Development of methods and feasibility of using hyperpolarized carbon‐13 imaging data for evaluating brain metabolism in patient studies

Park, Ilwoo; Larson, Peder E. Z.; Gordon, Jeremy W.; Carvajal, Lucas; Chen, Hsin‐Yu; Bok, Robert; Criekinge, Mark Van; Ferrone, Marcus; Slater, James B.; Xu, Duan; Kurhanewicz, John; Vigneron, Daniel B.; Chang, Susan M.; Nelson, Sarah J.

doi:10.1002/mrm.27077

Cited by 141 publications

(205 citation statements)

References 34 publications

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“…We have also applied the simulation framework for evaluating various analysis methods to other flip‐angle strategies, presented in the Supporting Information. The strategies presented there include a constant 10° for all time and metabolites, as well as a “multiband” 10° (pyruvate)–20° (lactate) strategy that has been used in several prostate and brain human HP pyruvate exams.…”

Section: Resultsmentioning

confidence: 99%

“…MRI with hyperpolarized (HP) 13 C‐labeled substrates has emerged as an extremely promising metabolic imaging modality, because it can probe key metabolic pathways in patient studies. () These studies utilize dissolution dynamic nuclear polarization (DNP) to enhance the 13 C nuclear polarization, providing > 50 000 fold sensitivity increases in vivo. () The most promising HP substrate to date is [1‐ 13 C]pyruvate, which provides the following: monitoring of a key metabolic pathway, conversion to [1‐ 13 C]lactate, which is highly upregulated in most cancer types (the “Warburg effect”); high levels of polarization via dissolution DNP; and biocompatibility at doses of 0.43 ml/kg body weight and 250mM as determined in a Phase 1 safety trial .…”

Section: Introductionmentioning

confidence: 99%

“…Clinical translation of HP [1‐ 13 C]pyruvate was initially demonstrated in prostate cancer patients, and currently there is clinical research underway at several institutions in prostate cancer, breast cancer, brain tumors, liver metastases, and heart failure. ()…”

Section: Introductionmentioning

confidence: 99%

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Investigation of analysis methods for hyperpolarized 13C‐pyruvate metabolic MRI in prostate cancer patients

et al. 2018

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MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1- C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, k , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in k , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate k maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless k fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1- C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1- C]pyruvate parameters (SNR, k , bolus characteristics) in the human prostate.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Investigation of analysis methods for hyperpolarized 13C‐pyruvate metabolic MRI in prostate cancer patients

et al. 2018

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“…The development and in vivo implementation of dissolution DNP combined with 13 C MRSI has opened the door to noninvasive monitoring of real‐time cellular metabolism. Most notably, monitoring the conversion of hyperpolarized [1‐ 13 C]pyruvate to hyperpolarized [1‐ 13 C]lactate has recently been implemented in the clinic . Importantly, previous studies have shown that this metabolic reaction can serve as an early biomarker of response to therapy in a range of tumor types, including in orthotopic intracranial GBM models .…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibition in glioblastoma monitored by hyperpolarized ¹³C MRSI

et al. 2018

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Vorinostat is a histone deacetylase (HDAC) inhibitor that inhibits cell proliferation and induces apoptosis in solid tumors, and is in clinical trials for the treatment of glioblastoma (GBM). The goal of this study was to assess whether hyperpolarized 13C MRS and magnetic resonance spectroscopic imaging (MRSI) can detect HDAC inhibition in GBM models. First, we confirmed HDAC inhibition in U87 GBM cells and evaluated real‐time dynamic metabolic changes using a bioreactor system with live vorinostat‐treated or control cells. We found a significant 40% decrease in the 13C MRS‐detectable ratio of hyperpolarized [1‐13C]lactate to hyperpolarized [1‐13C]pyruvate, [1‐13C]Lac/Pyr, and a 37% decrease in the pseudo‐rate constant, kPL, for hyperpolarized [1‐13C]lactate production, in vorinostat‐treated cells compared with controls. To understand the underlying mechanism for this finding, we assessed the expression and activity of lactate dehydrogenase (LDH) (which catalyzes the pyruvate to lactate conversion), its associated cofactor nicotinamide adenine dinucleotide, the expression of monocarboxylate transporters (MCTs) MCT1 and MCT4 (which shuttle pyruvate and lactate in and out of the cell) and intracellular lactate levels. We found that the most likely explanation for our finding that hyperpolarized lactate is reduced in treated cells is a 30% reduction in intracellular lactate levels that occurs as a result of increased expression of both MCT1 and MCT4 in vorinostat‐treated cells. In vivo 13C MRSI studies of orthotopic tumors in mice also showed a significant 52% decrease in hyperpolarized [1‐13C]Lac/Pyr when comparing vorinostat‐treated U87 GBM tumors with controls, and, as in the cell studies, this metabolic finding was associated with increased MCT1 and MCT4 expression in HDAC‐inhibited tumors. Thus, the 13C MRSI‐detectable decrease in hyperpolarized [1‐13C]lactate production could serve as a biomarker of response to HDAC inhibitors.

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“…Preliminary outcomes from Phase II patient studies further indicated that high k PL correlated very well with biopsy and pathological findings of aggressive human prostate cancer and poor response to therapy . Also, high lactate/pyruvate ratios were found in progressive glioblastoma …”

Section: Introductionmentioning

confidence: 95%

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion k_PL in hyperpolarized ¹³C imaging

et al. 2019

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Hyperpolarized 13C MRI takes advantage of the unprecedented 50 000‐fold signal‐to‐noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate‐to‐lactate conversion rate, kPL, a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient‐induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF‐induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID‐Delay,Crush/kPL,FID‐Delay = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% kPL error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower kPL was found using a delayed free induction decay (FID) acquisition versus a minimum‐TE version (kPL,FID‐Delay/kPL,FID = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δωlactate/Δωpyruvate = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T2*, shorter than that of pyruvate, can affect calculated kPL values. We also found that an FID sequence yielded significantly lower kPL versus a double spin‐echo sequence that includes spin‐echo spoiling, flow suppression from crusher gradients, and more T2 weighting (kPL,DSE/kPL,FID = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of kPL. The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible kPL measures for future preclinical and clinical studies.

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Development of methods and feasibility of using hyperpolarized carbon‐13 imaging data for evaluating brain metabolism in patient studies

Cited by 141 publications

References 34 publications

Investigation of analysis methods for hyperpolarized 13C‐pyruvate metabolic MRI in prostate cancer patients

Investigation of analysis methods for hyperpolarized 13C‐pyruvate metabolic MRI in prostate cancer patients

HDAC inhibition in glioblastoma monitored by hyperpolarized ¹³C MRSI

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion k_PL in hyperpolarized ¹³C imaging

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Development of methods and feasibility of using hyperpolarized carbon‐13 imaging data for evaluating brain metabolism in patient studies

Cited by 141 publications

References 34 publications

Investigation of analysis methods for hyperpolarized 13C‐pyruvate metabolic MRI in prostate cancer patients

Investigation of analysis methods for hyperpolarized 13C‐pyruvate metabolic MRI in prostate cancer patients

HDAC inhibition in glioblastoma monitored by hyperpolarized 13C MRSI

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion kPL in hyperpolarized 13C imaging

Contact Info

Product

Resources

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HDAC inhibition in glioblastoma monitored by hyperpolarized ¹³C MRSI

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion k_PL in hyperpolarized ¹³C imaging