Article
Assessment of treatment response in an orthotopic IDH1-mutant glioma model using in-vivo magnetic resonance spectroscopy – a feasibility study
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Authors
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Franziska Loebel
- Department of Neurosurgery, Charité University Medical Center, Berlin, Germany; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Athinoula Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA,USA; Brain Tumor Research Center, Tranlational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Kensuke Tateishi
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Brain Tumor Research Center, Tranlational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Philipp Huber
- Athinoula Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA,USA
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Hiroaki Wakimoto
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Brain Tumor Research Center, Tranlational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Andrew S. Chi
- Stephen E. and Catherine Pappas Center for Oncology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Brain Tumor Research Center, Tranlational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Daniel P. Cahill
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Brain Tumor Research Center, Tranlational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Ovidiu C. Andronesi
- Athinoula Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA,USA
| Published: | June 2, 2015 |
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Outline
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Objective: Recurrent IDH1-mutations in a distinct subset of human gliomas cause marked elevation of 2-hydroxyglutarate (2HG), which can be specifically detected using in-vivo Magnetic Resonance Spectroscopy (MRS). The present study demonstrates for the first time the use of in-vivo MRS in an orthotopic IDH1-mutant glioma model for assessment of treatment response to targeted therapies.
Method: Patient-derived IDH-mutant glioma stem cells were implanted stereotactically into the right frontal lobes of 26 immunodeficient (SCID-)mice. Tumor formation was confirmed in T2-weighted MRI-scans using a 15-Tesla small-bore animal scanner with a conventional spectroscopic imaging software. 1-dimensional unedited and spectral-edited multi-voxel spectroscopic measurements of 2HG were performed in mice with detectable tumors on T2-weighted imaging. The mice were then treated with small molecule inhibitors of IDH1 (400mg/kg p.o., 6 consecutive doses) and re-scanned following the treatment. Spectroscopic imaging was evaluated using LCModel software.
Results: Tumor formation was confirmed by T2-weighted imaging in 19/26 mice (73.1%). Detectable levels of 2HG were found in the majority (89.4%) of T2-confirmed gliomas. Significantly decreased levels of 2HG were found in post-treatment scans following targeted therapy with IDH1-inhibitors when compared to their corresponding baseline scans, confirming the feasibility of our method.
Conclusions: Our results show that assessment of treatment response is feasible in an orthotopic IDH1-mutant glioma model by assessment of 2HG with in-vivo MRS. This non-invasive, objective method has the potential to serve as diagnostic tool for pre-clinical testing of novel targeted therapies of IDH1-mutant gliomas. Further studies are needed to test and evaluate the potential of novel therapies.
