Advisor(s)

Jonathan McConathy
Anna Sorace

Committee Member(s)

Benjamin Larimer
Mary Kathryn Sewell-Loftin
Yu-Hua Dean Fang

Document Type

Dissertation

Date of Award

1-27-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Biomedical Engineering

Abstract

Triple-negative breast cancer (TNBC) and high-grade glioma (HGG) pose significant diagnostic and therapeutic challenges due to their aggressive biology and the limitations of [¹⁸F]FDG PET, which suffers from nonspecific uptake in inflammatory tissues, complicating differentiation of viable tumor from treatment-related effects. Computed Tomography, while strong for structural changes, has limited soft tissue contrast for distinguishing tumor from inflammation, and Magnetic Resonance Imaging, despite superior soft tissue resolution, struggles with differentiating active tumor from post-treatment changes like edema or necrosis due to nonspecific enhancement. These challenges highlight the necessity for complementary and advanced imaging strategies for improved diagnosis and monitoring. This dissertation explores amino acid (AA) PET imaging to target tumor-specific transporters, aiming to enhance diagnostic precision and guide personalized treatment in these malignancies. Three studies evaluate novel AA PET tracers to address these challenges. In the first study, [¹⁸F]MeFAMP (System A), [¹⁸F]fluciclovine (System L/ASCT2), and [¹⁸F]AFETP (cationic/neutral transport) were compared to [¹⁸F]FDG in TNBC mouse models (4T1 syngeneic, N=10; BCM3936 PDX, N=8). AA tracers showed uptake comparable to [¹⁸F]FDG but superior tumor-to-brain (TBR) and tumor-to-muscle (TMR) ratios, with [¹⁸F]MeFAMP achieving the highest TMR (4T1: 9.74±3.58; PDX: 2.72±1.31) and [¹⁸F]AFETP the highest TBR in PDX (p<0.0001), correlating with transporter expression via immunohistochemistry. These findings suggest AA tracers’ potential for imaging primary tumors and metastases. In the second study, [¹⁸F]fluciclovine was assessed in HGG (GL261, DBT) and early radiation necrosis (RN) mouse models. High lesion-to-normal brain ratios were observed in both conditions, with no significant difference in lesion uptake (p>0.05), contrasting with clinical reports of chronic RN distinction, indicating timing and model-specific limitations. This difference may be due to the shorter interval between radiation and imaging in this model than typically occurs in humans. Third, [¹⁸F]MeFAMP was evaluated for early immune checkpoint inhibitor (ICI) response in the MC38 colorectal cancer model (C57BL/6 mice, N=25). [¹⁸F]MeFAMP demonstrated significant SUV40% reduction in responders (pre: 1.08±0.16, post: 0.40±0.11, p<0.0001) but no change in non-responders (p=0.09), unlike [¹⁸F]FDG, which showed no differences (p>0.13). Histogram analysis revealed distinct uptake distributions (p<0.01), suggesting [¹⁸F]MeFAMP uptake may be able to distinguish potential responders from non-responders prior to therapy. These studies collectively advance AA PET imaging by improving diagnostic specificity, delineating tumor from treatment effects, and guiding precision therapy in TNBC and HGG, with ongoing clinical trials (e.g., NCT0567648) poised to translate these findings to enhance patient outcomes.

Keywords

amino acid PET;high-grade glioma;triple negative breast cancer;[¹⁸F]AFETP;[¹⁸F]fluciclovine;[¹⁸F]MeFAMP

ProQuest Publication Number

29068176

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