Selective inhibition of integrin αvβ6 leads to rapid induction of urinary bladder tumors in cynomolgus macaques

• DOI: 10.1093/toxsci/kfac128
• Publication Date: 2022-12-14T13:38:00Z
• Authors: Magali Guffroy; Bruce Trela; Takahito Kambara; Lukasz Stawski; Huidong Chen; Lia Luus; Monica S Montesinos; Lauren Olson; Yupeng He; Kevin Maisonave; Tracy Carr; Min Lu; Adrian S Ray; Lisa A Hazelwood
• Keywords: Atypia

Abstract Administration of a novel and selective small molecule integrin αvβ6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction epithelial proliferative changes urinary bladder 2 animals, absence test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae cells, variable cytologic atypia, high mitotic rate, without invasion into tunica muscularis. Morphologic features patterns tumor growth were consistent with diagnosis early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased proliferation several monkeys, including those tumors, was expressed some tissues, bladder, humans. Spontaneous carcinomas are extremely unusual healthy suggesting direct link finding agent. Inhibition is intended locally selectively block transforming factor beta (TGF-β) signaling, which implicated disorders. Subsequent vitro studies using panel inhibitors human cells replicated observed reversed through exogenous application TGF-β. Moreover, analysis vivo models liver lung fibrosis revealed evidence hyperplasia cell cycle dysregulation mice treated or TGF-β receptor I inhibitors. The cumulative suggests between inhibition decreased signaling local environment, implications carcinogenesis.