Pretreatment with an experimental focal adhesion kinase (FAK) inhibitor has been shown to improve chemotherapeutic efficiency and reduce metastasis in preclinical mouse and patient-derived models of pancreatic ductal adenocarcinoma (PDAC), with this priming regimen soon to enter phase II trials for PDAC using a novel, clinically relevant FAK inhibitor.

Notably, stratifying PDAC patient samples according to levels of the merlin tumor suppressor protein revealed a subset more likely to respond to such combination therapy, according to a multicenter Australian study reported in the Sept. 30, 2021, edition of Science Advances.

Led by researchers at the Garvan Institute of Medical Research and the University of New South Wales in Sydney, the study is the first to show that FAK inhibitor pretreatment enhanced PDAC's response to standard-of-care (SoC) gemcitabine/Abraxane chemotherapy and reduced metastasis by up to 50%.

"Low merlin levels have previously been shown to correlate with increased FAK inhibition sensitivity in other cancer types such as mesothelioma, prompting us to assess this in PDAC," said study co-leader Paul Timpson, professor and Cancer Research Theme leader at the Garvan Institute.

"FAK is known to regulate interaction between cells and their environment, including stromal remodeling and generation of a dense, fibrotic stroma, which we know is a key problem in pancreatic cancer patients."

FAK inhibition primes the tumor microenvironment (TME) by reducing stromal connective tissue rigidity, which may improve chemotherapeutic efficiency in PDAC patients, who currently have a very poor prognosis, despite SoC treatment.

Worldwide, PDAC is one of the most aggressive cancers, with a 5-year survival rate < 10%, which is below 3% if the cancer has already metastasized.

"By making cancer cells more sensitive to chemotherapy [by targeting the TME], we hoped to improve survival rates for pancreatic cancer patients," said Timpson.

To this end, the researchers investigated FAK, a cytoplasmic tyrosine kinase produced by pancreatic cancer cells, which increases stromal stiffness and helps cancer cells to grow, mobilize and metastasize.

Advanced imaging techniques revealed how living pancreatic cancers respond to an experimental FAK inhibitor before chemotherapy and whether it could increase their elimination in preclinical PDAC models.

"Priming with an FAK inhibitor was shown to reduce stromal stiffness and decrease fibrosis, or deposition and remodeling of extracellular matrix, which are known to promote metastasis and resistance to SoC chemotherapy," Timpson told BioWorld Science.

"We showed that FAK increased with stromal fibrosis during disease progression in our preclinical models and that high FAK in the stroma correlated with poor outcomes in pancreatic cancer patients.

"This prompted us to assess the therapeutic potential of combining FAK inhibition with SoC chemotherapy in greater detail," he said.

"We observed a decrease in stromal fibrosis by imaging collagen, a major stromal component, together with an improved chemotherapy response, using a biosensor showing when and where cancer cells were 'stalling'."

Merlin

The Garvan researchers also discovered that PDAC cell levels of the merlin tumor suppressor protein may help identify which patients would derive most benefit from FAK inhibition.

"We found that low levels of merlin, which is produced at varying levels by PDAC cells, resulted in FAK inhibition being more effective in our pancreatic cancer models," said study co-leader David Herrmann, senior research officer for invasion and metastasis in Timpson's laboratory.

"We hope that by determining which tumors produce less merlin, we will be able to identify those patients who are likely to benefit most from our new combination approach," said Herrmann.

"Our study provides proof-of-principle genetic data that low merlin levels can increase the efficacy of our combination treatment in pancreatic cancer patient samples.

"The correlation between merlin levels and sensitivity to FAK inhibition, hence merlin's role as a potential biomarker for combination therapy efficacy in PDAC, will be evaluated in a larger cohort in future clinical trials," said Herrmann.

Clinical trial

These findings will be further investigated in collaboration with Melbourne-based Amplia Therapeutics, which is slated to begin phase II trials early next year to determine if priming with the clinically relevant small-molecule FAK inhibitor, AMP-945, before chemotherapy will be effective in PDAC patients.

"AMP-945 has been shown to be safe in phase I trials by our collaborators at Amplia Therapeutics, while studies using AMP-945 in preclinical PDAC models are currently ongoing to support the planned phase II study," said Herrmann.

"The present Science Advances study used an experimental FAK inhibitor to demonstrate that priming could improve chemotherapy performance in the primary pancreatic tumor as well as in liver metastases, with up to a 50% reduction in metastasis being seen with combination therapy in our preclinical models," he explained.

"Survival rates of PDAC patients are dismal and have been largely unchanged for decades, with our new priming regimen offering a promising new clinically relevant approach to improving on current treatments," said Timpson.

"In a broader context, in future we will assess the efficacy of other antifibrotic drugs to target pancreatic cancer and thereby reduce metastasis and improve chemotherapy performance," he revealed.

"We recently generated a novel fibrosis-enriched cohort of pancreatic cancer patient samples, the Australian Pancreatic Cancer Matrix Atlas, which will be invaluable to further our understanding of antifibrotic targeting in pancreatic cancer.

"Furthermore, we aim to repurpose our findings to other aggressive, treatment-resistant cancer types known to exhibit a highly fibrotic stroma, such as triple-negative breast cancer."