Breakthrough research lowers pancreatic cancer resistance to chemo

MELBOURNE: A potential new treatment for pancreatic cancer has received a major boost, with research proving that “priming” cancer cells by targeting a molecule that inhibits the effectiveness of chemotherapy drugs led to a 50 per cent reduction in tumour spread.

Researchers at the Garvan Institute have been intensively studying a protein called focal ­adhesion kinase (FAK) which controls fibrosis and leads to the development of a fibrotic tissue “shield” that surrounds pancreatic tumour cells and makes them impenetrable by chemotherapy.

The Australian biopharma Amplia Therapeutics is preparing to conduct a Phase II clinical trial to test a new drug, AMP945, which targets FAK and may break down the fibrotic shield surrounding pancreatic tumours.

Now Garvan researchers have established that targeting FAK prior to treatment made the cancer cells more sensitive to chemotherapy and reduced cancer spread by 50 per cent in mice.

Their findings have been published in Science Advances.

“When we administered a treatment that targeted FAK prior to chemotherapy in our experimental models, that’s when we saw the most benefits,” said lead author Kendelle Murphy.

“By pre-treating the tumours with the FAK inhibitors we were changing the stiffness as well as the amount and the deposition of stromal tissue surrounding the cancer cells.

“On this softer surface, the cancer cells became stalled, rendering them more sensitive to chemotherapy. Effectively, we were increasing the window of ­vulnerability of these cancer cells to chemotherapy, reducing both pancreatic cancer growth and spread in our models.”

The new approach provides hope for patients with an aggressive form of cancer called pancreatic ductal adenocarcinoma which has a five-year survival rate of less than one in 10, and below 3 per cent if the cancer has already ­metastasised.

Paul Timpson, who heads the laboratory that has been con­ducting preclinical studies on FAK inhibition for the past eight years, said that priming the tumour environment meant that less chemotherapy was just as ­effective as larger doses in curbing tumour spread.

“We found that less drug was actually better than continuous treatments – and not only that, we could actually make the tumour cells more vulnerable to metastasis,” Professor Timpson said.

“We’re really delighted to not only be able to stall the tumours in the primary site but also simultaneously reduce the spread of the tumour.”

Researchers were able to test the impact of targeted FAK by taking samples from patients’ tumours and propagating the tumours in mice.

“We used patient samples ­direct from surgery and tested them and what we found was that we could reduce metastasis by 50 per cent by targeting FAK,” Professor Timpson said.

“Half of those had no metastasis, and that is something we very rarely see in a deadly disease.”

The researchers also found that the levels of another protein known as merlin – which is also found in pancreatic cancer cells – may determine how susceptible a tumour is to a treatment that ­targets FAK.

They found that low levels of merlin in the cancer models resulted in the priming approach of targeting FAK being more effective.

“We believe that patients with really low merlin and high levels of FAK is a subpopulation that will be exquisitely sensitive to our treatment,” Professor Timpson said.

Amplia Therapeutics will test the drug AMP945 in human clinical trials next year.

“The results of these preclinical studies have provided important insights and validated our decision to progress AMP945 to a Phase II clinical trial in pancreatic cancer patients,” said Amplia chief executive and managing director, Dr John Lambert.