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.

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

“…Furthermore, preclinical data provides a strong rationale for several combinations with radiation and chemotherapeutics, including the apoptotic agonist TRAIL (Fulda and Vucic, 2012). The preclinical data also point to the potential for on-target toxicities (Erickson et al, 2013; Yang and Novack, 2013). To date, clinical trials are too early to assess anticancer activity, but the clinical compounds appear to behave well and are tolerated at doses that show strong pharmacodynamics effects (Jeffrey R. Infante, 2010; Tolcher et al, 2013).…”

Small-molecule SMAC mimetics as new cancer therapeutics

“…A pertinent concern in the clinical development of SMAC mimetics surrounds the consequences of SMAC mimetic-stimulated NF-κB activation, including the potential adverse effects of elevated levels of cytokines and chemokines on normal tissues. Administration of GDC-0152, for example, causes acute induction of TNFα in the plasma of dogs and rats and GDC-0152 demonstrates a toxicity profile consistent with TNFα-mediated toxicity [145]. The onset and resolution of these acute toxicities generally tracks with the time course of GDC-0152-induced cytokine [145].…”

“…Administration of GDC-0152, for example, causes acute induction of TNFα in the plasma of dogs and rats and GDC-0152 demonstrates a toxicity profile consistent with TNFα-mediated toxicity [145]. The onset and resolution of these acute toxicities generally tracks with the time course of GDC-0152-induced cytokine [145]. Despite these potential toxicity concerns based upon in preclinical data, patients administered intravenous doses of GDC-0152 up to 1.48 mg/kg showed no signs of a severe TNFα-driven systemic inflammatory response [146] and severe cytokine release syndrome, caused by an acute increase in plasma TNFα and other inflammatory cytokines, has not been reported in patients [142–144].…”

Breast cancer: Small molecules targeting apoptosis, a prospective approach to safe scientific success

“…caspase-8, and its downstream targets [27]. Interestingly, TRAIL seems to exert selective toxicity towards neoplastic cells, possibly because of the presence in normal cells of high levels of decoy receptors or the caspase-8 antagonist FLICE-inhibitory protein [26].…”

“…Accordingly, expression of caspase-3 in the human MCF-7 breast tumor cell line (which is deficient for caspase-3) restores the apoptotic response to the topoisomerase II inhibitor, etoposide [50]. Caspase-3 was also involved in breast cancer cell apoptosis upon exposure to anthracyclines and cisplatin [27,51]. Its role in tumor cell response to paclitaxel has been challenged [11].…”