? Neuroblastoma accounts for 8-10% of all childhood malignancies. One of the key predictors of treatment failure in this disease is amplification of the N-myc oncogene. In this proposal, a screen for inhibitors of the N-myc oncoprotein will be used to identify new anti-neuroblastoma pharmaceuticals. A cell based readout system for screening small molecule chemical libraries has been developed based on the transactivation of luciferase activity by N-myc. Phase I of this project includes high throughput screening of chemical libraries with the aims of 1) identifying putative inhibitors of N-myc mediated transcription and 2) characterizing candidates for their ability to suppress a panel of neuroblastoma cell lines and other cancer cells.
These aims will be addressed by measuring the luciferase activity from small molecule-treated readout cells and filtering out non-specific and generally toxic chemicals. From these studies, prospective lead compounds will be identified. In Phase II, structure optimization of leads will be performed and compounds will be characterized in greater detail, including in vivo bioavailability and efficacy studies in human neuroblastoma xenografts and a murine model of this disease. Completion of Phase II will identify those molecules that have the potential to be used clinically in neuroblastoma treatment regimens. ? ? ? ?
