Novel therapeutic targets for pancreatic cancer
Lead Institution: The University of Melbourne
Chief Investigator: A/Prof Mehrdad Nikfarjam
Cancer type: Pancreatic
Study established: 2009 to current
About the research program
Pancare has long supported research investigating the mechanisms involved in the tumorigenesis of cancer to identify novel targets to improve treatment and patient outcomes.
Target P-21 activated kinase 1 (PAK1) in the treatment of pancreatic cancer
Several Pancare-supported discoveries in this area have established the framework globally for continuing research, including that undertaken by cell biologist Professor Graham Baldwin, who currently sits on the Pancare Medical Advisory Board. From 2015 onward, Prof Baldwin worked in an interdisciplinary collaboration with a pancreatic surgeon-scientist to create animal models of pancreatic cancer to investigate the biology of the protein-activated kinase (PAK) family of enzymes, the tumor microenvironment and the role of stromal activation.
Using these successful models, it is now known and widely-recognised that PAK enzymes play an important role in cancer growth and metastasis (spread) and are over-activated in most types of pancreatic cancer. The potential utility of targeting PAK enzymes to significantly improve patient treatment and survival was clear, so Pancare continued its investment in its Novel Therapies research program, which continues today.
In 2019, new Pancare-funded research began investigating how targeting P-21 activated kinase 1 (PAK1), a protein enzyme, could improve the treatment of pancreatic cancer. With a key role in many human cancer cells, the PAK1 enzyme was demonstrated to stimulate growth and metastasis in colorectal and pancreatic cancers, most notably pancreatic ductal adenocarcinoma (PDAC). In over 95% of cases of PDAC, there is a change, or mutation, in the PAK1 pathway within a specific gene called KRAS. It also is known to contribute to therapeutic resistance.
Therapeutic effect of cannabis in pancreatic cancer
More recent Pancare-supported research has explored the therapeutic roles of cannabis in pancreatic cancer, aiming to develop more efficient therapeutic regimes to extend patients’ survival. Plant-derived cannabinoids have been widely investigated for their anti-cancer effects. Cannabidiol (CBD) and (-)-trans-Δ9-tetrahydrocannabinol (THC) are the mostly studied cannabinoids from plant extracts. Both THC and CBD inhibited pancreatic cancer cells growth in vitro and in vivo through different mechanisms. THC suppressed pancreatic cancer growth via cannabinoid receptor 2 (CB2) while CBD inhibited pancreatic cancer growth synergistically with gemcitabine through antagonizing the G protein-coupled receptor GPR53.
University of Melbourne researchers, Dr Hong He and A/Prof Mehrdad Nikfarjam, showed that targeting the PAK 1 protein can reduce tumour growth and spread in PDAC, particularly in combination with chemotherapy. More recent research by the pair has been the first in the world to show that cannabinoids – biochemical compounds commonly termed CBD and THC – work to suppress pancreatic cancer through the PAK1 cell signalling pathway (International Journal of Molecular Sciences 2020). Specifically, they found that cannabinoids suppress KRAS activated pathway in pancreatic cancer by targeting PAK1 and can block the expression of PD-L1, a key target of immune “checkpoint” inhibition used in cancer immunotherapy.
These new findings have shown that cannabinoids, the type of chemical in medicinal cannabis, may be a potent therapy for certain types of pancreatic cancer and may have a role in improving outcomes for the more than 4,000 Australians diagnosed with pancreatic cancer each year. Pancreatic cancer remains notoriously difficult to detect with no early detection methods and limited effective treatment options available. Pancare will continue to collaborate and support research that can identify new and effective treatment options.
> Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer
Journal of Pancreatic Cancer, Volume 5.1, 2019 DOI: 10.1089/pancan.2018.0019
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