title: Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.
abstract: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.
authors.affiliation: Centre for Systems Medicine, Department of Physiology and Medical Physics, St Stephen's Green, Dublin, Ireland.
authors.forename: Á C
authors.initials: ÁC
authors.lastname: Murphy
authors.forename: B
authors.initials: B
authors.lastname: Weyhenmeyer
authors.forename: J
authors.initials: J
authors.lastname: Schmid
authors.forename: S M
authors.initials: SM
authors.lastname: Kilbride
authors.forename: M
authors.initials: M
authors.lastname: Rehm
authors.forename: H J
authors.initials: HJ
authors.lastname: Huber
authors.forename: C
authors.initials: C
authors.lastname: Senft
authors.forename: J
authors.initials: J
authors.lastname: Weissenberger
authors.forename: V
authors.initials: V
authors.lastname: Seifert
authors.forename: M
authors.initials: M
authors.lastname: Dunst
authors.forename: M
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: D
authors.initials: D
authors.lastname: Kögel
authors.forename: J H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: B M
authors.initials: BM
authors.lastname: Murphy
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000633:toxicity; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism; D000077204:Temozolomide; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D003606:Dacarbazine; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D000077204:Temozolomide