Neuroblastoma is a common and frequently lethal tumor of childhood. Amplification and over-expression of MYCN has been extensively characterized and is strongly correlated with an aggressive clinically course. We have generated mice that over-express MYCN in the neural crest. These mice develop tumors that have many clinical and genetic similarities to human neuroblastoma and therefore offer a model for the subset of tumors that are most refractory to current therapies. We hypothesize that the MYCN transgenic model will be valuable for the preclinical evaluation of biologically based therapies that hold promise in childhood neuroblastoma. This model should therefore lead to the rapid integration of rational therapeutic agents into treatment algorithms for high-risk neuroblastoma. This project has three Specific Aims. First, we will characterize this model in terms of the vascular biology, and to better assess its relationship with human neuroblastoma. We will define the natural history of murine neuroblastoma using serial MRI and necropsies, we will measure the expression of proteins important in angiogenesis and Trk signaling, and also compare the anti-tumor activity of a variety of cytotoxic agents with known activity against human neuroblastoma.
This aim i s designed to confirm that mice transgenic for MYCN are an important addition to preclinical developmental therapeutics for this disease. Second, we will test novel agents directed against neovascularization or neurotrophin signaling for efficacy in this model.
This Aim will validate the MYCN model for neuroblastoma-specific biologically based therapies and should lead to the clinical development of promising compounds. Third, we will test combination and low-dose continuous therapies. Successful completion of this aim should lead to an efficient mechanism to better characterize mechanisms, and to ascertain the preclinical efficacy of combination and continuous low dose therapies.
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| Huang, Miller; Miller, Matthew L; McHenry, Lauren K et al. (2016) Generating trunk neural crest from human pluripotent stem cells. Sci Rep 6:19727 |
| Vaughan, Lynsey; Clarke, Paul A; Barker, Karen et al. (2016) Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. Oncotarget 7:57525-57544 |
| Chen, Justin; Hackett, Christopher S; Zhang, Shile et al. (2015) The genetics of splicing in neuroblastoma. Cancer Discov 5:380-95 |
| Chen, J; Weiss, W A (2015) Alternative splicing in cancer: implications for biology and therapy. Oncogene 34:1-14 |
| Cage, Tene Aneka; Chanthery, Yvan; Chesler, Louis et al. (2015) Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer. Front Oncol 5:111 |
| Marshall, Glenn M; Carter, Daniel R; Cheung, Belamy B et al. (2014) The prenatal origins of cancer. Nat Rev Cancer 14:277-89 |
| Chen, Justin; Weiss, William A (2014) When deletions gain functions: commandeering epigenetic mechanisms. Cancer Cell 26:160-1 |
| Hackett, Christopher S; Quigley, David A; Wong, Robyn A et al. (2014) Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma. Cell Rep 9:1034-46 |
| Gustafson, William Clay; Meyerowitz, Justin Gabriel; Nekritz, Erin A et al. (2014) Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26:414-427 |
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