TOXICITY PROFILE OF SMALL-MOLECULE IAP ANTAGONIST GDC-0152 IS LINKED TO TNF-ALPHA PHARMACOLOGY.

TOXICITY PROFILE OF SMALL-MOLECULE IAP ANTAGONIST GDC-0152 IS LINKED TO TNF-ALPHA PHARMACOLOGY.

Toxicol Sci. 2012 Sep 5;

Authors: Erickson RI, Tarrant J, Cain G, Lewin-Koh SC, Dybdal N, Wong H, Blackwood E, West K, Steigerwalt R, Mamounas M, Flygare JA, Amemiya K, Dambach D, Fairbrother WJ, Diaz D

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-?B transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-?) is the most important for single-agent tumor activity. TNF-? 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-? upon IAP antagonism, increased TNF-? could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after intravenous dose administration once every two 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-?-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 MCP-1 and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers.

PMID: 22956632 [PubMed - as supplied by publisher]

NF-kB signaling NF-kappaB signaling pathway NF-kB signaling pathway