In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma

Koji Sagiyama, Tomoyuki Mashimo, Osamu Togao, Vamsidhara Vemireddy, Kimmo J. Hatanpaa, Elizabeth A. Maher, Bruce E. Mickey, Edward Pan, A. Dean Sherry, Robert M. Bachoo, Masaya Takahashi

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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.

Original languageEnglish
Pages (from-to)4542-4547
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number12
DOIs
Publication statusPublished - Mar 25 2014

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temozolomide
Glioblastoma
Amides
Protons
Glioma
Biomarkers
Therapeutics
Drug Therapy
Neoplasms
Tumor Burden
Longitudinal Studies
Cell Count
Cell Proliferation
Apoptosis
Biopsy

All Science Journal Classification (ASJC) codes

  • General

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In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma. / Sagiyama, Koji; Mashimo, Tomoyuki; Togao, Osamu; Vemireddy, Vamsidhara; Hatanpaa, Kimmo J.; Maher, Elizabeth A.; Mickey, Bruce E.; Pan, Edward; Sherry, A. Dean; Bachoo, Robert M.; Takahashi, Masaya.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 12, 25.03.2014, p. 4542-4547.

Research output: Contribution to journalArticle

Sagiyama, Koji ; Mashimo, Tomoyuki ; Togao, Osamu ; Vemireddy, Vamsidhara ; Hatanpaa, Kimmo J. ; Maher, Elizabeth A. ; Mickey, Bruce E. ; Pan, Edward ; Sherry, A. Dean ; Bachoo, Robert M. ; Takahashi, Masaya. / In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 12. pp. 4542-4547.
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