“Once you can fill in the gaps of where a cancer begins, then you can start to answer questions of what's driving the disease. And when you know that, all the dominoes start to fall and you can start to improve patient outcomes.” – Dr Philip Arandjelovic
Cancer is hundreds of different diseases, each with its own quirks. That’s why finding answers takes time, persistence – and a lot of ambitious thinking.
It can help to go back to the very beginning…
Dr Philip Arandjelovic, a Cancer Council Victoria Postdoctoral Fellowship recipient at WEHI, is part of a team asking one of the most pressing questions in liver cancer biology: Where does cancer begin in the liver?
Liver cancer – specifically hepatocellular carcinoma (HCC), the most common type of liver cancer in adults – is the fastest rising cause of cancer death in Australia and around the world. Only 28 per cent of patients survive five years after diagnosis.
“That's very grim,” says Phil. “We need to understand more about how this disease begins and what drives it. What is a key unknown is where exactly in the liver the cancer begins and in which type of liver cell.”
Liver cancer’s origin story?
Finding the ‘cell of origin’ of a cancer type is a relatively new area of study made possible by advances in research and technology in the past few years that are making the tools of study possible.
Generously funded by Cancer Council Victoria supporters, Phil’s research has zeroed in on a protein called ‘β-catenin’ that’s mutated in around half of all HCC cases. But the really exciting part of their discovery is that just one specific kind of liver cell appears to be responsible for HCC when β-catenin is mutated. Meanwhile, a neighbouring liver cell is resistant to forming cancer, even when the same protein is mutated.
“We found that the liver cells in one specific area of the liver are the ones that give rise to β-catenin mutated liver cancer, whereas the other liver cells do not,” says Phil.
“Finding the cell of origin like this is really one of the big questions you can answer about how a cancer begins, and once you know how a cancer begins, you can help work out the risk factors.”
Understanding the cell that triggers liver cancer can help researchers and clinicians get on the front foot of this rapidly rising and deadly disease. It can lead to more personalised treatments with deeper knowledge in what is likely to work – sparing patients from gruelling drug regimens that may not be effective.
It also opens the door to intervention for at-risk populations and the possibilities for pro-active treatments that could eliminate or lessen the potential for that cell of origin to form tumours.
“That would really be an ideal outcome – stopping mutant cells in their tracks before they even become cancerous,” says Phil.
Lessons for treating childhood liver cancer
The cutting-edge tools used in this research are incredibly expensive, but the discoveries made are priceless. Phil’s work not only holds hope for changing the poor outcomes for adults with liver cancer, but it could also hold the key to treating childhood liver cancer, called ‘Hepatoblastoma’.
Hepatoblastoma is the most common type of liver cancer diagnosed in children, and most patients are aged under three years.
“In children, the vast majority of cases don't arise due to chronic liver damage – after all, they're just kids. But hepatoblastoma is almost always driven by this same β-catenin mutation that we find in adults,” says Phil.
“We’re looking into how we can repurpose the tools that we're currently using to explore the origin of hepatoblastoma and to answer questions in that setting.”
With technology advancing, researchers like Phil are closer to finding these answers than ever before – including when and how mutations begin in very young patients.
From ‘where?’ to ‘why?’
“It's not every day that you get an answer as clear cut as what we've found. Biology is messy, it's shades of grey. Almost nothing is black and white. But this is about as black and white as you can get,” says Phil.
But like all good research projects, the answers they find raise even more questions – and now that they’ve answered the ‘what’ and the ‘where’, they’re looking at the ‘why’. Why is this biological phenomenon happening? And why, when other cancers are going down, does liver cancer continue to rise?
It’s the complexities of cancer that keeps researchers like Phil continuously striving for more answers – not stopping at just one. Because cancer isn’t just one disease, it’s hundreds.
“I owe it to the various funders and donors and all the people who give to Cancer Council to answer these questions to the best of my ability - to help achieve the outcome that we would all like to see, which is cures and treatments for these diseases,” says Phil.