Abstract 1423: Effects of DFMO-based combination therapy in advanced stage neuroblastoma

Abstract

Abstract Neuroblastoma (NB) is the most common extra-cranial pediatric tumor. The survival probability for NB patients with disseminated disease and chemo-resistant tumors are despairingly low. Therefore, understanding the mechanisms underlying NB metastasis and chemo-resistance will be critical for developing effective chemotherapeutic strategies for NB in the future. The goal of the present study was to determine the efficacy of DFMO-based combination therapy in NB with MYCN over-expression. MYCN is a transcription factor that directly regulates the expression of ornithine decarboxylase (ODC), a polyamine biosynthesis enzyme that has been shown to be critical for the development of MYCN-amplified NB. Our previous studies have shown that the ODC inhibitor, alpha-difluoromethylornithine (DFMO), activates two opposing pathways in NB cells, one that induced G1 cell cycle arrest by regulating p27kip1 expression and phosphorylation, and a second pathway that activated Akt/PKB signaling to promote cell survival (Cancer Res, 2008, 68:9825-31). Therefore, in the present study, we investigated the efficacy of DFMO-based combinations with PI3K/Akt inhibitors for the treatment of NB. Intracellular polyamines were depleted with the ODC inhibitor α-difluoromethylornithine (DFMO), and the effects of the PI3K and Akt inhibitors on NB cell proliferation, migration and invasion were examined in NB cells. Our results show that DFMO and PI3K/Akt inhibitors were able to significantly inhibit NB proliferation, migration and invasion. However, the inhibitory effects were significantly augmented when DFMO was combined with either the PI3K or Akt inhibitor. In addition, these inhibitors, when administered alone, were able to induce p27kip1 protein accumulation, an effect that was enhanced when DFMO was combined with either the PI3K or Akt inhibitor. These combination treatments appeared to be more effective in NB cells over-expressing MYCN. Furthermore, down-regulating Akt expression also attenuated the anti-apoptotic effect induced by DFMO. The results suggest that the combination of DFMO with PI3K/Akt inhibitors is particularly effective at inhibiting cell proliferation, migration and invasion of NB cells over-expressiong MYCN, and the mechanism by which these processes are regulated involve p27kip1. Overall, this study provides further evidence that targeting both the polyamine synthesis pathway and the PI3K/Akt signaling pathway simultaneously may be an effective treatment strategy for NB, particularly because this combination inhibits multiple steps in the malignant progression of NB. In addition, this drug combination appears to be more effective in cells over-expressing MYCN, suggesting that the efficacy of this combination treatment may be greater in advanced stage NB with MYCN gene amplification. 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 1423. doi:10.1158/1538-7445.AM2011-1423