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.