Novel drugs against pancreatic cancer
PDAC claims 34 000 deaths annually in the EU alone. Traditional cancer treatment approaches have no effect on this cancer, which rapidly metastasises and is the cause of death for nearly all patients. Based on these facts, the search for new drugs to combat PDAC progression and thus increase patient life expectancy and quality of life has been given high priority. The goal of the EU-funded PANACREAS (Integrating chemical approaches to treat pancreatic cancer: Making new leads for a cure) project was to develop the identification of PDAC molecular targets and for novel drug development. To this end, the PANACREAS team recruited clinicians, translational cancer researchers, chemists and pharmaceutical industry partners. In an integrated effort, they worked to synthesise and test drugs for PDACs that target various oncogenic pathways. Assays, models and in silico research was carried out to identify inhibitors of various tumour suppressors such as Yes-associated protein (YAP) or enzymes (SIRT6, IDO2, and alpha-mannosidase) that may be implicated in PDAC pathogenesis. A kinase inhibitor that interferes with YAP ability to activate transcription has been identified through a small-scale compound screen approach. There is strong evidence that the identified compound inhibits epithelial to mesenchymal transition in pancreatic cancer cells. Researchers confirmed that synthetic lysophospholipid edelfosine, known as cell death activator, was active in several PDAC models. Compounds with the potential to act as edelfosine analogues were identified, with one of them being active in vivo against PDAC xenografts. Another promising cell death modulator identified in the project is galectin family proteins. Several new galectin inhibitors were synthesised and their efficacies in PDAC models are currently under assessment. The most promising compounds identified during the project will be validated for their therapeutic potential using an established genetically engineered PDAC mouse model and orthotopic PDAC xenografts. Strong anticancer activity by any of these drugs will give the green light for their future testing in clinical studies and hopefully for their clinical application.
Keywords
Pancreatic cancer, PANACREAS, Yes-associated protein, edelfosine, galectin
