Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma

Oren J. Becher, Dolores Hambardzumyan, Talia R. Walker, Karim Helmy, Javad Nazarian, Steffen Albrecht, Rebecca L. Hiner, Sarah Gall, Jason T. Huse, Nada Jabado, Tobey J. MacDonald, Eric C. Holland

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

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 α 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.

Original languageEnglish (US)
Pages (from-to)2548-2557
Number of pages10
JournalCancer Research
Volume70
Issue number6
DOIs
StatePublished - Mar 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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