title: Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.
abstract: BACKGROUND
  Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG.
  
  
  METHODS
  A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo.
  
  
  RESULTS
  In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice.
  
  
  CONCLUSIONS
  Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America.|Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Tammy
authors.initials: T
authors.lastname: Hennika
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Guo
authors.initials: G
authors.lastname: Hu
authors.affiliation: Preclinical Therapeutics and Drug Delivery Research Program, Fundacio Sant Joan de Deu, Barcelona, Spain.|Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain.
authors.forename: Nagore G
authors.initials: NG
authors.lastname: Olaciregui
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Barton
authors.affiliation: Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.
authors.forename: Anahid
authors.initials: A
authors.lastname: Ehteda
authors.affiliation: Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.
authors.forename: Arjanna
authors.initials: A
authors.lastname: Chitranjan
authors.affiliation: Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chang
authors.affiliation: Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.|Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gifford
authors.affiliation: Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Tsoli
authors.affiliation: Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.|Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ziegler
authors.affiliation: Preclinical Therapeutics and Drug Delivery Research Program, Fundacio Sant Joan de Deu, Barcelona, Spain.|Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain.
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carcaboso
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America.|Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States of America.|Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D002999:Clone Cells; D005818:Genetic Engineering; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008810:Mice, Inbred C57BL; D000077767:Panobinostat; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat