Endersby said.
“Radiation and chemotherapy work by damaging the DNA in the cancer cells, but those cells can just fix that damage and keep on proliferating. When we give the cells prexasertib at the same time as chemotherapy we find they’re not able to repair their DNA, and therefore the cells undergo apoptosis, or cell death.”
Collaborators at elite children’s cancer centre, St Jude Children’s Research Hospital in Memphis, Tennessee, and at the Sanford Burnham Prebys Medical Discovery Institute in San Diego independently replicated the tests and found the same results, laying the groundwork for an international clinical trial that will involve up to 66 medulloblastoma patients in Australia, the US and Germany.
The trial is named in honour of four-year-old Perth boy Elliot Parish, who in 2011 lost a 15-month battle with medulloblastoma and whose parents began the fundraising campaign that initiated this work. Patients with relapsed medulloblastoma will be given increasing amounts of prexasertib at the same time as one of two other chemotherapies, to indicate the safe amount of prexasertib and chemotherapy the children can tolerate. The trial will also assess the disease’s response to the treatment.
The trial will run at Perth Children’s Hospital, Queensland Children’s Hospital, St Jude Children’s Research Hospital, and DFKZ in Heidelberg, Germany, expanding to Sydney Children’s Hospital and Royal Children’s Hospital in Melbourne.
Professor Gottardo said the project demonstrated the value of having Perth Children’s Hospital clinicians and The Kids researchers working together at the same site.
“It’s such a critical model, where the labs, clinic and patients are all together in the same building, because it inspires researchers when they see the patients that may end up benefiting from their discoveries, and equally the clinicians can see what’s coming in the near, medium or long-term future,” he said.
He said the drug discovery and trial would not have happened without the support of a number of charities focused on funding cancer research, including The Pirate Ship Foundation, Perth Children’s Hospital Foundation, Cancer Australia, Cancer Council WA, Cure Brain Cancer Foundation, The Kids’ Cancer Project, and the WA Child Research Fund.
“Getting research from the lab to a clinical trial is a long and expensive process, and having community support through funding is absolutely critical to see it through to the end,” Professor Gottardo said.
“The Pirate Ship Foundation funding in particular helped us get the early data we needed to attract more funds from government agencies and funding bodies.
“That community support remains essential because as excited as I am about this trial, it’s not suddenly going to cure every child with medulloblastoma – it will be a stepping stone.
“I’m hoping it will become another drug that we can add to our therapies that will increase survival. Then I would like to apply this as a model so we can bring other new therapies into the clinic using the same approach.”
Pirate Ship Foundation Chairman Matthew Fitzgerald, whose daughter Abigail survived medulloblastoma but now lives with multiple serious side effects, said the Foundation was committed to supporting the search for treatments which resulted in less damage to children.
“Some groups provide support post-diagnosis and post-treatment but The Pirate Ship Foundation is really invested in that front end approach, looking at cures and better treatments, which we think has the greatest potential to benefit future generations of kids and really tackle the disease rather than just the symptoms,” Mr Fitzgerald said.
“The fact that Dr Nick was Abby’s oncologist during her treatment and is also involved in the research side – the collaboration involved there – is also important to us. It connects the kids in the hospital and the researchers in the lab. We think that’s really going to accelerate their ability to come up with and discover new treatments and improve the lives of these kids.”
The researchers hope later to investigate prexasertib’s ability to be combined with radiotherapy.
“That’s really where I think the big difference will be made, because radiation is one of the most damaging components of treatment,” Dr Endersby said.
“Because this drug makes radiation therapy work much better, we are hopeful we can use it in combination to reduce the dose of radiation required, without compromising cure rates for our patients.”