Advisor(s)

Anna Sorace

Committee Member(s)

Benjamin Larimer
Lyse Norian

Document Type

Thesis

Date of Award

6-1-2026

Degree Name

Master of Biomedical Engineering (MBME)

School

Joint Health Sciences (Interdisciplinary)

Department

Biomedical Engineering

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks the expression of targetable markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2), resulting in a lack of effective treatment strategies. Obesity, defined as having a body mass index greater than 30 kg/m2, is a chronic health condition that is known to increase the risk of developing TNBC and diminish the effects of TNBC standard-of-care therapies, such as immunotherapy (IMT). Previous work has established that obesity induces a pro-tumoral landscape, characterized by increased tumor hypoxia and immunosuppressive shifts within the tumor microenvironment (TME); however, it remains unclear how these factors contribute to IMT response within an obese TNBC model. Assessment of these obesity-driven characteristics provides the opportunity to establish markers of response in this model, which have also not been explored. Response prediction early during treatment provides key biological metrics that could save cancer patients with obesity from time wasted on insufficient therapies, thus improving overall outcomes. This thesis utilized [18F]fluoromisonidazole (FMISO) positron emission tomography (PET) to characterize obesity-induced intratumoral hypoxia within a diet-induced obese murine model of TNBC. Our data suggests that obesity promotes a heterogeneous and hypoxic TME, which results in highly varied individual response to IMT. The longitudinal assessment of hypoxia via [18F]FMISO PET revealed that increased average tumor hypoxia within the first week of therapy was able to predict IMT outcomes with high sensitivity and specificity. This study demonstrates the potential for hypoxia-based PET imaging to be used as a diagnostic tool in a highly dysregulated and heterogenous model. Importantly, [18F]FMISO PET imaging presents the opportunity to inform the use of secondary therapies that target tumor hypoxia, thus limiting unnecessary toxicity while preserving tumor killing. The findings of this study support the personalization of therapeutic approaches in the cancer field based on patient characteristics, such as obesity status. Taken together, this work can elucidate obesity-driven factors that dictate IMT response kinetics, thus providing a potential target for response prediction and secondary therapies to improve therapeutic outcomes for those with TNBC and obesity.

Keywords

Breast Cancer;Evofosfamide;FMISO;Hypoxia;Immunotherapy;Obesity

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