Advisory Committee Chair
Anna Sorace
Advisory Committee Members
Lalita Shevde-Samant
Renata Jaskula-Sztul
Suzanne Lapi
Troy Randall
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subset of breast cancer which currently has no targeted therapies available due to lack of molecular therapeutic targets. Importantly, various radiopharmaceuticals can be imaged via positron emission tomography (PET) to quantify cellular and molecular features of the tumor microenvironment including glucose metabolism, receptor status, and immune activation. Somatostatin receptor subtype 2 (SSTR2) is G-protein coupled receptor overexpressed in neuroendocrine tumors (NETs) which can be imaged and targeted for theranostics via FDA-approved radiotherapy. SSTR2 expression is increased in hormone positive breast cancer but is expressed at low or variable levels in TNBC. However, histone deacetylase (HDAC) inhibitors have been shown to upregulate SSTR2 expression for NETs with low or variable basal expression. Our data demonstrate the ability of HDAC inhibitors to upregulate SSTR2 expression in TNBC at the transcriptional, translational, and functional levels. Model-dependent differences and epigenetic-induced changes in SSTR2 expression can be quantified non-invasively and monitored longitudinally via PET imaging. Despite recent additions of immunotherapy (IMT) to TNBC treatment regimens, there are no standardized biomarkers to identify which patients will respond well to this therapy. In addition, co-morbidities like obesity and type 2 diabetes (T2D) confound TNBC and are associated with a dysfunctional immune microenvironment, thereby decreasing immunotherapeutic efficacy and worsening overall survival for TNBC. Challenges exist in FDG PET imaging of IMT response including distinguishing true response from pseudo-progression, inflammation, and immune activation. Our data reveals GZP PET as a sensitive predictor of immunotherapy response in obese mice early in the course of treatment and prior to tumor volume changes. Our studies also show that T2D and obesity alter not only the tumor microenvironment, but also impact the immune landscape and glucose metabolism in systemic tissues. Repurposing clinically relevant molecular imaging techniques for TNBC can be used to personalize treatment approaches and greatly enhance therapeutic responses. This work utilizes molecular imaging to non-invasively characterize the TNBC tumor microenvironment to identify predictors of treatment response and modulate the TME to create targetable biomarkers for imaging and therapy.
Recommended Citation
Lynch, Shannon E., "Molecular Imaging Of Triple-Negative Breast Cancer: Characterization And Modulation Of The Tumor Microenvironment" (2025). All ETDs from UAB. 6866.
https://digitalcommons.library.uab.edu/etd-collection/6866
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