title: Promising therapeutic targets in neuroblastoma.
abstract: Neuroblastoma, the most common extracranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease and have a 5-year event-free survival of <50%. New approaches with targeted therapy may improve efficacy without increased toxicity. In this review we evaluate 3 promising targeted therapies: (i) (131)I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical that is taken up by human norepinephrine transporter (hNET), which is expressed in 90% of neuroblastomas; (ii) immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, which is expressed on 98% of neuroblastoma cells; and (iii) inhibitors of anaplastic lymphoma kinase (ALK), a tyrosine kinase that is mutated or amplified in ~10% of neuroblastomas and expressed on the surface of most neuroblastoma cells. Early-phase trials have confirmed the activity of (131)I-MIBG in relapsed neuroblastoma, with response rates of ~30%, but the technical aspects of administering large amounts of radioactivity in young children and limited access to this agent have hindered its incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also shown activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small-molecule inhibitor of ALK has shown promising preclinical activity for neuroblastoma and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma.
authors.affiliation: Department of Pediatrics, UCSF Helen Diller Family Comprehensive Cancer Center, and UCSF Benioff Children's Hospital, UCSF Medical Center, University of California, San Francisco, CA 94143-0106, USA. matthayk@peds.ucsf.edu
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Rani E
authors.initials: RE
authors.lastname: George
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
mesh_terms: D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000077548:Anaplastic Lymphoma Kinase; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D000077547:Crizotinib; D005732:Gangliosides / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009432:Neural Crest / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011720:Pyrazoles; D011725:Pyridines; D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine; D000077547:Crizotinib; C019403:ganglioside, GD2; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases