Abstract 5274: Noninvasive early assessment of tumor response to the SMAC mimetic TL32711 with a caspase-3/7-specific PET imaging radiotracer

Abstract

Abstract The development of new imaging methods is highly desirable for noninvasive molecular characterization of tumors. The endpoint for most effective anti-cancer cytotoxic or mechanism-based therapies is cell death through apoptosis, and monitoring of this process could provide important predictive outcome information in clinical trials and routine patient management. Of the molecular biochemical alterations that occur during apoptosis, activation of caspases, notably caspase-3, is probably the most attractive for developing specific molecular imaging probes. In this context, we have recently developed the caspase-3/7 specific positron emission tomography imaging radiotracer [18F]ICMT-11 characterized by sub-nanomolar affinity for activated capsase-3, high metabolic stability, and facile radiolabeling. In the present study, we have investigated the ability of [18F]ICMT-11 to detect response to treatment in the preclinical longitudinal setting where the same mouse is subjected to pre-, 6h, 24h and 48h post- treatment PET imaging. The experimental model used was colon carcinoma HCT116 tumor-bearing mouse treated with 15mg/kg single dose of TL32711, a small molecule SMAC mimetic that selectively antagonizes Inhibitor of Apoptosis Proteins (IAPs), thus, specifically triggers caspase activation, apoptosis and single agent activity for tumor regression in multiple animal models. For comparison, we also assessed 38C13 lymphoma tumor-bearing mice treated with 40mg/kg single dose of the alkylating agent cyclophosphamide, in which apoptosis is associated with tumor regression. [18F]ICMT-11 molecular detection of caspase activation was also compared to tumor glucose metabolic activity assessment by [18F]FDG-PET. [18F]ICMT-11-PET detected increased caspase activity following a single dose of TL32711 or cyclophosphamide as early as 6 and 24hours post-treatment, respectively (1.5- and 2-fold compared to pre-treatment, respectively). At 48h post-treatment, tumor [18F]ICMT-11 uptake had decreased to pre-treatment levels indicating rapid dynamics of the apoptosis process. At the dose of TL32711 used, tumor [18F]FDG uptake decreased at 6h (1.16-fold) returning to baseline by 48h. In contrast, the cyclophosphamide model was characterized by progressive reduction of [18F]FDG uptake at 24 and 48h (1.7- and 2.6-fold compared to baseline, respectively). The study indicates that the time course of apoptosis is different to that of glucose metabolism for both drugs, with the observed changes likely to be dose-related. We have demonstrated utility of [18F]ICMT-11 PET imaging for the early assessment of drug response induced by the SMAC mimetic TL32711. Further studies will investigate potential use for [18F]ICMT-11-based detection of caspase activation in additional tumor models with TL32711, repetitive single agent dosing and drug combinations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5274. doi:10.1158/1538-7445.AM2011-5274