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.
"[1- 13 C]Pyruvate also has relatively longer í µí±1 relaxation time and rapid transport into the cells for subsequent metabolism . 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     . 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  (Figure 1), and it paves the way to rapid translation of this exciting technology to clinical research and perhaps clinical practice . "
[Show abstract][Hide abstract] ABSTRACT: Cancer is known to have unique metabolic features such as Warburg effect. Current cancer therapy has moved forward from cytotoxic treatment to personalized, targeted therapies, with some that could lead to specific metabolic changes, potentially monitored by imaging methods. In this paper we addressed the important aspects to study cancer metabolism by using image techniques, focusing on opportunities and challenges of magnetic resonance spectroscopy (MRS), dynamic nuclear polarization (DNP)-MRS, positron emission tomography (PET), and mass spectrometry imaging (MSI) for mapping cancer metabolism. Finally, we highlighted the future possibilities of an integrated in vivo PET/MR imaging systems, together with an in situ MSI tissue analytical platform, may become the ultimate technologies for unraveling and understanding the molecular complexities in some aspects of cancer metabolism. Such comprehensive imaging investigations might provide information on pharmacometabolomics, biomarker discovery, and disease diagnosis, prognosis, and treatment response monitoring for clinical medicine.
"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 –. 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). "
[Show abstract][Hide abstract] ABSTRACT: Following radiation therapy (RT), tumor morphology may remain unchanged for days and sometimes weeks, rendering anatomical imaging methods inadequate for early detection of therapeutic response. Changes in the hyperpolarized [1-(13)C]lactate signals observed in vivo following injection of pre-polarized [1-(13)C]pyruvate has recently been shown to be a marker for tumor progression or early treatment response. In this study, the feasibility of using (13)C metabolic imaging with [1-(13)C]pyruvate to detect early radiation treatment response in a breast cancer xenograft model was demonstrated in vivo and in vitro. Significant decreases in hyperpolarized [1-(13)C]lactate relative to [1-(13)C]pyruvate were observed in MDA-MB-231 tumors 96 hrs following a single dose of ionizing radiation. Histopathologic data from the treated tumors showed higher cellular apoptosis and senescence; and changes in the expression of membrane monocarboxylate transporters and lactate dehydrogenase B were also observed. Hyperpolarized (13)C metabolic imaging may be a promising new tool to develop novel and adaptive therapeutic regimens for patients undergoing RT.
PLoS ONE 06/2013; 8(2):e56551. DOI:10.1371/journal.pone.0056551 · 3.23 Impact Factor
[Show abstract][Hide abstract] 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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