Remarkable progress has been made over the last decade in the characterization of in vivo metabolism using hyperpolarized (HP) 13C spectroscopy, with profound implications for the diagnosis and treatment of human cancers. The majority of studies have focused on metabolism of [1-13C] pyruvate by lactate dehydrogenase (LDH), which occurs to a larger extent in cancer and has been correlated with pathologic grade in a murine prostate tumor model. Although the molecular requirements of dynamic nuclear polarization (DNP) are rather strict, several additional hyperpolarized 13C agents have been developed that are potential markers for pH (13C bicarbonate), hexose metabolism ([2-13C] fructose), and necrosis ([1,4-13C] fumarate). More recently, we have developed the redox sensor [1-13C] dehydroascorbate (DHA), an oxidized version of Vitamin C that shares an uptake mechanism with glucose. This new probe demonstrates rapid in vivo reduction to [1-13C] Vitamin C, and is the principal agent used for the Specific Aims of this R01 proposal. In the proposed project, this new probe is employed to address the redox adaptation of tumors, which accumulate large quantities of GSH and other antioxidants, conferring resistance to therapies that are ROS- dependent, including radiation. Prostate cancer was chosen since (1) radiation therapy is a mainstay of treatment (2) several in vitro studies have implicated GSH and other redox components in resistance and (3) non-invasive biomarkers for disease aggressiveness are lacking. Our preliminary 1H studies on primary prostate cancer cells using high resolution magic-angle spinning (HR-MAS) NMR indicate high levels of GSH, and in vivo murine studies using HP [1-13C] DHA demonstrate reduction in organs that are known to be rich in GSH, including the liver, kidneys, and brain. Furthermore, numerous reports in the literature have established that reduction of DHA to VitC is GSH-mediated. However, other redox mechanisms are certainly possible for the reduction of HP [1-13C] DHA observed in vivo, and our first studies will determine which cellular redox (or transport) components are involved (Specific Aim 1). We will then turn to studies validating the use of HP [1- 13C] DHA to determine cancer aggressiveness, and predict response to radiation therapy in a murine prostate cancer (TRAMP) model (Specific Aim 2). Finally, we will compare this new 13C probe to related 18F ascorbates as well as to [2-deoxy-2-18F] fluoro-D-glucose (FDG), the radioisotope used in the vast majority of clinical positron emission tomography (PET) studies (Specific Aim 3). We anticipate HP 13C MRI emerging as an important technology to complement existing molecular imaging methods, including PET, and comparative studies (employing structurally or mechanistically related probes) will be important to validate both modalities. Our justification for pursuing 18F ascorbate probes is twofold: (1) to determine whether ascorbate-based PET probes demonstrate similar in vivo characteristics to HP [1-13C] DHA and (2) to compare the ability of PET and HP methods to predict tumor aggressiveness/ treatment response in prostate cancer.

Public Health Relevance

This proposal describes a new MRI technology that can potentially both determine prostate cancer aggressiveness, and predict how patients will respond to radiation therapy. Potential advantages include avoiding unnecessary biopsies, optimizing treatment regimens, and identifying appropriate response to therapy non-invasively. The project also compares this cutting-edge MRI technology to a method already used in the clinic, positron emission tomography (PET) in order to address how these two complementary techniques might best serve the needs of prostate cancer patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA166766-03
Application #
8627148
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Prasanna, Pat G
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Flavell, Robert R; Truillet, Charles; Regan, Melanie K et al. (2016) Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography. Bioconjug Chem 27:170-8
Carroll, V N; Truillet, C; Shen, B et al. (2016) [(11)C]Ascorbic and [(11)C]dehydroascorbic acid, an endogenous redox pair for sensing reactive oxygen species using positron emission tomography. Chem Commun (Camb) 52:4888-90
Korenchan, D E; Flavell, R R; Baligand, C et al. (2016) Dynamic nuclear polarization of biocompatible (13)C-enriched carbonates for in vivo pH imaging. Chem Commun (Camb) 52:3030-3
Di Gialleonardo, Valentina; Wilson, David M; Keshari, Kayvan R (2016) The Potential of Metabolic Imaging. Semin Nucl Med 46:28-39
Flavell, Robert R; von Morze, Cornelius; Blecha, Joseph E et al. (2015) Application of Good's buffers to pH imaging using hyperpolarized (13)C MRI. Chem Commun (Camb) 51:14119-22
Keshari, Kayvan R; Wilson, David M; Sai, Victor et al. (2015) Noninvasive in vivo imaging of diabetes-induced renal oxidative stress and response to therapy using hyperpolarized 13C dehydroascorbate magnetic resonance. Diabetes 64:344-52
Sriram, Renuka; Van Criekinge, Mark; Hansen, Ailin et al. (2015) Real-time measurement of hyperpolarized lactate production and efflux as a biomarker of tumor aggressiveness in an MR compatible 3D cell culture bioreactor. NMR Biomed 28:1141-9
Brown, Jacob D; Saeed, Maythem; Do, Loi et al. (2015) CT-guided injection of a TRPV1 agonist around dorsal root ganglia decreases pain transmission in swine. Sci Transl Med 7:305ra145
Keshari, Kayvan R; Wilson, David M; Van Criekinge, Mark et al. (2015) Metabolic response of prostate cancer to nicotinamide phophoribosyltransferase inhibition in a hyperpolarized MR/PET compatible bioreactor. Prostate 75:1601-9
Yu, John-Paul J; Wilson, David M; Chang, Edward F et al. (2014) Isolated intracerebral light chain deposition disease: novel imaging and pathologic findings. Clin Imaging 38:868-71

Showing the most recent 10 out of 19 publications