Abstract 1599: Radiosensitization of GBM by a novel peptidomimetic of the Second Mitochondria-derived Activator of Caspases (SMAC).

Abstract

Abstract TL32711 is a novel small molecule peptidomimetic of the SMAC (Second Mitochondria-derived Activator of Caspases) that promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway. Normally SMAC is located in the mitochondria; however it is released into the cytosol when cells undergo apoptosis. Release into the cytosol and cleavage of SMAC promotes caspase-9 activation by binding to inhibitors of apoptosis proteins, IAPs. Removing the inhibitory activity of IAPs increases cells’ sensitivity to apoptotic stimuli and abrogates NF-κB survival signaling. Thus, by targeting and eliminating IAPs, SMAC mimetics re-activate death signals in cancer cells, inhibit resistance mechanisms and induce tumor death by apoptosis. This study was undertaken to determine radiation sensitization potential of TL32711 in GBM using in vitro and in vivo approaches. TL32711 alone did not cause any killing effects in GBM cells. However, in vitro apoptosis was increased when TL32711 was combined with radiation in GBM cell lines. In vivo data demonstrated that TL32711 alone delayed the growth of implanted xenograft tumors that were further delayed when combined with radiation. The survival of mice was greatly increased in TL32711 plus radiation treated GBM intracranial orthotopic model when compared to TL32711 or radiation treatment alone. Mechanistically, TL32711 confers radiation sensitization by abrogating NFκB activity that is elevated by radiation-induced TNF-α. Taken together, this is the first report that provides strong evidence that TL32711 in combination with ionizing radiation has potential to increase the effectiveness of radiotherapy. Funded by NCI Contract No. HHSN261200800001E. Citation Format: David Cerna, Donna Carter, Naoko Takebe, C. Norman Coleman, Mansoor M. Ahmed, Stephen Yoo. Radiosensitization of GBM by a novel peptidomimetic of the Second Mitochondria-derived Activator of Caspases (SMAC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1599. doi:10.1158/1538-7445.AM2013-1599