title: PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma.
abstract: Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.
authors.affiliation: Department of Pediatrics, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, United States of America.
authors.forename: Alok R
authors.initials: AR
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, United States of America.
authors.forename: Shweta
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Pediatrics, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, United States of America.
authors.forename: Muamera
authors.initials: M
authors.lastname: Zulcic
authors.affiliation: Department of Pediatrics, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Alcaraz
authors.affiliation: SignalRx Pharmaceuticals, San Diego, CA, United States of America.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Garlich
authors.affiliation: SignalRx Pharmaceuticals, San Diego, CA, United States of America.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Morales
authors.affiliation: Departments of Neurology and Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Yoon J
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Biostatistics Department, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Neurosurgery, UCSD Rady Children's Hospital, La Jolla, CA, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Levy
authors.affiliation: Department of Pathology, UCSD Rady Children's Hospital, La Jolla, CA, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Newbury
authors.affiliation: Department of Pathology, UCSD Rady Children's Hospital, La Jolla, CA, United States of America.
authors.forename: Denise
authors.initials: D
authors.lastname: Malicki
authors.affiliation: Biostatistics Department, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.affiliation: Department of Neurosciences Division of Child Neurology, UCSD Rady Children's Hospital, La Jolla, CA, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Crawford
authors.affiliation: Department of Pediatrics, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, United States of America.|Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, La Jolla, CA, United States of America.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005647:Fucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D005647:Fucosyltransferases; D053823:Hedgehog Proteins; D009025:Morpholines; D009245:NADH Dehydrogenase; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C000604649:NADH dehydrogenase subunit 2, mouse; C571178:NVP-BKM120; C465570:Shh protein, mouse; C541914:Fut4 protein, mouse; C487757:Pten protein, mouse