Galanin 2 Receptor: A Novel Target for a Subset of Pancreatic Ductal Adenocarcinoma.

Galanin is a 30 amino acid peptide that stimulates three subtype receptors (GAL 1-3 R). M89b is a lanthionine-stabilized, C-terminally truncated galanin analog that specifically stimulates GAL 2 R. We investigated the potential of M89b as a therapeutic for pancreatic ductal adenocarcinoma (PDAC) and assessed its safety. The anti-tumor activity of subcutaneously injected M89b on the growth of patient-derived xenografts of PDAC (PDAC-PDX) in mice was investigated. In addition, the safety of M89b was assessed in vitro using a multi-target panel to measure the off-target binding and modulation of enzyme activities. In a PDAC-PDX with a high GAL 2 R expression, M89b completely inhibited the growth of the tumor ( p < 0.001), while in two PDAC-PDXs with low GAL 2 R expression, low or negligeable inhibition of tumor growth was measured, and in the PDX without GAL 2 R expression no influence on the tumor growth was observed. The M89b treatment of the GAL 2 R high-PDAC-PDX-bearing mice led to a reduction in the expression of RacGap1 ( p < 0.05), PCNA ( p < 0.01), and MMP13 ( p < 0.05). In vitro studies involving a multi-target panel of pharmacologically relevant targets revealedexcellent safety of M89b. Our data indicated that GAL 2 R is a safe and valuable target for treating PDACs with high GAL 2 R expression.