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Softening tumours before chemo improves pancreatic cancer survival

April 7, 2017

Australian cancer researchers have uncovered a promising new approach to treating pancreatic cancer by targeting the tissue around the tumour to make it ‘softer’ and more responsive to chemotherapy.

In the study, which was carried out in mice and in patient-derived samples, researchers primed pancreatic tumours with a three-day course of Fasudil, a drug that softens the surrounding tissue and makes the blood vessels around tumours ‘leaky’. Followed by the priming, they were treated with standard-of-care chemotherapy for pancreatic cancer.

Remarkably, the two-step approach doubled survival time and also impaired the spread of cancer to other tissues.

“Our team, with pancreatic researchers around the world, is inspired by an international goal to double pancreatic cancer survival by 2020 – so it’s particularly exciting that we have been able to achieve this in preclinical models,” said study co-leader Dr Paul Timpson from the Garvan Institute of Medical Research.

Dr Marina Pajic, who co-led the study with Dr Timpson, emphasised the clinical relevance of the study.

“We have tested the efficacy of priming before chemotherapy in multiple models, including patient-derived models of pancreatic cancer – so we believe our findings bring us closer to clinical translation.”

Which is better – targeting the tumour or surrounding tissue?

Pancreatic tumours, like all solid tumours, exist within a complex ‘nest’ of surrounding cells, blood vessels and other structures, known as the stroma. Interactions between cancer cells and the surrounding stromal architecture are important for tumour survival and progression.

By priming tumours with Fasudil, the researchers took aim at the stroma rather than at the tumour itself. Fasudil is an inhibitor of the protein ROCK, which typically acts on cells surrounding tumours to make them stiffer, and to drive the progression of cancer.

Dr Timpson said: “There has been a heated and longstanding controversy in cancer research about whether targeting the stroma can make pancreatic tumours more susceptible to therapy.”

“I think we have resolved that debate. We’ve been able to show for the first time that it’s crucial to treat the stroma first and the tumour second, and to fine-tune the treatment timing to maximise outcome, while minimising side effects.”

Individualised cancer treatment

The researchers concluded that priming with Fasudil makes tumours more susceptible to chemotherapy in two ways: by softening the stroma and by aiding the delivery of chemotherapies to the tumour by way of leakier blood vessels.

Importantly, the research team also showed that some pancreatic tumours respond more favourably than others to the sequential ‘priming therapy’.

Using patient tumour samples from the Australian Pancreatic Cancer Genome Initiative, the team developed an automated analysis of tumour tissue to predict an individual tumour’s response to the sequential treatment.

Dr Timpson said, “What we’re seeing is that the therapy works best for tumours with large amounts of surrounding stroma, and tumours with a high density of surrounding blood vessels.”

Clinical implications

For Drs Timpson and Pajic, the most exciting aspect of the research is its clinical potential.

“Fasudil is already in clinical use as a treatment for stroke in Japan and is off-patent – so there is strong potential to repurpose it for the treatment of pancreatic cancer,” said Dr Pajic.

“Moreover, in the clinic, Fasudil is administered over a short 3-day period, just as we have done in our study, and there is extensive safety data to validate this approach.”

“We’d like to see Fasudil or other therapies translate into precision medicine approaches for pancreatic cancer in the future – so that individuals receive the therapies that are most appropriately matched based on the biology of their individual tumour.”

An early-stage clinical study to examine the safety of the new approach has been planned.

Drs Pajic and Timpson are excited also about the potential to translate the new approach to other solid tumours, which like pancreatic cancer are surrounded by stroma and have poor drug delivery and might be sensitised to treatment through priming.

In 2017, it is estimated that 3,270 Australians will be diagnosed with pancreatic cancer, which has a dismal five-year survival rate of only 7%.

The findings have been published in Science Translational Medicine this week.

This news was first published on Garvan’s website, image of blood vessels (red) and stroma surrounding a pancreatic tumour courtesy of Garvan Institute of Medical Research.

The Australian Cancer Research Foundation has supported cancer research at Garvan by providing three grants, totalling AUD $6.13million, towards cutting edge cancer research equipment and technology.

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