Author ORCID Identifier
0000-0001-6271-9879
Date of Graduation
8-2020
Document Type
Dissertation (PhD)
Program Affiliation
Medical Physics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Pratip Bhattacharya, PhD
Committee Member
Ho-Ling Anthony Liu, PhD
Committee Member
Richard Wendt, PhD
Committee Member
John Hazle, PhD
Committee Member
Christopher Logothetis, MD
Committee Member
Frederick Lang, MD
Abstract
Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma (GBM) can improve patient survival by providing physicians the time to optimally deliver treatment. This includes early in development, while the tumor is still manageable, or following initial therapy, when alternative treatments should be considered. The main goal of this project was to determine whether metabolic imaging with hyperpolarized magnetic resonance spectroscopy (MRS) could detect changes in tumor progression more rapidly than conventional anatomic magnetic resonance imaging (MRI) in patient-derived GBM murine models. To comprehensively capture the dynamic nature of cancer metabolism, in vivo pyruvate-to-lactate conversion with hyperpolarized MRI, ex vivo metabolite pool size with nuclear magnetic resonance (NMR) spectroscopy, and ex vivo protein expression with immunohistochemistry (IHC) were measured at several time-points throughout tumor progression (tumor development, regression, and recurrence).
Hyperpolarized MRS was capable of detecting significant changes in pyruvate-to-lactate conversion throughout tumor progression, whereas tumor volume measured with anatomic MRI was not significantly altered during regression or recurrence. This was accompanied by alterations in amino acid and phospholipid lipid metabolism and MCT1 expression. It is discussed how hyperpolarized MRS can help address clinical challenges such as identifying malignant disease prior to aggressive growth, differentiating pseudoprogression from true progression, quantifying treatment response, and predicting relapse. The individual evolution of these metabolic assays as well as their correlations with one another provides context for further academic research.
In addition to investigating GBM tumor progression, preliminary and supporting metabolic profiling data acquired with NMR spectroscopy is presented in the context of immunometabolism. Specifically, metabolic events associated with the licensing process of natural killer cells as well as macrophage polarization are analyzed. Collectively, this work demonstrates the value of interrogating the metabolism of GBM and tumor-associated immune cells with hyperpolarized MRS and NMR spectroscopy.
Keywords
Hyperpolarization, 13C Magnetic Resonance Spectroscopy, Magnetic Resonance Imaging, 1H Nuclear Magnetic Resonance, Glioblastoma, Tumor Development, Tumor Regression, Tumor Recurrence, Tumor Metabolism, Longitudinal Study
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Diagnosis Commons, Medical Biophysics Commons, Neoplasms Commons, Nervous System Commons, Oncology Commons, Radiology Commons