title: Preclinical evaluation of the combination of mTOR and proteasome inhibitors with radiotherapy in malignant peripheral nerve sheath tumors.
abstract: About one half of malignant peripheral nerve sheath tumors (MPNST) have Neurofibromin 1 (NF1) mutations. NF1 is a tumor suppressor gene essential for negative regulation of RAS signaling. Survival for MPNST patients is poor and we sought to identify an effective combination therapy. Starting with the mTOR inhibitors rapamycin and everolimus, we screened for synergy in 542 FDA approved compounds using MPNST cells with a native NF1 loss in both alleles. We further analyzed the cell cycle and signal transduction. In vivo growth effects of the drug combination with local radiation therapy (RT) were assessed in MPNST xenografts. The synergistic combination of mTOR inhibitors with bortezomib yielded a reduction in MPNST cell proliferation. The combination of mTOR inhibitors and bortezomib also enhanced the anti-proliferative effect of radiation in vitro. In vivo, the combination of mTOR inhibitor (everolimus) and bortezomib with RT decreased tumor growth and proliferation, and augmented apoptosis. The combination of approved mTOR and proteasome inhibitors with radiation showed a significant reduction of tumor growth in an animal model and should be investigated and optimized further for MPNST therapy.
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Johns Hopkins University, Koch Building Rm. 257, 1550 Orleans Street, Baltimore, MD, 21231, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Yamashita
authors.forename: G S
authors.initials: GS
authors.lastname: Baia
authors.forename: J S Y
authors.initials: JS
authors.lastname: Ho
authors.forename: E
authors.initials: E
authors.lastname: Velarde
authors.forename: J
authors.initials: J
authors.lastname: Wong
authors.forename: G L
authors.initials: GL
authors.lastname: Gallia
authors.forename: A J
authors.initials: AJ
authors.lastname: Belzberg
authors.forename: E T
authors.initials: ET
authors.lastname: Kimura
authors.forename: G J
authors.initials: GJ
authors.lastname: Riggins
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009442:Neurilemmoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D010455:Peptides / Q000494:pharmacology; D010524:Peripheral Nervous System Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011839:Radiation, Ionizing; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; C544608:T2635 peptide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus