Pancreatic Chemotherapy Could be Improved by Blocking Key Kinase

Pancreatic Chemotherapy Could be Improved by Blocking Key Kinase

A preclinical study by researchers at the Garvan Institute of Medical Research demonstrates a new approach that may improve how effective chemotherapy is for pancreatic ductal adenocarcinoma (PDAC).

The findings are published in the journal Science Advances in a paper titled, “Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status.”

“PDAC is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression,” the researchers wrote.

“By making cancer cells more sensitive to chemotherapy, we hope to improve survival rates for pancreatic cancer patients,” said Paul Timpson, PhD, cancer research theme leader at the Garvan Institute, professor, and co-senior author of the study. “This work is a powerful example of cutting-edge research in the laboratory leading to a partnership with industry and potential clinical translation.”

The researchers investigated focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase that is overexpressed in many types of tumors, including pancreatic cancer, and plays an important role in cell adhesion and survival signaling.

The researchers used imaging techniques to reveal how live pancreatic cancers in mouse models respond to treatment. They observed whether blocking FAK using an experimental therapy could prime the cancer cells to be more readily destroyed by chemotherapy.

“A combination of 2D and 3D in vitro techniques was used to deconstruct the benefits by which stromal and epithelial FAK inhibition may reduce PDAC aggressiveness in the context of gemcitabine/Abraxane chemotherapy,” the researchers wrote.

The researchers reported seeing the most benefits when they administered a treatment that targeted FAK prior to chemotherapy in their experimental models.

“By pre-treating the tumors with the FAK inhibitors we were changing the stiffness as well as the amount and the deposition of stromal tissue surrounding the cancer cells,” said Kendelle Murphy, PhD, first author of the paper and research officer at Garvan Institute. “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 researchers also discovered that the levels of a protein called merlin pancreatic cancer cells, which may assist in identifying which individuals would benefit most from FAK targeting.

“Merlin is a protein that is produced at different levels in pancreatic cancer patients. We found that low levels of merlin in our experimental pancreatic cancer models resulted in our ‘priming’ combination approach targeting FAK being more effective,” said David Herrmann, PhD, co-senior author of the study and a senior research officer, Garmin Institute of Medical Research.

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

The findings will be investigated as part of a new clinical trial in collaboration with Melbourne-based Amplia Therapeutics.

“The survival rates of pancreatic ductal adenocarcinoma patients are dismal and have been largely unchanged for decades,” added Timpson. “Our approach is a promising new clinically relevant avenue to improve on current treatments, and potentially make a real difference for patients.”