Detection of Early Response to Temozolomide Treatment in Brain Tumors Using Hyperpolarized C-13 MR Metabolic Imaging
ABSTRACT 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.
SourceAvailable from: Olivier Keunen[Show abstract] [Hide abstract]
ABSTRACT: The vast majority of malignant gliomas relapse after surgery and standard radio-chemotherapy. Novel molecular and cellular therapies are thus being developed, targeting specific aspects of tumor growth. While histopathology remains the gold standard for tumor classification, neuroimaging has over the years taken a central role in the diagnosis and treatment follow up of brain tumors. It is used to detect and localize lesions, define the target area for biopsies, plan surgical and radiation interventions and assess tumor progression and treatment outcome. In recent years the application of novel drugs including anti-angiogenic agents that affect the tumor vasculature, has drastically modulated the outcome of brain tumor imaging. To properly evaluate the effects of emerging experimental therapies and successfully support treatment decisions, neuroimaging will have to evolve. Multimodal imaging systems with existing and new contrast agents, molecular tracers, technological advances and advanced data analysis can all contribute to the establishment of disease relevant biomarkers that will improve disease management and patient care. In this review, we address the challenges of glioma imaging in the context of novel molecular and cellular therapies, and take a prospective look at emerging experimental and pre-clinical imaging techniques that bear the promise of meeting these challenges. (C) 2014 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.Advanced Drug Delivery Reviews 09/2014; 76. DOI:10.1016/j.addr.2014.07.010 · 12.71 Impact Factor
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ABSTRACT: Non-invasive monitoring of response to treatment of glioblastoma (GB) is nowadays carried out using MRI. MRS and MR spectroscopic imaging (MRSI) constitute promising tools for this undertaking. A temozolomide (TMZ) protocol was optimized for GL261 GB. Sixty-three mice were studied by MRI/MRS/MRSI. The spectroscopic information was used for the classification of control brain and untreated and responding GB, and validated against post-mortem immunostainings in selected animals. A classification system was developed, based on the MRSI-sampled metabolome of normal brain parenchyma, untreated and responding GB, with a 93% accuracy. Classification of an independent test set yielded a balanced error rate of 6% or less. Classifications correlated well both with tumor volume changes detected by MRI after two TMZ cycles and with the histopathological data: a significant decrease (p < 0.05) in the proliferation and mitotic rates and a 4.6-fold increase in the apoptotic rate. A surrogate response biomarker based on the linear combination of 12 spectral features has been found in the MRS/MRSI pattern of treated tumors, allowing the non-invasive classification of growing and responding GL261 GB. The methodology described can be applied to preclinical treatment efficacy studies to test new antitumoral drugs, and begets translational potential for early response detection in clinical studies. Copyright © 2014 John Wiley & Sons, Ltd.NMR in Biomedicine 11/2014; 27(11). DOI:10.1002/nbm.3194 · 3.56 Impact Factor
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ABSTRACT: Recent findings show that exposure to temozolomide (TMZ), a DNA damaging drug used to treat glioblastoma, can suppress the conversion of pyruvate to lactate. To understand the mechanistic basis for this effect and its potential utility as a TMZ response biomarker, we compared the response of isogenic glioblastoma cell populations differing only in expression of the DNA repair protein MGMT, a TMZ-sensitivity determinant, after exposure to TMZ in vitro and in vivo. Hyperpolarized [1-(13)C]-pyruvate-based magnetic resonance imaging was used to monitor temporal effects on pyruvate metabolism in parallel with DNA damage responses and tumor cell growth. TMZ exposure decreased conversion of pyruvate to lactate only in MGMT-deficient cells. This effect coincided temporally with TMZ-induced increases in levels of the DNA damage response protein pChk1. Changes in pyruvate to lactate conversion triggered by TMZ preceded tumor growth suppression and were not associated with changes in levels of NADH or lactate dehydrogenase activity in tumors. Instead, they were associated with a TMZ-induced decrease in the expression and activity of pyruvate kinase PKM2, a glycolytic enzyme that indirectly controls pyruvate metabolism. PKM2 silencing decreased pyruvate kinase activity, intracellular lactate levels, and conversion of pyruvate to lactate in the same manner as TMZ, and Chk1 silencing blocked the TMZ-induced decrease in PKM2 expression. Overall, our findings showed how TMZ-induced DNA damage is linked through PKM2 to changes in pyruvate metabolism, and how these changes can be exploited by magnetic resonance imaging methods as an early sensor of TMZ therapeutic response.Cancer Research 10/2014; 74(23). DOI:10.1158/0008-5472.CAN-14-0849 · 9.28 Impact Factor