title: In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma.
abstract: Glioblastoma multiforme (GBM), which account for more than 50% of all gliomas, is among the deadliest of all human cancers. Given the dismal prognosis of GBM, it would be advantageous to identify early biomarkers of a response to therapy to avoid continuing ineffective treatments and to initiate other therapeutic strategies. The present in vivo longitudinal study in an orthotopic mouse model demonstrates quantitative assessment of early treatment response during short-term chemotherapy with temozolomide (TMZ) by amide proton transfer (APT) imaging. In a GBM line, only one course of TMZ (3 d exposure and 4 d rest) at a dose of 80 mg/kg resulted in substantial reduction in APT signal compared with untreated control animals, in which the APT signal continued to increase. Although there were no detectable differences in tumor volume, cell density, or apoptosis rate between groups, levels of Ki67 (index of cell proliferation) were substantially reduced in treated tumors. In another TMZ-resistant GBM line, the APT signal and levels of Ki67 increased despite the same course of TMZ treatment. As metabolite changes are known to occur early in the time course of chemotherapy and precede morphologic changes, these results suggest that the APT signal in glioma may be a useful functional biomarker of treatment response or degree of tumor progression. Thus, APT imaging may serve as a sensitive biomarker of early treatment response and could potentially replace invasive biopsies to provide a definitive diagnosis. This would have a major impact on the clinical management of patients with glioma.
authors.affiliation: Advanced Imaging Research Center, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, and Departments of Neurology and Neurotherapeutics, Pathology, Neurosurgery, and Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Koji
authors.initials: K
authors.lastname: Sagiyama
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mashimo
authors.forename: Osamu
authors.initials: O
authors.lastname: Togao
authors.forename: Vamsidhara
authors.initials: V
authors.lastname: Vemireddy
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maher
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Mickey
authors.forename: Edward
authors.initials: E
authors.lastname: Pan
authors.forename: A Dean
authors.initials: AD
authors.lastname: Sherry
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bachoo
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011379:Prognosis; D000077204:Temozolomide; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D000077204:Temozolomide
keywords: chemical exchange transfer imaging; chemoresistance; molecular MRI