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 is 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 Statement 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.
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