Assessing Metabolic Changes in Response to mTOR Inhibition in a Mantle Cell Lymphoma Xenograft Model Using AcidoCEST MRI

Akhenblit, Paul J.; Hanke, Neale T.; Gill, Alexander; Persky, Daniel O.; Howison, Christine M.; Pagel, Mark; Baker, Amanda F.

doi:10.1177/1536012116645439

Cited by 19 publications

(26 citation statements)

References 43 publications

(51 reference statements)

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“…Glycolysis inhibition through mTOR targeting has also been observed in mantle cell lymphoma (MCL). In fact, everolimus downregulated glucose transporters, glycolytic enzymes, and lactate dehydrogenase, thus inducing a decrease in lactate production [127], while the dual mTORC1/2 inhibitor AZD-2014 caused the activation of AMPK and the downregulation of glycolysis-related proteins [128]. Despite the already mentioned metabolic difference with the other NHL, in DBLCL interfering with the glucose catabolism has been reported to generate the same results, the mTOR inactivation, that in turn causes the downregulation of the pro-survival factor Mcl-1 [129].…”

Section: Lymphomasmentioning

confidence: 99%

mTOR Regulation of Metabolism in Hematologic Malignancies

Mirabilii

Ricciardi

Tafuri

2020

Cells

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Neoplastic cells rewire their metabolism, acquiring a selective advantage over normal cells and a protection from therapeutic agents. The mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular activities, including the control of metabolic processes. mTOR is hyperactivated in a large number of tumor types, and among them, in many hematologic malignancies. In this article, we summarized the evidence from the literature that describes a central role for mTOR in the acquisition of new metabolic phenotypes for different hematologic malignancies, in concert with other metabolic modulators (AMPK, HIF1α) and microenvironmental stimuli, and shows how these features can be targeted for therapeutic purposes.

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“…Iopamidol has been employed to measure extracellular pH and assess tumor acidosis, and thus this method has been termed acidoCEST MRI . Studies with small animal models of solid tumors have shown that acidoCEST MRI results are correlated with tumor growth rate, upregulation of biomarkers associated with aerobic glycolysis and acid transport, and decreased metabolism in rapid response to treatment . More recently, acidoCEST MRI has been translated to the clinic at 3T magnetic field strength and low 1.5 μT saturation power, and has successfully measured the extracellular pH in kidney and metastatic ovarian tumors (Fig.…”

Section: Exogenous Cest Agentsmentioning

confidence: 99%

Clinical applications of chemical exchange saturation transfer (CEST) MRI

Jones

Pollard

Pagel

2017

J. Magn. Reson. Imaging

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189

210

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Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has been developed and employed in multiple clinical imaging research centers worldwide. Selective radiofrequency (RF) saturation pulses with standard 2D and 3D MRI acquisition schemes are now routinely performed, and CEST MRI can produce semiquantitative results using magnetization transfer ratio asymmetry (MTRasym) analysis while accounting for B0 inhomogeneity. Faster clinical CEST MRI acquisition methods and more quantitative acquisition and analysis routines are under development. Endogenous biomolecules with amide, amine, and hydroxyl groups have been detected during clinical CEST MRI studies, and exogenous CEST agents have also been administered to patients. These CEST MRI tools show promise for contributing to assessments of cerebral ischemia, neurological disorders, lymphedema, osteoarthritis, muscle physiology, and solid tumors. This review summarizes the salient features of clinical CEST MRI protocols and critically evaluates the utility of CEST MRI for these clinical imaging applications. Level of Evidence: 5 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:11–27.

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“…AcidoCEST MRI has been used to measure extracellular pH in tumor models of lymphoma, breast, ovarian, pancreatic, and lung cancer . These studies have shown that tumor extracellular pH is lower in faster‐growing tumors, and increases in early response to drug treatments, demonstrating that acidoCEST MRI is sensitive to the level of tumor metabolism.…”

Section: Acidocest Mrimentioning

confidence: 99%

Assessments of tumor metabolism with CEST MRI

Goldenberg

Pagel

2018

NMR in Biomedicine

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Chemical exchange saturation transfer (CEST) is a relatively new contrast mechanism for MRI. CEST MRI exploits a specific MR frequency (chemical shift) of a molecule while generating an image with good spatial resolution using standard MRI techniques, combining the specificity of MRS with the spatial resolution of MRI. Many CEST MRI acquisition methods have been developed to improve analyses of tumor metabolism. GluCEST, CrCEST, and LATEST can map glutamate, creatine, and lactate, which are important metabolites involved in tumor metabolism. GlucoCEST MRI tracks the pharmacokinetics of glucose transport and cell internalization within tumors. CatalyCEST MRI detects enzyme catalysis that changes a substrate CEST agent. AcidoCEST MRI measures extracellular pH of the tumor microenvironment by exploiting a ratio of two pH-dependent CEST signals. This review describes each technique, the technical issues involved with CEST MRI and each specific technique, and the merits and challenges associated with applying each CEST MRI technique to study tumor metabolism.

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“…Using these methods, tumors with faster growth rates have been shown to have lower pHe values, indicating that tumor pHe is a biomarker for tumor viability that may compliment [ 18 F]FDG PET studies [5]. Also, these CEST MRI methods have shown that tumor pHe can significantly increase in response to drugs that generally decrease tumor metabolism, which may also compliment [ 18 F]FDG PET studies [13]. Similarly, these methods have measured an increase in tumor pHe in response to an inhibitor of the lactic acid production pathway [14, 15], and a decrease in tumor pHe in response to a mitochondrial poison that redirects glucose metabolism towards glycolysis and lactic acid production [16].…”

Section: Introductionmentioning

confidence: 99%

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [18F]FDG PET and acidoCEST MRI

2018

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Purpose We sought to determine if the synergy between evaluations of glucose uptake in tumors and extracellular tumor acidosis measured with simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) can improve longitudinal evaluations of the response to metformin treatment. Procedures A standard 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET protocol that evaluates glucose uptake in tumors, and a standard acidoCEST MRI protocol that measures extracellular pH (pHe) in tumors, were simultaneously performed to assess eight vehicle-treated (control) mice and eight metformin-treated mice 1 day before treatment, 1 day after initiating daily treatment with metformin, and 7 days after initiating treatment. Longitudinal changes in SUVmax and extracellular pH (pHe) were evaluated for each treatment group, and differences in SUVmax and pHe between metformin-treated and control groups were also evaluated. Results MRI acquisition protocols had little effect on the PET count rate, and the PET instrumentation had little effect on image contrast during acidoCEST MRI, verifying that [18F]FDG PET and acidoCEST MRI can be performed simultaneously. The average SUVmax of the tumor model had a significant decrease after 7 days of treatment with metformin, as expected. The average tumor pHe decreased after 7 days of metformin treatment, which reflected the inhibition of the consumption of cytosolic lactic acid caused by metformin. However, the average SUVmax of the tumor model was not significantly different between the metformin-treated and control groups after 7 days of treatment, and average pHe was also not significantly different between these groups. For comparison, the combination of average SUVmax and pHe measurements significantly differed between the treatment group and control group on Day 7. Conclusions [18F]FDG PET and acidoCEST MRI studies can be performed simultaneously. The synergistic combination of assessing glucose uptake and tumor acidosis can improve differentiation of a drug-treated group from a control group during drug treatment of a tumor model.

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“…AcidoCEST MRI has been used to show that acidic tumors have a faster growth rate and are associated with higher expression levels of carbonic anhydrase ; thus, acidoCEST MRI can improve initial diagnoses and prognostications of the tumor. AcidoCEST MRI has also been used to track the early metabolic response to chemotherapy in a mouse model of human breast cancer, which shows that this imaging method may impact the choice of personalized medicine for each individual patient . In addition, acidoCEST MRI has been used to show a correlation between pHe and lesion size in a lung fibrosis model, demonstrating that acidoCEST MRI has the potential to assess other pathologies in addition to solid tumors .…”

Section: Introductionmentioning

confidence: 99%

Multislice CEST MRI improves the spatial assessment of tumor pH

et al. 2016

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Purpose Multislice maps of extracellular pH (pHe) are needed to interrogate the heterogeneities of tumors and normal organs. To address this need, we have developed a multislice acidoCEST MRI acquisition method with a CEST spectrum fitting method that measures in vivo pHe over a range of 6.3 to 7.4. Methods The Phase Offset MultiPlanar (POMP) method was adapted for CEST-FISP MRI to acquire multiple image slices with a single CEST saturation pulse. The Bloch-McConnell equations were modified to include pH based on a calibration of pH and chemical exchange rate for the contrast agent, iopamidol. These equations were used to estimate the pixelwise pHe values throughout the multislice acidoCEST MR images of the tumor, kidney, bladder and other tissues of a MDA-MB-231 tumor model. Results Multislice acidoCEST MRI successfully mapped a gradient of pHe from 6.73 to 6.81 units from the tumor core to rim, and mapped a gradient of pHe 6.56 to 6.97 across the mouse kidney. The bladder was found to be pHe 6.3. Conclusion AcidoCEST MRI with POMP acquisition and Bloch-McConnel analysis can map pHe in multiple imaging slices through the tumor, kidney, and bladder. This multislice evaluation facilitates assessments of spatial heterogeneity of tissue pHe.

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Assessing Metabolic Changes in Response to mTOR Inhibition in a Mantle Cell Lymphoma Xenograft Model Using AcidoCEST MRI

Cited by 19 publications

References 43 publications

mTOR Regulation of Metabolism in Hematologic Malignancies

Clinical applications of chemical exchange saturation transfer (CEST) MRI

Assessments of tumor metabolism with CEST MRI

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [18F]FDG PET and acidoCEST MRI

Multislice CEST MRI improves the spatial assessment of tumor pH

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