Locals make pancreatic advance
Australian researchers have made a significant step towards personalised medicine for pancreatic cancer.
A team at the Garvan Institute of Medical Research has found a newly-approved breast cancer drug could be highly effective against some forms of pancreatic cancer, and also developed a straightforward way to test which patients might respond positively to treatment.
Five-year survival rates after diagnosis of pancreatic cancer stand at just 7 per cent.
Most pancreatic cancers are diagnosed after the tumour has spread beyond the pancreas, making treatment particularly challenging.
Dr Marina Pajic, leader of the Personalised Cancer Therapeutics Group at the Garvan, says the group’s latest study was designed to meet an urgent need for new, targeted therapies for pancreatic cancer.
“We are thrilled to have shown, in preclinical models, that the breakthrough breast cancer drug palbociclib targets a major subtype of pancreatic cancer,” she said.
“We know that the underlying drivers of pancreatic cancer at the molecular level differ from person to person. Despite this, there are currently few treatments that directly target the molecular drivers of an individual’s pancreatic cancer, but only a one-size-fits-all combination chemotherapy approach – and the fact is that this simply isn’t effective for most patients.”
The researchers first examined over 550 tumour biopsies from pancreatic cancer patients.
In about two-thirds of those tumours, they found, a cellular pathway known as the “Cdk4/6 pathway” was switched on, driving tumour cells to grow and divide.
“This was an important clue for us,” Dr Pajic said.
“We started to look in depth at how best to block the Cdk4/6 pathway. We know that the drug palbociclib switches off the Cdk4/6 protein, so we reasoned that palbociclib might halt the growth of the many pancreatic cancers where this pathway is “ON”.
Crucially, the researchers showed that the RB protein – another protein in the Cdk4/6 pathway – was present in high levels in Cdk4/6 “ON” tumours and so could act as a biomarker of the tumour subtype.
“Having a good biomarker is essential for personalised medicine, because it gives us a way to predict who is likely to respond to treatment,” said Dr Angela Chou, first author on the new study.
“Importantly, we can test RB levels quickly and easily by using standard preparations of biopsy tissue that are a part of the regular workflow in Australian diagnostic laboratories – so a test like this could be routine in the future.”
The researchers also tested the efficacy of palbociclib in mouse models of pancreatic cancer. At each step, they compared palbociclib (with or without gemcitabine chemotherapy) with standard chemo-only approaches.
The effects were dramatic, and were seen at all stages of pancreatic cancer progression.
“Time and again, we found that pancreatic tumours with high RB levels responded powerfully to palbociclib,” Dr Chou said.
“Mice treated with palbociclib as a first-line treatment had a lifespan of more than 100 days longer than those treated with chemo alone – and the effect was even stronger when we combined palbociclib with chemotherapy.
“We also went on to test palbociclib as a second-line treatment following progression of pancreatic cancer and in a model of metastatic cancer – and again, palbociclib extended lifespan far beyond chemotherapy.”
Importantly, only mice with high RB tumours responded to palbociclib, highlighting its role as a targeted, subtype-specific therapy.
“This gives us hope that, in people, measuring levels of RB could one day help us get the right treatment to the right patient,” Dr Pajic said.
“Excitingly, data from our patient samples shows us that, if a primary tumour has high RB levels, then it’s likely that the metastatic tumours will also. This means there’s a possibility that both primary and metastatic tumours could be targeted in the same patient in the future,” adds Dr Chou.
The researchers also showed how palbociclib could inhibit the spread of pancreatic cancer to distant tissues.
As they spread through the bloodstream, cancer cells are placed under physical stress (shear stress). The researchers showed that, when treated with palbociclib, RB-high tumour cells became very susceptible to shear stress – making it more difficult for them to thrive in the blood, and to survive and spread to distant organs.
Their latest study has been published online in the journal Gut.