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)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166766-02
Application #
8462946
Study Section
Special Emphasis Panel (ZRG1-SBIB-X (03))
Program Officer
Prasanna, Pat G
Project Start
2012-04-24
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$468,859
Indirect Cost
$162,499
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Keshari, Kayvan R; Wilson, David M (2014) Chemistry and biochemistry of 13C hyperpolarized magnetic resonance using dynamic nuclear polarization. Chem Soc Rev 43:1627-59
Keshari, Kayvan R; Sriram, Renuka; Koelsch, Bertram L et al. (2013) Hyperpolarized 13C-pyruvate magnetic resonance reveals rapid lactate export in metastatic renal cell carcinomas. Cancer Res 73:529-38
Koelsch, Bertram L; Keshari, Kayvan R; Peeters, Tom H et al. (2013) Diffusion MR of hyperpolarized 13C molecules in solution. Analyst 138:1011-4
Keshari, Kayvan R; Sriram, Renuka; Van Criekinge, Mark et al. (2013) Metabolic reprogramming and validation of hyperpolarized 13C lactate as a prostate cancer biomarker using a human prostate tissue slice culture bioreactor. Prostate 73:1171-81