title: New strategies in neuroblastoma: Therapeutic targeting of MYCN and ALK.
abstract: Clinical outcome remains poor in patients with high-risk neuroblastoma, in which chemoresistant relapse is common following high-intensity conventional multimodal therapy. Novel treatment approaches are required. Although recent genomic profiling initiatives have not revealed a high frequency of mutations in any significant number of therapeutically targeted genes, two exceptions, amplification of the MYCN oncogene and somatically acquired tyrosine kinase domain point mutations in anaplastic lymphoma kinase (ALK), present exciting possibilities for targeted therapy. In contrast with the situation with ALK, in which a robust pipeline of pharmacologic agents is available from early clinical use in adult malignancy, therapeutic targeting of MYCN (and MYC oncoproteins in general) represents a significant medicinal chemistry challenge that has remained unsolved for two decades. We review the latest approaches envisioned for blockade of ALK activity in neuroblastoma, present a classification of potential approaches for therapeutic targeting of MYCN, and discuss how recent developments in targeting of MYC proteins seem to make therapeutic inhibition of MYCN a reality in the clinic.
authors: Authors' Affiliations: Paediatric Solid Tumour Biology and Therapeutics Team, Division of Clinical Studies, The Institute of Cancer Research; Children's and Young People's Unit Royal Marsden NHS Trust, Sutton; and Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, London, United Kingdom.
authors: Giuseppe
authors: G
authors: Barone
authors: John
authors: J
authors: Anderson
authors: Andrew D J
authors: AD
authors: Pearson
authors: Kevin
authors: K
authors: Petrie
authors: Louis
authors: L
authors: Chesler
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D058990:Molecular Targeted Therapy; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
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