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Oncotarget. 2017 Sep 1;8(41):69295-69302. doi: 10.18632/oncotarget.20619. eCollection 2017 Sep 19.

Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor.

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Department of Oncology, Division of Neuro-Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Radiological Sciences, Division of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pediatric Medicine, Division of Endocrinology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Division of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Starship Blood and Cancer Centre, Starship Children's Hospital, Auckland, NZ, USA.
Division of Pediatric Hematology/Oncology, The Haley Center for Children's Cancer and Blood Disorders at Arnold Palmer Hospital, Orlando, FL, USA.
Department of Haematology and Oncology, Princess Margaret Hospital for Children, School of Paediatrics and Child Health, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
Department of Neurology, Division of Child Neurology, Lucile Packard Children's Hospital at Stanford, Stanford University, Palo Alto, CA, USA.
Cancer and Blood Disorders Program, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
Pediatric Medical Neuro-Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Orthopedic Surgery, Campbell Clinic, University of Tennessee College of Medicine, Germantown, TN, USA.
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.


The permanent defects in bone growth observed in preclinical studies of hedgehog (Hh) pathway inhibitors were not substantiated in early phase clinical studies of vismodegib in children. Consequently, vismodegib advanced into pediatric trials for malignancies suspected of being driven by aberrant activation of the Hh pathway. In one multicenter phase II trial, vismodegib was added to the therapy regimen for newly diagnosed Hh pathway activated medulloblastoma. Herein, we report on 3 children (2 on trial and one off trial) treated with vismodegib who developed widespread growth plate fusions that persist long after cessation of therapy. Currently, all 3 patients exhibit profound short stature and disproportionate growth, and 2 subsequently developed precocious puberty. Notably, the growth plate fusions only developed after a prolonged exposure to the drug (> 140 days). These findings resulted in a major trial amendment to restrict the agent to skeletally mature patients as well as a product label warning and update. Moreover, these findings alter the risk-benefit ratio of Hh inhibitors and underscore the importance of careful study of targeted agents in children.


childhood toxicity; hedgehog inhibitor; medulloblastoma; premature physeal fusion; targeted therapy

Conflict of interest statement

CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

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