title: Identification of targets for rational pharmacological therapy in childhood craniopharyngioma.
abstract: BACKGROUND
  Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75-95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP.
  
  
  RESULTS
  Using mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib - LCK, EPHA2 and SRC; EGFR pathway targets - AREG, EGFR and ERBB3; and other potentially actionable cancer targets - SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples.
  
  
  CONCLUSIONS
  We report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Jacob.Gump@ucdenver.edu.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Gump
authors.affiliation: Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.affiliation: Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.affiliation: Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Amani
authors.affiliation: Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Karun K
authors.initials: KK
authors.lastname: Rao
authors.affiliation: Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Griesinger
authors.affiliation: Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.|Departments of Pathology and Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Kleinschmidt-DeMasters
authors.affiliation: Department of Neurosurgery, Children's Hospital Alabama, Birmingham, AL, 35233, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Johnston
authors.affiliation: Department of Neurological Surgery, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Richard C E
authors.initials: RC
authors.lastname: Anderson
authors.affiliation: Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, 85016, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Rosenfeld
authors.affiliation: Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.|Department of Neurosurgery, Children's Hospital Colorado, Aurora, CO, 80045, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Handler
authors.affiliation: Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.|Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, 80045, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.affiliation: Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.|Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, 80045, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Foreman
authors.affiliation: Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Todd.Hankinson@childrenscolorado.org.|Department of Neurosurgery, Children's Hospital Colorado, Aurora, CO, 80045, USA. Todd.Hankinson@childrenscolorado.org.|Adult and Child Center for Health Outcomes Research, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Todd.Hankinson@childrenscolorado.org.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Hankinson
mesh_terms: D000293:Adolescent; D066258:Amphiregulin; D002648:Child; D002675:Child, Preschool; D003397:Craniopharyngioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D066255:EGF Family of Proteins / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D011788:Quality of Life / Q000523:psychology*; D012333:RNA, Messenger / Q000378:metabolism*; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D012333:RNA, Messenger; C512478:EGFR protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D036104:Receptor, EphA2; D020893:Receptor, ErbB-3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases