Detection of Early Response to Temozolomide Treatment in Brain Tumors Using Hyperpolarized C-13 MR Metabolic Imaging

Surbeck Laboratory of Advanced Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
Journal of Magnetic Resonance Imaging (Impact Factor: 3.21). 06/2011; 33(6):1284-90. DOI: 10.1002/jmri.22563
Source: PubMed


To demonstrate the feasibility of using DNP hyperpolarized [1-(13)C]-pyruvate to measure early response to temozolomide (TMZ) therapy using an orthotopic human glioblastoma xenograft model.
Twenty athymic rats with intracranial implantation of human glioblastoma cells were divided into two groups: one group received an oral administration of 100 mg/kg TMZ (n = 10) and the control group received vehicle only (n = 10). (13)C 3D magnetic resonance spectroscopic imaging (MRSI) data were acquired following injection of 2.5 mL (100 mM) hyperpolarized [1-(13)C]-pyruvate using a 3T scanner prior to treatment (day D0), at D1 (days from treatment) or D2.
Tumor metabolism as assessed by the ratio of lactate to pyruvate (Lac/Pyr) was significantly altered at D1 for the TMZ-treated group but tumor volume did not show a reduction until D5 to D7. The percent change in Lac/Pyr from baseline was statistically different between the two groups at D1 and D2 (P < 0.008), while percent tumor volume was not (P > 0.2).
The results from this study suggest that metabolic imaging with hyperpolarized [1-(13)C]-pyruvate may provide a unique tool that clinical neuro-oncologists can use in the future to monitor tumor response to therapy for patients with brain tumors.

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    • "[1- 13 C]Pyruvate also has relatively longer í µí±‡1 relaxation time and rapid transport into the cells for subsequent metabolism [96]. Hyperpolarized [1- 13 C]pyruvate has been used to study the real-time flux of pyruvate to lactate noninvasively following anticancer therapies in xenograft models [97] [98] [99] [100] [101]. The first clinical trial of DNP-MRS has recently demonstrated the use of hyperpolarized [1- 13 C]pyruvate to examine prostate cancer metabolism in human [47] (Figure 1), and it paves the way to rapid translation of this exciting technology to clinical research and perhaps clinical practice [96]. "
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    Full-text · Article · Mar 2014
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    • "The duration of data acquisition was 60 s (12 temporally resolved images for each metabolite). This imaging approach allows the imaging window to be extended beyond a shorter (10–20 s), fixed window centered around a presumed temporal maximum of metabolites used in prior 13C MR spectroscopic imaging studies [6]–[8]. The magnitude images of 13C pyruvate and lactate were reconstructed by the default MR scanner software (k-space data were zero filled to 128×128 in plane matrix prior to Fourier transform). "
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    ABSTRACT: The phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is activated in more than88% of glioblastomas (GBM). New drugs targeting this pathway are currently in clinical trials. However, noninvasive assessment of treatment response remains challenging. By using magnetic resonance spectroscopy (MRS), PI3K/Akt/mTOR pathway inhibition was monitored in 3 GBM cell lines (GS-2, GBM8, and GBM6; each with a distinct pathway activating mutation) through the measurement of 2 mechanistically linked MR biomarkers: phosphocholine (PC) and hyperpolarized lactate.(31)P MRS studies showed that treatment with the PI3K inhibitor LY294002 induced significant decreases in PC to 34 %± 9% of control in GS-2 cells, 48% ± 5% in GBM8, and 45% ± 4% in GBM6. The mTOR inhibitor everolimus also induced a significant decrease in PC to 62% ± 14%, 57% ± 1%, and 58% ± 1% in GS-2, GBM8, and GBM6 cells, respectively. Using hyperpolarized (13)C MRS, we demonstrated that hyperpolarized lactate levels were significantly decreased following PI3K/Akt/mTOR pathway inhibition in all 3 cell lines to 51% ± 10%, 62% ± 3%, and 58% ± 2% of control with LY294002 and 72% ± 3%, 61% ± 2%, and 66% ± 3% of control with everolimus in GS-2, GBM8, and GBM6 cells, respectively. These effects were mediated by decreases in the activity and expression of choline kinase α and lactate dehydrogenase, which respectively control PC and lactate production downstream of HIF-1. Treatment with the DNA damaging agent temozolomide did not have an effect on either biomarker in any cell line. This study highlights the potential of PC and hyperpolarized lactate as noninvasive MR biomarkers of response to targeted inhibitors in GBM.
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