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

   

Authors:	Becher, O. J.; Hambardzumyan, D.; Walker, T. R.; Helmy, K.; Nazarian, J.; Albrecht, S.; Hiner, R. L.; Gall, S.; Huse, J. T.; Jabado, N.; MacDonald, T. J.; Holland, E. C.
Article 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 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. ©2010 AACR.
Keywords:	immunohistochemistry; signal transduction; adolescent; cancer chemotherapy; cancer survival; child; clinical article; controlled study; preschool child; school child; human cell; nonhuman; cancer radiotherapy; radiation dose; combined modality therapy; nuclear magnetic resonance imaging; glioma; mouse; animals; mice; animal tissue; platelet derived growth factor alpha receptor; gene overexpression; receptor, platelet-derived growth factor alpha; animal experiment; animal model; gene locus; tumor biopsy; mice, inbred balb c; genetic engineering; quantitative analysis; clinical evaluation; cell cycle arrest; external beam radiotherapy; disease models, animal; nick end labeling; brain stem neoplasms; nestin; perifosine; phosphorylcholine; platelet derived growth factor b; brain aqueduct; brain fourth ventricle; brain stem glioma; posterior fossa; inbreeding
Journal Title:	Cancer Research
Volume:	70
Issue:	6
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2010-03-15
Start Page:	2548
End Page:	2557
Language:	English
DOI:	10.1158/0008-5472.can-09-2503
PUBMED:	20197468
PROVIDER:	scopus
PMCID:	PMC3831613
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-77950232139&partnerID=40&md5=497f7094c3ed01213244c7bb3d63b80a
Notes:	--- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus"

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