title: A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy.
abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumor and among the most difficult to treat malignancies per se. In almost 90% of all GBM alterations in the PI3K/Akt/mTOR have been found, making this survival cascade a promising therapeutic target, particular for combination therapy that combines an apoptosis sensitizer, such as a pharmacological inhibitor of PI3K, with an apoptosis inducer, such as radio- or chemotherapy. However, while in vitro data focusing mainly on established cell lines has appeared rather promising, this has not translated well to a clinical setting. In this study, we analyze the effects of the dual kinase inhibitor PI-103, which blocks PI3K and mTOR activity, on three matched pairs of GBM stem cells/differentiated cells. While blocking PI3K-mediated signaling has a profound effect on cellular proliferation, in contrast to data presented on two GBM cell lines (A172 and U87) PI-103 actually counteracts the effect of chemotherapy. While we found no indications for a potential role of the PI3K signaling cascade in differentiation, we saw a clear and strong contribution to cellular motility and, by extension, invasion. While blocking PI3K-mediated signaling concurrently with application of chemotherapy does not appear to be a valid treatment option, pharmacological inhibitors, such as PI-103, nevertheless have an important place in future therapeutic approaches.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany; Department of Neurosurgery, University Medical Center Ulm, Ulm, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ströbele
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany; Department of Neurosurgery, University Medical Center Ulm, Ulm, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Schneele
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nonnenmacher
authors.affiliation: Department of Clinical Chemistry, University Medical Center Ulm, Ulm, Germany.
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Zhou
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massler
authors.affiliation: Department of Neurosurgery, University Medical Center Ulm, Ulm, Germany; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massle
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Mike-Andrew
authors.initials: MA
authors.lastname: Westhoff
authors.affiliation: Department of Neurosurgery, University Medical Center Ulm, Ulm, Germany.
authors.forename: Marc-Eric
authors.initials: ME
authors.lastname: Halatsch
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005663:Furans / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide; C522973:PI103