title: A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.
abstract: The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase alpha in malignant glioma.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Qi-Wen
authors.initials: QW
authors.lastname: Fan
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Knight
authors.forename: David D
authors.initials: DD
authors.lastname: Goldenberg
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Keith E
authors.initials: KE
authors.lastname: Mostov
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D009944:Organoplatinum Compounds; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C448661:platinum 103; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C497132:PIK3CB protein, human