title: Molecular imaging coupled to pattern recognition distinguishes response to temozolomide in preclinical glioblastoma.
abstract: Non-invasive monitoring of response to treatment of glioblastoma (GB) is nowadays carried out using MRI. MRS and MR spectroscopic imaging (MRSI) constitute promising tools for this undertaking. A temozolomide (TMZ) protocol was optimized for GL261 GB. Sixty-three mice were studied by MRI/MRS/MRSI. The spectroscopic information was used for the classification of control brain and untreated and responding GB, and validated against post-mortem immunostainings in selected animals. A classification system was developed, based on the MRSI-sampled metabolome of normal brain parenchyma, untreated and responding GB, with a 93% accuracy. Classification of an independent test set yielded a balanced error rate of 6% or less. Classifications correlated well both with tumor volume changes detected by MRI after two TMZ cycles and with the histopathological data: a significant decrease (p < 0.05) in the proliferation and mitotic rates and a 4.6-fold increase in the apoptotic rate. A surrogate response biomarker based on the linear combination of 12 spectral features has been found in the MRS/MRSI pattern of treated tumors, allowing the non-invasive classification of growing and responding GL261 GB. The methodology described can be applied to preclinical treatment efficacy studies to test new antitumoral drugs, and begets translational potential for early response detection in clinical studies.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain; Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain; Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5PT, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Delgado-Goñi
authors.forename: Margarida
authors.initials: M
authors.lastname: Julià-Sapé
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Candiota
authors.forename: Martí
authors.initials: M
authors.lastname: Pumarola
authors.forename: Carles
authors.initials: C
authors.lastname: Arús
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D010363:Pattern Recognition, Automated; D000077204:Temozolomide; D047368:Tumor Burden
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide
keywords: DMSO; GL261 glioblastoma; pattern recognition; perturbation-enhanced MRSI; therapy response detection