title: Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide.
abstract: Due to its molecular heterogeneity and infiltrative nature, glioblastoma multiforme (GBM) is notoriously resistant to traditional and experimental therapeutics. To overcome these hurdles, targeted agents have been combined with conventional therapy. We evaluated the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor (XL765) in in vitro and in vivo studies. In vivo serially passaged human GBM xenografts that are more genetically stable than GBM cell lines in culture were used for all experiments. Biochemical downstream changes were evaluated by immunoblot and cytotoxicity by colorimetric ATP-based assay. For in vivo experiments, human xenograft GBM 39 grown intracranially in nude mice was altered to express luciferase to monitor tumor burden by optical imaging. XL765 resulted in concentration-dependent decreases in cell viability in vitro. Cytotoxic doses resulted in specific inhibition of PI3K signaling. Combining XL765 with temozolomide (TMZ) resulted in additive toxicity in 4 of 5 xenografts. In vivo, XL765 administered by oral gavage resulted in greater than 12-fold reduction in median tumor bioluminescence compared with control (Mann-Whitney test p = 0.001) and improvement in median survival (logrank p = 0.05). TMZ alone showed a 30-fold decrease in median bioluminescence, but the combination XL765 + TMZ yielded a 140-fold reduction in median bioluminescence (Mann-Whitney test p = 0.05) with a trend toward improvement in median survival (logrank p = 0.09) compared with TMZ alone. XL765 shows activity as monotherapy and in combination with conventional therapeutics in a range of genetically diverse GBM xenografts.
authors.affiliation: Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA. dhaaskogan@radonc.ucsf.edu
authors.forename: Gautam
authors.initials: G
authors.lastname: Prasad
authors.forename: Theo
authors.initials: T
authors.lastname: Sottero
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Mei-Yin
authors.initials: MY
authors.lastname: Polley
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozawa
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Dana T
authors.initials: DT
authors.lastname: Aftab
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide