title: Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma.
abstract: Brainstem gliomas (BSG) are a rare group of central nervous system tumors that arise mostly in children and usually portend a particularly poor prognosis. We report the development of a genetically engineered mouse model of BSG using the RCAS/tv-a system and its implementation in preclinical trials. Using immunohistochemistry, we found that platelet-derived growth factor (PDGF) receptor alpha is overexpressed in 67% of pediatric BSGs. Based on this observation, we induced low-grade BSGs by overexpressing PDGF-B in the posterior fossa of neonatal nestin tv-a mice. To generate high-grade BSGs, we overexpressed PDGF-B in combination with Ink4a-ARF loss, given that this locus is commonly lost in high-grade pediatric BSGs. We show that the likely cells of origin for these mouse BSGs exist on the floor of the fourth ventricle and cerebral aqueduct. Irradiation of these high-grade BSGs shows that although single doses of 2, 6, and 10 Gy significantly increased the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei, only 6 and 10 Gy significantly induce cell cycle arrest. Perifosine, an inhibitor of AKT signaling, significantly induced TUNEL-positive nuclei in this high-grade BSG model, but in combination with 10 Gy, it did not significantly increase the percent of TUNEL-positive nuclei relative to 10 Gy alone at 6, 24, and 72 hours. Survival analysis showed that a single dose of 10 Gy significantly prolonged survival by 27% (P = 0.0002) but perifosine did not (P = 0.92). Perifosine + 10 Gy did not result in a significantly increased survival relative to 10 Gy alone (P = 0.23). This PDGF-induced BSG model can serve as a preclinical tool for the testing of novel agents.
authors.affiliation: Departments of Cancer Biology and Genetics, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
authors.forename: Talia R
authors.initials: TR
authors.lastname: Walker
authors.forename: Karim
authors.initials: K
authors.lastname: Helmy
authors.forename: Javad
authors.initials: J
authors.lastname: Nazarian
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hiner
authors.forename: Sarah
authors.initials: S
authors.lastname: Gall
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: MacDonald
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
mesh_terms: D000818:Animals; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005818:Genetic Engineering; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D007178:Inbreeding; D051379:Mice; D008807:Mice, Inbred BALB C; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis
chemical_list: D010767:Phosphorylcholine; C105905:perifosine; D020796:Receptor, Platelet-Derived Growth Factor alpha