All ETDs from UAB

Advisory Committee Chair

Benjamin M Larimer

Advisory Committee Members

Suzanne E Lapi

Jonathan E McConathy

Anna G Sorace

Jason Warram

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The use of biomarkers has significantly enhanced patient outcome by improving diagnosis, personalizing therapy, and monitoring therapeutic response yet most cancers remain non-responsive. Thus, there is a need to better understand the underlying biological mechanisms and tumor microenvironment to enhance therapeutic efficacy. Molecular imaging, including magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) are used to assess response during oncology therapy. Molecular imaging can also provide a noninvasive approach to accurately quantify biomarkers correlated with the tumor microenvironment, including glucose metabolism and hypoxia. 18F-Fluoromisonidazole (18F-FMISO) hypoxia targeted cellular uptake has been shown to correlate with negative outcome during targeted therapy and radiation. Hypoxia has been shown to have a negative effect on the anti-tumor immune response, thus providing strong rationale for quantification. Here we demonstrate that hypoxia has a harmful effect on the immune response and decreased 18F-FMISO uptake is predictive of response post-therapy initiation. Moreover, we demonstrate hypoxia has more nuanced classifications consistent with decreasing concentrations of oxygenation, in which each classification correlates with unique specific biomarker differences in the tumor microenvironment. iv Currently, Fluorodeoxyglucose (18F-FDG) is used as a gold standard for metastasis and anatomical staging, yet this technique lacks the ability to distinguish between the infiltration of immune cells and an overall increase in tumor size as both demonstrate increased glucose uptake. Due to a continuously increasing number of treatments and combinations in clinical trials that result in immune cell infiltration, there is an abundant need to monitor TME differences at earlier stages. This has given rise to a number of novel molecular imaging biomarkers that are being developed and integrated into clinical trials, such as granzyme B peptide (GZP) PET imaging. However, GZP has limited imaging capabilities due to half-life and potential degradation challenges. Due to this, we have completed stability studies with GZP, initiated radiosynthesis using diverse radionuclides, developed in vitro assays to assess differentiation between T cell and cancer cell metabolism, and successfully designed a novel in vivo model to assess human targeted proteins to provide crucial insight within current knowledge gaps to enhance therapeutic outcomes.

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