This proposal will continue the development of an innovative MRI method that can measure the extracellular pH (pHe) of the tumor microenvironment. Our MRI method uses Chemical Exchange Saturation Transfer (CEST) agents that accurately and precisely measure pH. We have used our CEST agents and CEST MRI methods to map tumor pHe in mouse tumor models. We propose to improve the detection sensitivity of CEST MRI to facilitate our pre-clinical studies eventual clinical translation. Our research has strong impact because tumor pHe measurements may be used to predict the effects of weak-base and weak-acid chemotherapies before they are administered to a patient. Tumor pHe measurements may also be used to monitor alkalinizing therapies that can increase survival and decrease metastasis. We propose to establish that our CEST MRI method can measure tumor pHe with sufficient accuracy and precision to impact the choice of cancer therapies. ? Specific Aim 1: To improve the detection sensitivity of CEST MRI methods and CEST agents that measure tumor pHe. We will optimize the saturation period of the CEST MRI pulse sequence, and improve our paramagnetic CEST agents to have larger chemical shifts. ? Specific Aim 2: To monitor the effect of alkalinizing therapy using tumor pHe measurements. We hypothesize that monitoring pHe can be used to optimize the dose of an alkalinizing therapy to raise tumor pHe without affecting kidney pHe. ? Specific Aim 3: To quantitatively predict chemotherapeutic effects with tumor pHe measurements. We hypothesize that a single tumor pHe measurement before initiating chemotherapy can quantitatively predict the therapeutic effect on tumor growth. Our deliverable is a clinically-translatable imaging method that can profoundly impact personalized medicine. By quantitatively measuring the acidity of a solid tumor, a physician may then select the weak-base or weak- acid chemotherapy that should have a better therapeutic effect for that individual patient. By monitoring the pHe of the tumor and kidney, a physician may adjust an alkalinizing treatment dosage to provide an optimal therapeutic effect for an individual patient. Although our research focuses on breast cancer, our methodology can impact personalized medicine for many other cancers and other pathologies.

Public Health Relevance

This research project will refine CEST agents and CEST MRI methods that measure extracellular pH (pHe) in pre-clinical tumor models. These methods will be used to optimize the dose of an alkalinizing therapy and to predict the efficacy of weak-base and weak-acid chemotehrapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Zhang, Huiming
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University of Arizona
Biomedical Engineering
Schools of Engineering
United States
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Randtke, Edward A; Granados, Jeffry C; Howison, Christine M et al. (2017) Multislice CEST MRI improves the spatial assessment of tumor pH. Magn Reson Med 78:97-106
Yoshimaru, Eriko S; Randtke, Edward A; Pagel, Mark D et al. (2016) Design and optimization of pulsed Chemical Exchange Saturation Transfer MRI using a multiobjective genetic algorithm. J Magn Reson 263:184-192
Kobes, Joseph E; Daryaei, Iman; Howison, Christine M et al. (2016) Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded With a Novel AKT/PDK1 Inhibitor. Pancreas 45:1158-66
Hingorani, Dina V; Montano, Luis A; Randtke, Edward A et al. (2016) A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals. Contrast Media Mol Imaging 11:130-8
Akhenblit, Paul J; Hanke, Neale T; Gill, Alexander et al. (2016) Assessing Metabolic Changes in Response to mTOR Inhibition in a Mantle Cell Lymphoma Xenograft Model Using AcidoCEST MRI. Mol Imaging 15:
Jones, Kyle M; Randtke, Edward A; Howison, Christine M et al. (2016) Respiration gating and Bloch fitting improve pH measurements with acidoCEST MRI in an ovarian orthotopic tumor model. Proc SPIE Int Soc Opt Eng 9788:
Akhenblit, Paul J; Pagel, Mark D (2016) Recent Advances in Targeting Tumor Energy Metabolism with Tumor Acidosis as a Biomarker of Drug Efficacy. J Cancer Sci Ther 8:20-29
Chen, Liu Qi; Pagel, Mark D (2015) Evaluating pH in the Extracellular Tumor Microenvironment Using CEST MRI and Other Imaging Methods. Adv Radiol 2015:
Moon, Brianna F; Jones, Kyle M; Chen, Liu Qi et al. (2015) A comparison of iopromide and iopamidol, two acidoCEST MRI contrast media that measure tumor extracellular pH. Contrast Media Mol Imaging 10:446-55
Chen, Liu Qi; Randtke, Edward A; Jones, Kyle M et al. (2015) Evaluations of Tumor Acidosis Within In Vivo Tumor Models Using Parametric Maps Generated with Acido CEST MRI. Mol Imaging Biol 17:488-96

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