Abstract Despite improvements in survival rates for childhood cancer over recent decades, a number of malignancies remain refractory to standard chemotherapy. Amongst these is neuroblastoma, the commonest solid tumour of young children. Children diagnosed with high-risk neuroblastoma still have dismal survival rates, hence alternative therapies are urgently required. The MYCN oncogene is the single most powerful biologic prognostic factor identified in childhood neuroblastoma. Children whose tumours display MYCN amplification have particularly poor prognosis, and the possibility of delivering highly effective therapies targeting the MYCN pathway is an area of research with enormous potential. In this regard, we have used a variety of approaches, to identify and validate key genes associated with MYCN, to use existing or novel therapeutics in new combinations to develop promising treatment strategies targeting these genes, and finally, to develop novel inhibitors of key MYCN-associated genes through cell-based screening of chemical small molecule libraries. One of the best characterised MYCN downstream target genes is the ornithine decarboxylase (ODC1) gene, which is role-limiting for polyamine biosynthesis. We have previously shown that ODC1 is a therapeutic target for neuroblastoma (Hogarty et al 2008, Cancer Res 68 (23): 9735-9745), and that in a range of pre-clinical models, targeting multiple steps in the polyamine pathway enhances therapeutic efficacy. Based on these findings, an international Phase I trial for refractory neuroblastoma, coordinated by the NANT consortium is now active, using ODC1 inhibition by high dose DFMO and SAT1 induction by celecoxib. We have since shown that MYCN regulates not only ODC1 but every gene in the polyamine pathway, in order to drive cellular proliferation, highlighting the importance of this pathway as a therapeutic target in neuroblastoma. In seeking to identify molecular targets that interact with or regulate MYCN/myc, are relevant to neuroblastoma biology and which have clear potential for molecular targeting in the clinical setting, we have recently focused on FACT (Facilitates Chromatin Transcription), a chromatin remodelling complex which has been shown to associate with myc. High levels of the genes encoding each of the two FACT subunits are strongly predictive of poor neuroblastoma outcome. Chromatin-trapping of the FACT complex by Curaxins, a recently described class of non-genotoxic compounds which simultaneous inhibit NFkB and active p53, is associated with strong anti-tumour activity (Gasparian et al 2011, Sci Transl Med 3:95ra74. DOI:10.1126). We have studied the effects of the lead curaxin compound in clinical trials, CBL0137, in two independent mouse models of neuroblastoma. As a single agent, CBL0137, administered either by gavage or iv had remarkable anti-tumour activity in both MYCN transgenic mice and also in nude mice xenografted with human neuroblastoma BE(2)-C cells. Most dramatic results were observed when iv CBL0137 was combined with the cyclophosphamide/topotecan, commonly used to treat relapsed neuroblastoma. This treatment resulted in cure of 90% of tumour-bearing MYCN-transgenic mice and a doubling of the lifespan of nude mice xenografted with BE(2)-C human neuroblastoma cells. These results are the most impressive we have ever observed for any therapeutic protocols in these models, and a Phase I trial of CBL0137 in refractory pediatric cancer patients is currently being planned. We have previously shown that the Multidrug Resistance-associated Proteins MRP1 and MRP4 are regulated by the MYCN oncogene and that high levels of these genes are strongly predictive of poor outcome in neuroblastoma (Henderson et al 2011, J Natl Cancer Inst 103 (16): 1236-1251). We have employed cell based screening of chemical small molecule libraries to successfully identify inhibitors of these molecular targets. More recently, we have used chemical library screening to identify a novel molecule, M606, which dramatically reduces MYCN protein levels and activity in human MYCN-amplified neuroblastoma cells, as well as c-myc protein levels in myc-overexpressing tumour cells. M606 inhibits growth of human neuroblastoma cells in a dose-dependent manner. M606 causes HIF1a protein accumulation and nuclear translocation, but this effect is independent of MYCN/MYC down-regulation. M606 is structurally related to a family of prolyl hydroxylase inhibitors, and inhibits prolyl hydroxylase activity. In common with some, but not all propyl hydroxylase inhibitors, for example, desferrioxamine (DFO), M606 appears to have iron chelating activity, and the effects of M606 on MYCN/Myc and HIF1a levels are entirely reversible by addition of iron. However, M606 is far more potent and less toxic than DFO, and inhibits the progression of tumours in MYCN transgenic mice. M606 thus appears to represent a novel molecule for targeting the MYCN oncogene in neuroblastoma. Citation Format: Michelle Haber. Targeting MYCN-driven neuroblastoma using novel therapeutic approaches. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA24.
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Jul 16, 2021
Susumu Ohya + 5
