MB-67DUAL TARGETING OF PI3K AND mTOR SIGNALING IN MEDULLOBLASTOMA

Abstract

MB-67. DUAL TARGETING OF PI3K AND mTOR SIGNALING IN MEDULLOBLASTOMA Jessica Clymer1,2, Frank Eckerdt2, Jonathan Bell2, Rishi Lulla1,2, Stewart Goldman1,2, and Leonidas Platanias2,3; Division of Hematology/ Oncology/Stem Cell Transplantation, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA BACKGROUND: Aberrant activation of the PI3K pathway has been shown to play a role in medulloblastoma cell proliferation, while mTOR activation contributes to therapy resistance. Here we sought to evaluate the effects of combined targeting of the PI3K and mTOR pathways in medulloblastoma. METHODS: Medulloblastoma cell lines Daoy and D556 were grown in 2-D cultures to investigate the effects of pharmacologic inhibition of PI3K and mTORon kinase signaling, medulloblastomacell proliferation, colony formation, and apoptosis. After knockdown of p110 isoforms, cells were also grown under stem cell conditions as 3-D neurospheres and subjected to extreme limiting dilution analysis (ELDA) for assessment of stem-like cancer cell growth. RESULTS: Of all class I PI3K isoforms (p110a, p110b, p110d, and p110g), only p110a was essential for medulloblastoma cell proliferation, colony formation and neurosphere growth. Accordingly, pharmacologic targeting of the p110a isoform of PI3K with BYL-719 synergizedwith the mTOR inhibitor OSI-027, as it resulted in inhibition of effector pathways, blocked cell proliferation and colony formation, and increased malignant cell death by apoptosis. Finally,BYL-719and OSI-027 greatly impairedgrowthof stem-likecancer cells as 3-D neurospheres. CONCLUSIONS: The p110a isoform of PI3K exerts crucial roles in medulloblastoma. Inhibition of p110a and mTOR exerts potent antineoplastic effects on medulloblastoma cells and also blocks neurosphere growth. Dual inhibition of p110a and mTOR might be promising for targeting both malignant medulloblastoma cells and the therapy-resistant cancer stem cell population. Neuro-Oncology 18:iii97–iii122, 2016. doi:10.1093/neuonc/now076.63 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.