Evaluation of Hyperpolarized [1-13C]-Pyruvate by Magnetic Resonance to Detect Ionizing Radiation Effects in Real Time

Sandulache, Vlad C.; Chen, Yunyun; Lee, Jae-Hyuk; Rubinstein, Ashley; Ramirez, Marc S.; Skinner, Heath D.; Walker, Christopher M.; Williams, Michelle D.; Tailor, Ramesh; Court, Laurence Edward; Bankson, James A.; Lai, Stephen Y.

doi:10.1371/journal.pone.0087031

Cited by 39 publications

(75 citation statements)

References 43 publications

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“…Tumor metabolism was challenged using 2DG (31) (N=9), external radiation therapy (32) (N=7), or conditional gene expression (19) (N=3); controls were tested prior to or without perturbation (N=33) or administered a negative control (N=3). All three kinetic models fit these datasets (N=55) reasonably well, as summarized in Figure 3.…”

Section: Resultsmentioning

confidence: 99%

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

et al. 2015

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Hyperpolarized [1-13C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion, and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison to alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly under-sampled imaging data from tumor-bearing animals. Compared to naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements.

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Section: Resultsmentioning

confidence: 99%

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

et al. 2015

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“…For orthotopic tumors, U-HTH83 luciferase expressing cells (2.5×10 5 /mouse) were injected into the right thyroid lobe under direct visualization as previously described. (5) For flank tumors, cells (2×10 6 /mouse) were injected into both flanks of each animal. Tumor size was ascertained regularly throughout the experimental period using bioluminescence imaging and manual measurements as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…(5–10) IR-induced ROS perturb cellular metabolism in a measurable and quantifiable manner which could theoretically be exploited for therapeutic purposes. (5) Our group has demonstrated a proportional relationship between IR-induced ROS levels and cell death, and showed that this relationship at least partially accounts for some of the radioresistance encountered in solid tumors. (6, 8) This relationship identifies an important therapeutic window to target radioresistant tumors, such as those driven by mutations in TP53.…”

Section: Introductionmentioning

confidence: 99%

“…This hypothesis is based on previous studies by our group which found that magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13 C pyruvate can detect acute changes in tumor lactate levels following metabolic inhibition and/or irradiation. (5) In this study, we sought to determine whether measurements of acute lactate changes provide a consistent and reliable means of detecting genotoxic stress with a temporal resolution suitable for clinical translation. To confirm translational relevance we aimed to demonstrate the following: 1) dose-dependent relationship between acute, transient changes in lactate levels and IR exposure; 2) correlation with acquired (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

Sandulache

Chen

Skinner

et al. 2015

Molecular Cancer Therapeutics

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Ionizing radiation is the primary non-surgical treatment modality for solid tumors. Its effectiveness is impacted by temporal constraints such as fractionation, hypoxia and development of radioresistant clones. Biomarkers of acute radiation response are essential to developing more effective clinical algorithms. We hypothesized that acute perturbations in tumor lactate levels act as a surrogate marker of radiation response. In vitro experiments were carried out using validated human derived cell lines from 3 histologies: anaplastic thyroid carcinoma (ATC), head and neck squamous cell carcinoma (HNSCC) and papillary thyroid carcinoma (PTC). Cellular metabolic activity was measured using standard biochemical assays. In vivo validation was performed using both an orthotopic and a flank derivative of a previously established ATC xenograft murine model. Irradiation of cells and tumors triggered a rapid, dose-dependent, transient decrease in lactate levels which was reversed by free radical scavengers. Acute lactate perturbations following irradiation could identify hypoxic conditions and correlated with hypoxia-induced radioresistance. Mutant TP53 cells and cells in which p53 activity was abrogated (shRNA) demonstrated a blunted lactate response to irradiation, consistent with a radioresistant phenotype. Lactate measurements therefore rapidly detected both induced (i.e. hypoxia) and intrinsic (i.e. mutTP53 driven) radioresistance. We conclude that lactate is a quantitative biomarker of acute genotoxic stress, with a temporal resolution which can inform clinical decision-making. Combined with the spatial resolution of newly developed metabolic imaging platforms, this biomarker could lead to the development of truly individualized treatment strategies.

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“…10 Many studies have demonstrated detection of aerobic glycolysis using hyperpolarized 13 C-labeled pyruvate to be a robust probe of cancer metabolism, correlating with disease presence, stage, and response to therapy. 2,[11][12][13][14] Researchers have successfully completed testing the use of HP-pyruvate in phase 1 clinical trials 13 in prostate cancer patients, with trials in patients with cancer at other sites scheduled to start soon.…”

Section: Introductionmentioning

confidence: 99%

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

et al. 2016

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Purpose: Magnetic resonance spectroscopy of hyperpolarized agents allows real-time detection of metabolism in vivo. However, the nonrenewable nature of these signals necessitates data acquisitions that differ significantly from conventional magnetic resonance imaging. Signal evolution is permanently altered by the data acquisition scheme, potentially leading to sequence parameter-dependent bias in quantification. The authors have developed a novel simulation environment to characterize the effects of sequence parameters on magnetic resonance spectroscopy-based chemical exchange measurements using hyperpolarized pyruvate. Methods: Conventional Bloch-McConnell equations were coupled with a pharmacokinetic model for perfusion to allow realistic simulation of in vivo dynamic hyperpolarized signal evolution. In this study, simulations were conducted to explore effects of excitation angle and repetition time on the observed signal and subsequent parametric analysis. Both high and low apparent exchange rates were modeled under assumption of both perfused and closed systems. Bias due to sampling strategy bias was subsequently tested in vivo. Results: Simulation of dynamic magnetic resonance spectroscopy studies using hyperpolarized pyruvate demonstrated that for closed systems, accurate measurement of the apparent exchange rate was possible over a wide range of sequence parameters. This was true for both high and low apparent exchange rates, although a low exchange rate was associated with larger errors when excitation angles were high. When effects of perfusion were included to account for pyruvate delivery, a more restricted range of settings led to accurate quantification of exchange rates. Perfusion alleviated some of the errors seen at high excitation angles for low exchange rates. Residuals from parametric analysis did not generally correlate with fit accuracy, implying that the quality of the analysis model was not a major driver of error. Animal studies acquired with sequence parameters that are predicted to impart bias showed a significant under estimation of exchange rates (P < 0.035) compared to parameter combinations that are not expected to bias measurements. Conclusions: The authors' results suggest that great care must be taken when measuring dynamic processes by magnetic resonance spectroscopy of hyperpolarized substrates. When comparing apparent exchange rates, choice of sequence parameters will affect the results. Bias introduced by parameters of more advanced acquisition and reconstruction schemes will likely increase compared to the relatively simple dynamic spectroscopy methods tested herein. The modified Bloch-McConnell equations the authors describe will be crucial tools for characterizing and optimizing the performance of these more advanced techniques. C

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Evaluation of Hyperpolarized [1-13C]-Pyruvate by Magnetic Resonance to Detect Ionizing Radiation Effects in Real Time

Cited by 39 publications

References 43 publications

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

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