We have developed a non-invasive imaging method that can quantitatively measure the extracellular pH (pHe) in tumors. Our MRI method uses Chemical Exchange Saturation Transfer (CEST) MRI to assess tumor acidosis, termed acidoCEST MRI. We have recently translated acidoCEST MRI to a clinical 3T MRI scanner, we have tested volunteers with our protocol, we have an approved IRB protocol for our first clinical trial, and we have assembled an exceptionally strong team of investigators to perform our clinical studies. Therefore, all steps are in place to start our clinical trials. For Specific im 1, we propose to correlate tumor pHe in breast cancer patients with tumor subtype and ex vivo correlates of acidosis, hypoxia, and glycolysis. Our rationale is based on our extensive results from our pre-clinical studies that have shown how more aggressive tumor models have a higher tumor acidosis. We have also shown that tumor pHe is correlated with high expression of carbonic anhydrase IX, which is an established biomarker of tumor hypoxia. We will perform acidoCEST MRI scans with breast cancer patients, and obtain ex vivo correlates from resected tissues during their standard care.
For Specific Aim 2, we propose to use acidoCEST MRI to monitor the early response to neoadjuvant chemotherapy in breast cancer patients. Our rationale is based on our pre-clinical imaging results that have shown how Everolimus (an mTOR inhibitor) raises tumor pHe in a lymphoma model within 1 day of initiating therapy, and then returns to an acidic state after 7 days of daily treatment, which foreshadowed the temporary tumor growth delay of this drug treatment. We will perform acidoCEST MRI scans before and 4 weeks after initiating neoadjuvant chemotherapy with dose dense doxorubicin-cyclophosphamide followed by paclitaxel. We will correlate initial tumor pHe and the change in tumor pHe with clinical outcome. Based on these results, our DELIVERABLE is an innovative, noninvasive imaging method that can generate parametric maps of tumor pHe, which can be used to improve diagnosis and evaluate early response to chemotherapy for breast cancer patients.

Public Health Relevance

We have developed an innovative MRI method based on Chemical Exchange Saturation Transfer (CEST) that accurately measures the extracellular pH in tumors, termed acidoCEST MRI. We propose to conduct an early phase clinical trial to investigate the correlation between acidosis, tumor phenotype and hypoxia in breast cancer patients, and also to use acidoCEST MRI to track the early response to neoadjuvant chemotherapy in breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA197029-02
Application #
9095288
Study Section
Special Emphasis Panel (ZRG1)
Project Start
2015-06-19
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Arizona
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Jones, Kyle M; Pollard, Alyssa C; Pagel, Mark D (2018) Clinical applications of chemical exchange saturation transfer (CEST) MRI. J Magn Reson Imaging 47:11-27
Jones, Kyle M; Pagel, Mark D; Cárdenas-Rodríguez, Julio (2018) Linearization improves the repeatability of quantitative dynamic contrast-enhanced MRI. Magn Reson Imaging 47:16-24
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
Jones, Kyle M; Randtke, Edward A; Yoshimaru, Eriko S et al. (2017) Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI. Mol Imaging Biol 19:617-625
Jones, Kyle M; Stuehm, Carol A; Hsu, Charles C et al. (2017) Imaging Lung Cancer by Using Chemical Exchange Saturation Transfer MRI With Retrospective Respiration Gating. Tomography 3:201-210
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
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:
Sinharay, Sanhita; Pagel, Mark D (2016) Advances in Magnetic Resonance Imaging Contrast Agents for Biomarker Detection. Annu Rev Anal Chem (Palo Alto Calif) 9:95-115