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.