Histamine H1 receptor: A target to treat pancreatic ductal adenocarcinoma (PDAC) by repurposing approved H1-antihistamines?

New efficacious and safe therapies are needed for patients with pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. A bioinformatic approach comparing human PDAC tumors to normal pancreas identified differentially expressed G protein-coupled receptors (GPCRs). The GPCRs with higher differential expression in PDAC included the histamine H1 receptor (HRH1), which, on average, is ~20-fold higher expressed in PDAC tumors. HRH1 is readily targetable by approved H1-antihistamines. Studies with human and murine PDAC tumor cells revealed that HRH1 agonists increase intracellular calcium in cancer cells and promote their migration and invasion. Fexofenadine, an H1-antihistamine, decreased pancreas tumor size and altered expression of cancer relevant genes in a mouse model of PDAC. These findings complement data for HRH1 and H1-antihistamines, especially second generation cationic amphiphilic antihistamines, observed in numerous other cancers. Studies are needed to determine if H1-antihistamines can augment anti-tumor response by current therapeutics and improve outcomes for PDAC patients. These findings with HRH1 suggest that other differentially expressed GPCRs with approved drugs may be therapeutic targets for PDAC and other cancers.