Selective Inhibition of Integrin Αvβ6 Leads to Rapid Induction of Urinary Bladder Tumors in Cynomolgus Macaques

Administration of a novel and selective small molecule integrin alpha v beta 6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction of epithelial proliferative changes in the urinary bladder of 2 animals, in the absence of test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae of epithelial cells, variable cytologic atypia, and high mitotic rate, without invasion into the tunica muscularis. Morphologic features and patterns of tumor growth were consistent with a diagnosis of early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased epithelial proliferation in the urinary bladder of several monkeys, including those with tumors, and alpha v beta 6 was expressed in some epithelial tissues, including urinary bladder, in monkeys and humans. Spontaneous urothelial carcinomas are extremely unusual in young healthy monkeys, suggesting a direct link of the finding to the test agent. Inhibition of integrin alpha v beta 6 is intended to locally and selectively block transforming growth factor beta (TGF-beta) signaling, which is implicated in epithelial proliferative disorders. Subsequent in vitro studies using a panel of integrin alpha v beta 6 inhibitors in human bladder epithelial cells replicated the increased urothelial proliferation observed in monkeys and was reversed through exogenous application of TGF-beta. Moreover, analysis of in vivo models of liver and lung fibrosis revealed evidence of epithelial hyperplasia and cell cycle dysregulation in mice treated with integrin alpha v beta 6 or TGF-beta receptor I inhibitors. The cumulative evidence suggests a direct link between integrin alpha v beta 6 inhibition and decreased TGF-beta signaling in the local bladder environment, with implications for epithelial proliferation and carcinogenesis.