21.08.2023: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. A research group led by the University of Veterinary Medicine Vienna with researchers from Germany, Israel, and Austria has now developed a promising new approach that simultaneously blocks all ERBB receptor ligands, thereby significantly reducing tumour burden. The results of this approach, which was tested in an in vivo animal model, were recently published in Molecular Oncology.
PDAC is not only one of the deadliest cancers, it is also one of the most common ones. To date, no effective early detection methods exist, not even for high-risk individuals. Advances in the diagnosis and treatment of pancreatic cancer have so far resulted in only a modest reduction in mortality. Now a promising new treatment approach, which has already proven effective in vitro, has been successfully tested in vivo in a mouse model.
Molecular decoy is inhibiting an entire receptor family
The goal – as had already been done with pancreatic cancer cells in the laboratory – was to inhibit the EGFR/ERBB receptor family, which is harnessed by some oncogenic mechanisms in PDAC carcinogenesis. “To explore the effects on pancreatic lesions, we attempted a simultaneous blockade of all ERBB ligands – growth factors that can bind to a receptor – in a PDAC mouse model. To this end, we engineered a molecular decoy, TRAP-FC, capable of trapping all ERBB ligands,” says study director and last author Maik Dahlhoff, head of the Institute of in vivo and in vitro Models at Vetmeduni.
Decreased cell proliferation, migration, and tumour growth
Next, the researchers generated a transgenic mouse model expressing TRAP-FC. The TRAP- FC mice displayed a significantly decreased emergence of pancreatic lesions, reduced RAS activity, and decreased ERBB receptor activity, with the exception of ERBB4, which surprisingly showed increased activity. The researchers then deleted each ERBB receptor in a human pancreatic cancer cell line using CRISPR to analyse the mechanism of each receptor. Deleting each member of the ERBB family altered signalling downstream of the other three ERBB receptors and decreased cell proliferation, migration, and tumour growth.
Promising approach for therapeutic treatment in patients
“We conclude that simultaneously blocking the entire ERBB receptor family would be therapeutically more effective than individually inhibiting only one receptor or ligand in terms of reducing pancreatic tumour burden,” Dahlhoff said. According to the researchers, this could represent a promising approach to the treatment of pancreatic cancer.
The article “Trapping all ERBB ligands decreases pancreatic lesions in a murine model of pancreatic ductal adenocarcinoma” by Kathrin Hedegger, Andreas Blutke, Theresa Hommel, Kerstin E. Auer, Nishanth B. Nataraj, Moshit Lindzen, Yosef Yarden and Maik Dahlhoff was published in Molecular Oncology.