Through this Pathway to Independence Award, I hope to acquire the skills necessary to obtain a faculty position with an independent research program focused on the bioengineering and implementation of novel 3D cell and tissue culture bioreactors, and the use this platform in conjunction with hyperpolarized (HP) 13C MR to better study cancer metabolism. Due to the biologic and pathologic complexity of prostate cancer, there is an urgent clinical need to develop more sensitive and specific imaging markers for improved prostate cancer patient-specific treatment planning and early assessment of therapeutic failure. An extraordinary new technique utilizing hyperpolarized (HP) metabolic substrates has the potential to provide these MR biomarkers. Recent HP MR studies in cell and animal models suggest that HP metabolic markers reflect enzymatic fluxes and may provide a more accurate measure of prostate cancer presence, progression and response to therapy. However, available murine and cell culture models don't reliably mimic human disease, thus we propose a novel combination of HP 13C MR and NMR-compatible 3D tissue culture bioreactors to study the real-time metabolism of living human prostate tissue slices (TSCs). The overall objective of this research are to engineer an NMR-compatible, 3D Tissue Culture Bioreactor for use with human TSCs and use it to identify HP molecular imaging markers for improved prostate cancer patient- specific treatment planning and early assessment of response to targeted therapy. Accomplishing these aims will require additional training in the areas of primary cell and tissue cultures, prostate biochemistry and pathology, HP probe development, micro-engineering, biotransport, and pharmacokinetics. Utilizing this new training, the first aim i to optimize conditions for maintaining human prostate TSCs in an NMR-compatible, 3D tissue culture bioreactor and to verify the metabolic integrity of TSCs over time. Continuous 31P will be used to monitor the progression of tissue slices in the bioreactor with time. Dynamic acquisitions of HP 13C MR will be used to calculate fluxes associated with metabolism of pyruvate and other probes in real time. This data will be compared to histopathology before and after culture in the bioreactor to assess changes.
The second aim i s to use this new experimental model to compare normal and malignant prostate tissues metabolism, and importantly, determine whether HP metabolites correlate with pathologic grade and their relationship to metabolism and biotransport.
The third aim i s to use this platform to identify HP markers of therapeutic response to PI3K/mTOR inhibitors. It is the goal of this proposal to develop an engineered system, which can overcome the limitations of current murine and cell cultures models and aid in the development of relevant biomarkers for translation to the clinic. While the focus of the research in this Pathway to Independence Award is on prostate cancer, the combination of NMR-compatible primary tissue culture bioreactor platform combined with high sensitivity HP MR probes would have wide applicability across a variety of diseases and imaging modalities.

Public Health Relevance

Through this Pathway to Independence Award project, I will gain the necessary knowledge and training to become a faculty member with an independent research program focused on the engineering and implementation of novel 3D cell and tissue culture bioreactors, and the use this platform in conjunction with hyperpolarized MR to better study cancer metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Career Transition Award (K99)
Project #
1K99EB014328-01A1
Application #
8384396
Study Section
Special Emphasis Panel (ZEB1-OSR-B (M2))
Program Officer
Erim, Zeynep
Project Start
2012-08-01
Project End
2013-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$87,686
Indirect Cost
$6,495
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
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
Tee, Sui-Seng; Keshari, Kayvan R (2015) Novel Approaches to Imaging Tumor Metabolism. Cancer J 21:165-73
Salamanca-Cardona, Lucia; Keshari, Kayvan R (2015) (13)C-labeled biochemical probes for the study of cancer metabolism with dynamic nuclear polarization-enhanced magnetic resonance imaging. Cancer Metab 3:9
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
Chen, Ligong; Shu, Yan; Liang, Xiaomin et al. (2014) OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A 111:9983-8
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
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
Keshari, Kayvan R; Sai, Victor; Wang, Zhen J et al. (2013) Hyperpolarized [1-13C]dehydroascorbate MR spectroscopy in a murine model of prostate cancer: comparison with 18F-FDG PET. J Nucl Med 54:922-8
Keshari, Kayvan R; Kurhanewicz, John; Macdonald, Jeffrey M et al. (2012) Generating contrast in hyperpolarized 13C MRI using ligand-receptor interactions. Analyst 137:3427-9