Hyperpolarized 13C Spectroscopy Detects Early Changes in Tumor Vasculature and Metabolism after VEGF Neutralization

Bohndiek, Sarah E.; Kettunen, Mikko I.; Hu, De‐En; Brindle, Kevin M.

doi:10.1158/0008-5472.can-11-2795

Cited by 69 publications

(63 citation statements)

References 47 publications

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“…Our results show that the net change in 13 C fumarate conversion into malate marker was more sensitive than DW-MRI. However, it must be remembered that the value of a biomarker is directly related to the magnitude of change, normalized to its test–retest reproducibility, and this has yet to be assessed in a larger cohort and others tumor models before generalization, although our results are in agreement with other recent preclinical studies comparing fumarate with pyruvate and ADC w (28, 47). Also, ADC w has been reported to be highly reproducible within a single institution.…”

Section: Discussionsupporting

confidence: 85%

Monitoring Chemotherapeutic Response by Hyperpolarized 13C-Fumarate MRS and Diffusion MRI

et al. 2014

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Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by 13C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized 13C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, 13C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration.

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Section: Discussionsupporting

confidence: 85%

Monitoring Chemotherapeutic Response by Hyperpolarized 13C-Fumarate MRS and Diffusion MRI

et al. 2014

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“…Therefore, the K trans of Gd-DTPA is sensitive to both tumor perfusion and permeability changes in response to anti-angiogenic treatments. The consensus from previous studies is that the usage of only early time points from the time intensity curves after a bolus injection of the Gd-chelate minimizes the effect of vascular permeability changes and primarily reflects the change in perfusion (7,31). However, there can be uncertainties in unequivocally determining the contributions of perfusion and permeability to an MRI signal change.…”

Section: Discussionmentioning

confidence: 99%

“…Samples of [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvic acid (30 ll) containing 15 mM TAM and 2.5 mM gadolinium chelate ProHance (Bracco Diagnostics) were polarized at 3.35 T and 1.4 K in the Hypersense DNP polarizer (Oxford Instruments), according to the manufacturer's instructions. After 40-60 min, the hyperpolarized sample was rapidly dissolved in 4.5 ml of a superheated alkaline buffer composed of 40 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 30 mM NaCl, and 100 mg/L ethylendiaminetetraacetic acid (EDTA).…”

Section: Animal Experimentsmentioning

confidence: 99%

In VivoImaging of Tumor Physiological, Metabolic, and Redox Changes in Response to the Anti-Angiogenic Agent Sunitinib: Longitudinal Assessment to Identify Transient Vascular Renormalization

Matsumoto

Saito

Takakusagi

et al. 2014

Antioxidants & Redox Signaling

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Aims: The tumor microenvironment is characterized by a highly reducing redox status, a low pH, and hypoxia. Anti-angiogenic therapies for solid tumors frequently function in two steps: the transient normalization of structurally and functionally aberrant tumor blood vessels with increased blood perfusion, followed by the pruning of tumor blood vessels and the resultant cessation of nutrients and oxygen delivery required for tumor growth. Conventional anatomic or vascular imaging is impractical or insufficient to distinguish between the two steps of tumor response to anti-angiogenic therapies. Here, we investigated whether the noninvasive imaging of the tumor redox state and energy metabolism could be used to characterize anti-angiogenic drug-induced transient vascular normalization. Results: Daily treatment of squamous cell carcinoma (SCCVII) tumor-bearing mice with the multityrosine kinase inhibitor sunitinib resulted in a rapid decrease in tumor microvessel density and the suppression of tumor growth. Tumor pO 2 imaging by electron paramagnetic resonance imaging showed a transient increase in tumor oxygenation after 2-4 days of sunitinib treatment, implying improved tumor perfusion. During this window of vascular normalization, magnetic resonance imaging of the redox status using an exogenously administered nitroxide probe and hyperpolarized 13 C MRI of the metabolic flux of pyruvate/lactate couple revealed an oxidative shift in tumor redox status. Innovation: Redox-sensitive metabolic couples can serve as noninvasive surrogate markers to identify the vascular normalization window in tumors with imaging techniques. Conclusion: A multimodal imaging approach to characterize physiological, metabolic, and redox changes in tumors is useful to distinguish between the different stages of anti-angiogenic treatment.

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“…Using 13 C MR spectroscopic imaging, we showed in several different tumor models, treated with a variety of different drugs, that there was an increase in hyperpolarized [1,4-13 C 2 ]malate production, compared with the untreated tumors (23). The technique, which was also shown to detect necrosis in normal tissues, such as the kidney (24), appears, under some circumstances, to be more sensitive than diffusion-weighted MR imaging at detecting low levels of diffuse necrosis (25).…”

Section: Dna Fragmentation and Loss Of Plasma Membrane Integritymentioning

confidence: 98%

Imaging Cell Death

2014

Self Cite

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There is currently a need for imaging methods capable of detecting cell death in tissues and the early onset of tumor cell death resulting from therapy. However, to date, no probe has been approved for routine imaging of cell death in the clinic. The challenge is to identify hallmarks of cell death, which have clinical relevance, and then to develop and validate imaging biomarkers for these hallmarks. We focus here on cell death imaging probes, which either have been trialed in the clinic or have significant promise, based on preclinical studies.

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Hyperpolarized 13C Spectroscopy Detects Early Changes in Tumor Vasculature and Metabolism after VEGF Neutralization

Cited by 69 publications

References 47 publications

Monitoring Chemotherapeutic Response by Hyperpolarized 13C-Fumarate MRS and Diffusion MRI

Monitoring Chemotherapeutic Response by Hyperpolarized 13C-Fumarate MRS and Diffusion MRI

In VivoImaging of Tumor Physiological, Metabolic, and Redox Changes in Response to the Anti-Angiogenic Agent Sunitinib: Longitudinal Assessment to Identify Transient Vascular Renormalization

Imaging Cell Death

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