Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma.
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.
Becher
Oren J
OJ
Departments of Cancer Biology and Genetics, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Hambardzumyan
Dolores
D
Walker
Talia R
TR
Helmy
Karim
K
Nazarian
Javad
J
Albrecht
Steffen
S
Hiner
Rebecca L
RL
Gall
Sarah
S
Huse
Jason T
JT
Jabado
Nada
N
MacDonald
Tobey J
TJ
Holland
Eric C
EC
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
D010767:Phosphorylcholine; C105905:perifosine; D020796:Receptor, Platelet-Derived Growth Factor alpha