title: Pulling the plug on a cancer cell by eliminating XIAP with AEG35156.
abstract: XIAP, the X-linked inhibitor of apoptosis, is the best example of an endogenous cellular suppressor of apoptosis. XIAP is effective because it directly limits the activity of several critical death-inducing caspases, notably caspase-3, -7 and -9, either by direct enzyme inhibition or through ubiquitin-mediated proteasomal degradation. Furthermore, XIAP acts simultaneously at several nodes in the apoptotic cascade, blocking both the intrinsic and extrinsic death pathways, and thereby preventing feed-forward amplification loops that would otherwise lead to cell death. XIAP over-expression, or increased activity, is associated with cancer progression, resistance to therapy and poor prognosis. Targeting XIAP gene expression by antisense oligonucleotides, or other approaches, demonstrates anti-cancer effects with XIAP down-regulation. These early preclinical studies led to the development of a clinical candidate mixed-backbone antisense oligonucleotide, AEG35156, against XIAP for the treatment of cancer. Published clinical results for the first-in-class and first-in-human trials of AEG35156 are summarized herein, including single agent and combination chemotherapy phase-I or -II trials for solid tumors, lymphoma, and acute myeloid leukemia. These trials demonstrate the safety of AEG35156, as well as some initial promising signs of anti-cancer activity.
authors: Apoptosis Research Centre, CHEO RI2, Children's Hospital of Eastern Ontario, 401 Smyth Rd., Ottawa, ON, Canada K1H 8L1. eric@arc.cheo.ca
authors: Eric C
authors: EC
authors: LaCasse
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002986:Clinical Trials as Topic; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011379:Prognosis; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: C498209:AEG 35156; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D051636:X-Linked Inhibitor of Apoptosis Protein; D020169:Caspases