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

Authors: Becher, Oren J  Hambardzumyan, Dolores  Walker, Talia R  Helmy, Karim  Nazarian, Javad  Albrecht, Steffen  Hiner, Rebecca L  Gall, Sarah  Huse, Jason T  Jabado, Nada  MacDonald, Tobey J  Holland, Eric C 
Citation: Becher OJ, etal., Cancer Res. 2010 Mar 15;70(6):2548-57. doi: 10.1158/0008-5472.CAN-09-2503. Epub 2010 Mar 2.
Pubmed: (View Article at PubMed) PMID:20197468
DOI: Full-text: DOI:10.1158/0008-5472.CAN-09-2503

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.

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CRRD Object Information
CRRD ID: 13702892
Created: 2018-07-23
Species: All species
Last Modified: 2018-07-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.