Abstract 1939: TL32711, a novel Smac mimetic, exerts significant antitumor efficacy in primary pancreatic adenocarcinoma model
Authors: Ma Wen Wee , Zhang Hao , Hylander Bonnie , LeVea Charles , Repasky Elizabeth , Weng David , Burns Jennifer , Chunduru Srinivas , Graham Martin , Fetterly Gerald , McKinlay Mark , Adjei Alex 
Published: August 2012

Abstract
Introduction. Pancreatic cancer is highly resistant to treatment. Inhibitors of apoptosis (IAPs) were overexpressed in pancreatic cancer cells and IAPs downregulation were shown to induce sensitivity to death receptor signaling, cytotoxic agents and radiation. TL32711, a novel Smac mimetic, is a potent IAP antagonist that induces caspase-dependent apoptosis and NFkB canonical pathway inactivation. Here, we investigated the efficacy of TL32711 using a patient-derived primary pancreatic cancer explant model that mirrors the disease's biological heterogeneity. Methods. Effect of TL32711 alone and with TRAIL was evaluated in Panc1 by immunoblotting and Trypan blue staining. Dose escalation studies were performed in 2 primary pancreatic tumors at i.p. 30 mg/kg, 45 mg/kg and 60 mg/kg twice weekly and tumor volume were measured for 28 days. No significant toxicity was observed in tumor-bearing mice at all dose levels. An additional 6 primary pancreatic tumors were evaluated at 60 mg/kg. H&E slides of donor patients for these tumors were evaluated and untreated tumors analyzed by gene microarrays to explore for potential efficacy biomarkers. Tumor, plasma and liver samples were obtained from dose escalation studies for pharmacokinetic analysis. Results. TL32711 treatment resulted in rapid cIAP1 degradation leading to caspase-3 activation in Panc1, and exerted a dose-dependent pro-apoptotic effect that was synergized with TRAIL co-incubation in in vitro studies. In primary tumor explant studies, TL32711 dosed at 60 mg/kg exerted significant growth arrest/inhibition in 6 primary tumors (T/C range −0.1 to 0.2) and suboptimal growth inhibition in 2 (T/C ∼0.4). H&E slides of resected pancreatic cancer specimens for 7 donor patients were available for evaluation, and there was no relationship between histological findings (inflammatory infiltrate, stroma, neutrophil/lymphocyte ratio and necrosis) and in vivo TL32711 efficacy. Dose escalation studies showed a dose-dependent growth inhibitory effect of TL32711 in 2 primary tumors: 30mg/kg achieved significant growth inhibition in #17624 but not #12872. Significant growth inhibition was achieved in both at &gt;= 45 mg/kg. Pharmacokinetic analysis showed that TL32711 efficacy correlated with tumor drug exposure and that tumor concentrations at the effective doses were in the range of what is achievable in patients’ tumors at clinically tolerable doses. Results from gene microarray analysis will be summarized. Conclusions. TL32711 demonstrated significant single agent efficacy in pancreatic cancer that correlated with tumor drug exposure, and the efficacious tumor drug exposure here is achievable in tumors at tolerated doses in clinical studies. Clinical trials evaluating TL32711 in pancreatic cancer are planned.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1939. doi:1538-7445.AM2012-1939