title: Toxicity profile of small-molecule IAP antagonist GDC-0152 is linked to TNF-α pharmacology.
abstract: Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising inflammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after iv dose administration once every 2 weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic inflammatory response, and hepatic injury. Laboratory findings included elevated plasma cytokines, an inflammatory leukogram, and increased liver transaminases with histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues; a toxicology profile consistent with TNF-α-mediated toxicity. Dogs exhibited more severe findings than rats, and humans did not exhibit these findings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum monocyte chemoattractant protein-1, and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers.
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, California 94080, USA. erickson.rebecca@gene.com
authors.forename: Rebecca I
authors.initials: RI
authors.lastname: Erickson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tarrant
authors.forename: Gary
authors.initials: G
authors.lastname: Cain
authors.forename: Sock-Cheng
authors.initials: SC
authors.lastname: Lewin-Koh
authors.forename: Noel
authors.initials: N
authors.lastname: Dybdal
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.forename: Kristina
authors.initials: K
authors.lastname: West
authors.forename: Ronald
authors.initials: R
authors.lastname: Steigerwalt
authors.forename: Michael
authors.initials: M
authors.lastname: Mamounas
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.forename: Kenjie
authors.initials: K
authors.lastname: Amemiya
authors.forename: Donna
authors.initials: D
authors.lastname: Dambach
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000633:toxicity*; D018925:Chemokines / Q000097:blood; D003510:Cyclohexanes / Q000097:blood / Q000633:toxicity*; D004285:Dogs; D005260:Female; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D011758:Pyrroles / Q000097:blood / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D018675:Toxicity Tests; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D003510:Cyclohexanes; D051034:Inhibitor of Apoptosis Proteins; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; C579046:GDC-0152