Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Terence P. Gade

Second Advisor

Mitchell Schnall

Abstract

Functional molecular imaging facilitates non-invasive tissue evaluation for the distinction of pathology from physiology on the basis of spatiotemporal variation in probe accumulation and conversion. Dynamic nuclear polarization (DNP) modifies the energy distribution of stable isotopes, including 13C, enhancing available signal for magnetic resonance spectroscopic imaging (MRSI), an emerging functional molecular imaging technique. The guiding hypothesis of this compendium is that clinical adoption of DNP-13C-MRSI for disease assessment and response evaluation in cancer will be accelerated by tailoring probe selection to the biology of the target disease. Genetic screening with CRISPR-Cas9 served as a high-throughput tool to identify disease-specific vulnerabilities in cancer according to gene dependency, informing DNP-13C-MRSI probe selection based upon the relative essentiality of probe-specific metabolic enzymes. Subsequent investigations in an autochthonous rodent model of hepatocellular carcinoma (HCC) permitted study of intratumoral metabolism in a manner representative of human disease. Genetic screening identified lactate dehydrogenase (LDH) as a therapeutic vulnerability of HCC; DNP-13C-MRSI with pyruvate quantified intratumoral LDH activity and predicted efficacy of LDH inhibition. Additionally, DNP-13C-MRSI with pyruvate predicted efficacy of transarterial embolization, a locoregional therapy for HCC, demonstrating enhanced sensitivity to tumor perfusion and persistent viability relative to conventional imaging approaches. To address concerns pertinent to clinical translation of quantitative DNP-13C-MRSI of tumor metabolism, the significance of probe dose and persistence within the body were experimentally investigated. The presented precision imaging approach provides a framework for personalizing therapy selection and evaluating its efficacy non-invasively. Beyond demonstrating a theranostic imaging strategy for management of HCC, this body of work establishes a paradigm for functional metabolic imaging of metabolic diversity in cancer with DNP-13C-MRSI.

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Available to all on Saturday, September 09, 2023

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