PMID- 20197468 OWN - NLM STAT- MEDLINE DCOM- 20100426 LR - 20211020 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 70 IP - 6 DP - 2010 Mar 15 TI - Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. PG - 2548-57 LID - 10.1158/0008-5472.CAN-09-2503 [doi] AB - 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. FAU - Becher, Oren J AU - Becher OJ AD - Departments of Cancer Biology and Genetics, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. FAU - Hambardzumyan, Dolores AU - Hambardzumyan D FAU - Walker, Talia R AU - Walker TR FAU - Helmy, Karim AU - Helmy K FAU - Nazarian, Javad AU - Nazarian J FAU - Albrecht, Steffen AU - Albrecht S FAU - Hiner, Rebecca L AU - Hiner RL FAU - Gall, Sarah AU - Gall S FAU - Huse, Jason T AU - Huse JT FAU - Jabado, Nada AU - Jabado N FAU - MacDonald, Tobey J AU - MacDonald TJ FAU - Holland, Eric C AU - Holland EC LA - eng GR - R01 CA100688/CA/NCI NIH HHS/United States GR - U01 CA141502/CA/NCI NIH HHS/United States GR - U54 CA126518/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20100302 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 107-73-3 (Phosphorylcholine) RN - 2GWV496552 (perifosine) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha) SB - IM MH - Animals MH - Brain Stem Neoplasms/*drug therapy/genetics/pathology/*radiotherapy MH - Combined Modality Therapy MH - *Disease Models, Animal MH - Genetic Engineering MH - Glioma/*drug therapy/genetics/pathology/*radiotherapy MH - Inbreeding MH - Mice MH - Mice, Inbred BALB C MH - Phosphorylcholine/*analogs & derivatives/pharmacology MH - Receptor, Platelet-Derived Growth Factor alpha/biosynthesis PMC - PMC3831613 MID - NIHMS171774 EDAT- 2010/03/04 06:00 MHDA- 2010/04/27 06:00 PMCR- 2013/11/18 CRDT- 2010/03/04 06:00 PHST- 2010/03/04 06:00 [entrez] PHST- 2010/03/04 06:00 [pubmed] PHST- 2010/04/27 06:00 [medline] PHST- 2013/11/18 00:00 [pmc-release] AID - 0008-5472.CAN-09-2503 [pii] AID - 10.1158/0008-5472.CAN-09-2503 [doi] PST - ppublish SO - Cancer Res. 2010 Mar 15;70(6):2548-57. doi: 10.1158/0008-5472.CAN-09-2503. Epub 2010 Mar 2.