For the past four years, scientists at Melbourne’s Peter MacCallum Cancer Centre and Boston’s Dana-Farber Cancer Institute have been collaborating on a new study that looks set to change the fundamental understanding of a particular childhood leukaemia.
A recent breakthrough has led to the development of a new class of treatment developed in pre-clinical models of acute myeloid leukemia with the ultimate aim of curing this form of cancer in children.
The Kids’ Cancer Project is providing funding for the Australian arm of the study, which is being directed by Professor Ricky Johnstone, head of both the Gene Regulation Laboratory at the Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology at the University of Melbourne.
While there have been significant advancements in the survival rates of children with leukaemia, Professor Johnstone isn’t satisfied that the 80 per cent figure is high enough.
“It still leaves one in five or one in six of these children who don't have a good outcome,” he said. “Until we're at 100 per cent cure rate, I don't think we should be comfortable.”
A cancer can be initiated through uncontrolled gene expression allowing the cancer cells to grow and multiply too rapidly. Professor Johnstone and his team are studying the enzymes that drive the first step of gene expression, known as transcription, in paediatric leukaemias. These enzymes are called cyclin-dependent kinases or CDKs.
“We believe that if transcription is important for the long-term proliferation and survival of tumour cells, if we block the activity of those enzymes, and therefore quieten down transcription, then we will have a negative effect on the leukaemia cells by slowing them and, in some case, killing them,” Professor Johnstone explained.
“That was the hypothesis when we started the study and, essentially, we've found that that's the case,” he said.
A career of discovery
It was the thrill of discovery that led Professor Johnstone to pursue a career in cancer research.
“Each day, I come to work, and I learn something new,” he said. “The predictions that we make sometimes come through and sometimes don't.”
“To be honest, it's the times when they don't come through and we discover something we could never have predicted that we gain the greatest insight into biology,” said Professor Johnstone.
Professor Johnstone expressed that while discovery is the exciting part of his role, it is underpinned by the hope that his work will be of benefit.
“I work in a cancer hospital where every day I see sick kids with this disease,” he said. “I've got three children, so that personally resonates with me.”
“Hopefully, what we're doing here, either directly or indirectly, will help those patients, or the families of those patients, or someone else out there in the community,” said Professor Johnstone.
Each CDK enzyme works in a different ways and Professor Johnstone along with his team are collaborating with scientists in Boston who are developing drugs (or small molecules) that inhibit CDK activity.
“With a postdoctoral fellow in my lab, Dr Stephin Vervoort, we are working with a fantastic group of researchers at the Dana-Farber Cancer Institute, which is one of the best cancer institutes in the world,” said Professor Johnstone.
“They are making these small molecules over there and we’re working on the biology here. It’s a beautiful example of a collaborative project where we've each got different skill sets and we're applying them to a common problem,” he said.
The study has two breakthrough aspects as Professor Johnstone explained.
“The first is that we are identifying new ways that the expression of genes in cells is regulated,” he said. “It’s the sort of stuff that we hope will someday be in textbooks.”
“The second thing is the way that we can apply this new knowledge. We’re starting to come up with therapeutic treatments in preclinical models and this will hopefully allow further clinical development of molecules that would be used for paediatric patients,” he said.
The value of funding
Some of the drugs are currently in clinical trials for adult patients and may someday be available for clinical trials for children.
“We’re not just using these drugs as single agents,” said Professor Johnstone. “In the lab, we're starting to combine them with other agents where we can increase the efficacy. We’ve been working on this study since about 2016, which is when The Kids’ Cancer Project started to provide funding. Now that the work is maturing, we hope to publish our first series of papers within the next six months.”
Professor Johnstone shared how funding from The Kids’ Cancer Project has helped drive the study forward.
“It has funded the salary of Dr Vervoort, an unbelievably talented postdoctoral fellow from the Netherlands and for two PhD students working on this project,” said Professor Johnstone.
“The funding has allowed really talented people to do this important work,” he added. “With our clinical colleagues, we’re now looking to see how we might be able to translate this work into clinical trials for kids.”