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

Available for download on Tuesday, August 10, 2021

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