Advisory Committee Chair
Anna G Sorace
Advisory Committee Members
Suzanne E Lapi
Benjamin M Larimer
Jianmei W Leavenworth
Jason M Warram
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Molecular imaging plays an important role in predicting and evaluating treatment response and revealing the underlying biological mechanisms in the cancer field. Especially, PET imaging serves as a valuable tool for comprehending the tumor microenvironment (TME), allowing us to track tumor metabolism, proliferation, receptor expression, and immune infiltration. In this comprehensive study, three distinct aspects of cancer research were explored using molecular imaging techniques.The first study aimed to evaluate the accuracy of the fluorescence ubiquitination cell cycle indicator (FUCCI) system with fluorescence in vivo imaging compared to 3'-Deoxy-3'-[18F]fluorothymidine ([18F]-FLT) positron emission tomography (PET)/computed tomography (CT) in assessing cancer cell proliferation. The results demonstrated a significant correlation between the RFP fluorescent signal and tumor volume, indicating the effectiveness of the FUCCI system. Additionally, the GFP fluorescent signal correlated with tumor growth rate, and the spatial distribution of GFP+ cells and [18F]-FLT uptake regions suggested the potential of the FUCCI-IVIS method to assess tumor heterogeneity of cell proliferation. These findings highlight the noninvasive and accurate depiction of tumor progression and therapeutic response provided by fluorescent imaging of the cell cycle. The second study focused on the correlation between human epidermal growth factor receptor 2 (HER2) expression and the efficacy of paclitaxel (PTX) treatment in HER2+ breast cancer mouse models using advanced molecular PET imaging. The results revealed a positive correlation between PTX treatment efficacy and HER2 expression level. Molecular imaging facilitated the quantification of HER2 expression and provided deep insights into biological interactions, aiding in the identification of chemotherapy responders and potentially enhancing clinical decision-making. Lastly, the third study investigated the impact of immune checkpoint blockade (ICB) treatment on the "cold" tumor immune microenvironment in breast cancer models using CD4- and CD8-PET imaging. The findings showed enhanced intratumoral infiltration of CD4+ and CD8+ cell populations and reduced heterogeneity in CD4+ and CD8+ cell distribution are key markers for ICB response and may provide imaging metrics to evaluate TILs kinetics in immunogenically “cold” tumors. The kinetic study of immune cell trafficking between multiple sites via PET imaging provided us with a systemic understanding of the spatial and temporal changes in response to ICB. The molecular imaging approach provided insights into immunological alterations, monitored immunotherapy response, and offered guidance for clinical decision-making in tumors with varying response kinetics. These combined studies highlight the significance of molecular imaging techniques in cancer research, ranging from assessing cell proliferation and tumor heterogeneity to evaluating treatment response and characterizing the tumor immune microenvironment. Such noninvasive approaches have the potential to enhance our understanding of cancer biology, facilitate translational imaging methods, and guide the development of novel cancer therapeutics.
Recommended Citation
Lu, Yun, "Molecular imaging to evaluate tumor heterogeneity and guide treatment of breast cancer" (2023). All ETDs from UAB. 3515.
https://digitalcommons.library.uab.edu/etd-collection/3515