Grant: Team Grant: Terry Fox New Frontiers Program in Cancer (LOI)

The inhibitors of apoptosis (IAPs) are oncogenes and important cancer targets. Small molecule pan-IAP antagonists, particularly bivalent Smac mimetics, represent a novel class of drugs with unexpected mechanism of action. Smac mimetic compounds have the potential to treat a diverse group of cancers that can respond to activation of various death receptor pathways. Clinical proof of principle has been demonstrated by members of this team with respect to the specific antagonism of one such IAP, through an antisense-based approach. As an extension to our findings, we seek to take a clinical candidate Smac mimetic into phase I/II trials for pediatric neural tumors (neuroblastoma, medullo-blastoma, glioblastoma) and adult hematological cancers (acute myeloid leukemia, lymphoma, myeloma). In addition, the specific mechanism of action and the identi-fication of biomarkers for Smac mimetics, will be defined. The present proposal assembles an emerging team with the necessary basic and clinical expertise to translate our findings to the clinic for the treatment of cancer.