Tackling the scar tissue that shields pancreatic tumours from effective drug access is a promising advance in a notoriously hard-to-treat cancer.
UNSW medical researchers have found a way to starve pancreatic cancer cells and ‘disable’ the cells that block treatment from working effectively. Their findings in mice and human lab models – which have been ten years in the making and are about to be put to the test in a human clinical trial – are published this week in Cancer Research.
Senior author Associate Professor Phoebe Phillips from UNSW Medicine & Health said, ‘Pancreatic cancer has seen minimal improvement in survival for the last four decades – and without immediate action, it is predicted to be the world’s second biggest cancer killer by 2025.
‘But our latest advance means today I am the most optimistic and hopeful I have been in my career,’ she said.
Like a fortress
Pancreatic cancer is notoriously difficult to treat because of the dense scar tissue surrounding tumours – the tissue acts like a fortress that blocks chemotherapy delivery.
Associate Professor Phillips explained, ‘This scar tissue is produced by critical “helper cells” – also called cancer-associated fibroblasts – which cancer cells recruit to support their growth and spread. Yet, these helper cells have been ignored in current treatment strategies.
‘Our approach hits both the tumour cells and the helper cells, so it’s ideal for overcoming the aggressiveness and drug resistance of the disease.’
In the new paper, the UNSW team demonstrates a novel way to metabolically rewire helper cells by targeting one particular protein called SLC7A11, which in turn shuts off the cells’ tumour-promoting activity and reduces the scar tissue they produce.
‘We found that switching off SLC7A11 in mice with pancreatic tumours directly killed pancreatic cancer cells, reduced the spread of tumour cells throughout their body and decreased the scar tissue fortress,’ said Dr George Sharbeen, a postdoc researcher in Associate Professor Phillips’ lab who led the experimental work.
Comprehensive models, in-depth study
SLC7A11 has been studied in pancreatic cancer cells before, but this is the first piece of research to show that it also plays a critical role in non-tumour helper cells.
Co-first author Associate Professor Joshua McCarroll from the Children’s Cancer Institute said, ‘We also used cutting-edge nanomedicine developed in a multi-disciplinary collaboration with engineers – UNSW Professor Cyrille Boyer and University of Queensland Professor Thomas Davis – to deliver a gene therapy to inhibit SLC7A11.
‘This therapy is advantageous because our nano-drug is tiny and able to penetrate the scar tissue in pancreatic cancer,’ said Associate Professor McCarroll.
Clinical trial about to commence
The team’s findings have formed the foundation for a clinical trial which was funded by a recently awarded Cancer Institute NSW Translational Program Grant.
‘In this trial, we will repurpose an anti-arthritis drug called sulfasalazine – which we know potently inhibits SLC7A11 – for the treatment of pancreatic cancer patients with tumours that have high SLC7A11 levels, which we’ve shown to be the case in more than half of patients,’ said Associate Professor Phillips.
‘It has the potential to improve treatment response and ultimately survival of these patients.
‘Using an approved drug has allowed us to get this piece into the clinic much faster than what would be the case if we started from scratch with drug development too,’ said Associate Professor Phillips.
‘We are taking this exciting development all the way from the lab bench through to the clinic, with the sole purpose of improving outcomes for patients with pancreatic cancer,’ she said.
The research team hopes to analyse and publish the first set of results of the trial within three years.
Improving outcomes that haven’t changed in decades
In addition to the clinical trial, the team hopes to assess how their approach interferes with the exchange of nutrients between tumour cells and helper cells. They also want to identify the ideal drugs to combine with their therapeutic approach to enhance anti-tumour effects.
Pancreatic cancer is a highly lethal disease, with only one in ten patients surviving beyond five years. In 2020, an estimated 4000 Australians were diagnosed with pancreatic cancer – about 90 per cent of them will die, often within a few months of diagnosis.
‘We clearly need improved treatments to turn these dismal statistics around, and we hope clinical translation of our findings will ultimately increase the number of pancreatic cancer survivors,’ said Associate Professor Phillips.
‘We will not give up until we improve the quality of life of patients and provide them with an effective treatment,’ she said.
This work was funded by NHMRC, Cancer Institute NSW and PanKind (The Australian Pancreatic Cancer Foundation).