APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo

Abstract

Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomide. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted.

Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer

“…Previously published studies have shown several approaches to target FAS/FAS ligand signaling for cancer therapy, including administration of FAS agonist antibodies or FAS ligand recombinant proteins (22–26), FAS ligand gene therapy (27–29) or use of chemotherapeutic drugs to induce FAS or FAS ligand expression (30–32). Here, to overcome radioresistance in SUM159 and HCC1954 tumors, we hypothesized that activating FAS signaling with radiation may have a synergistic apoptotic effect.…”

Clinical targeting of the TNF and TNFR superfamilies

“…Agonist antibodies targeting FAS, or FASL expressed through adenoviral vector transfer, have shown antitumour activity in murine models, although this approach has been associated with hepatotoxicity and has therefore generated less interest than TRAILR-targeting antibodies 184 . Alternative reagents that might exhibit agonistic activity but low toxicity have been pursued, and a recombinant hexameric form of FASL (APO010) was found to reduce tumour survival in vitro and in animal tumour models 185,186 . A Phase I trial of APO010 was planned in 2007 in patients with solid tumours but the study was not carried out.…”

Targeting TRAIL in the treatment of cancer: new developments

“…Moreover, TNF failed to achieve durable responses, and eventually was abandoned from further clinical development beyond efforts that have continued for regional targeting of localized disease. Fas ligand (Apo1 ligand) was discovered as a putative anti-cancer drug development approach but was also abandoned [33,34]. A Fas receptor agonistic antibody strategy was developed, but discontinued from development after massive apoptosis in hepatocytes.…”