Abstract CN04-04: Targeting death receptors and SMAC mimetics.

Abstract

Abstract Evasion of apoptosis is a hallmark of human cancers and contributes to tumor formation and progression as well as resistance to current cancer therapies, which largely rely on intact cell death pathways in cancer cells. Apoptosis resistance can be caused by aberrant expression of antiapoptotic proteins, for example Inhibitor of Apoptosis (IAP) proteins, which are expressed at high levels in many human cancers. Since IAP proteins block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases, they present promising therapeutic targets. Smac mimetics are small-molecule inhibitors that mimick the IAP-binding motif of the endogenous IAP antagonist Smac and are among the most widely used strategies to antagonize IAP proteins. In addition to their use as single agents, Smac mimetics have been used in combination with various cytotoxic stimuli to trigger cell death in cancer cells, in particular together with death receptor ligands such as soluble TRAIL or TRAIL receptor agonists. For example in pancreatic cancer_ one of the most lethal types of cancer_ IAP antagonists were shown to synergize with TRAIL receptor agonists to induce apoptosis and suppress tumor growth in preclinical in vitro and in vivo models. Furthermore, Smac mimetics and TRAIL acted in concert to trigger apoptosis in CLL, even in patients with poor prognostic features such chemoresistant disease, p53 mutation or chromosome 17p deletion. Thus, Smac mimetics may open new perspectives to overcome resistance to death receptor-mediated apoptosis in various forms of human cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN04-04. Citation Format: Simone Fulda. Targeting death receptors and SMAC mimetics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN04-04.