title: Targeting ALK in neuroblastoma--preclinical and clinical advancements.
abstract: Despite improvements in cancer therapies in the past 50 years, neuroblastoma remains                 a devastating clinical problem and a leading cause of childhood cancer deaths.                 Advances in treatments for children with high-risk neuroblastoma have, until                 recently, involved addition of cytotoxic therapy to dose-intensive regimens. In this                 era of targeted therapies, substantial efforts have been made to identify optimal                 targets for different types of cancer. The discovery of hereditary and somatic                 activating mutations in the oncogene ALK has now placed neuroblastoma among                 other cancers, such as melanoma and non-small-cell lung cancer (NSCLC), which                 benefit from therapies with oncogene-specific small-molecule tyrosine kinase                 inhibitors. Crizotinib, a small-molecule inhibitor of ALK, has transformed the                 landscape for the treatment of NSCLC harbouring ALK translocations and has                 demonstrated activity in preclinical models of ALK-driven neuroblastomas. However,                 inhibition of mutated ALK is complex when compared with translocated ALK and                 remains a therapeutic challenge. This Review discusses the biology of ALK in the                 development of neuroblastoma, preclinical and clinical progress with the use of ALK                 inhibitors and immunotherapy, challenges associated with resistance to such                 therapies and the steps being taken to overcome some of these hurdles.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research,                     Children's Hospital of Philadelphia, 3501 Civic Center                     Boulevard, Philadelphia, PA                 19104, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Carpenter
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mossé
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases