Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular and Molecular Physiology

First Advisor

Perry, Rachel

Abstract

Triple-negative breast cancer (TNBC), an aggressive and often lethal subtype of breast cancer, continues to challenge researchers and clinicians due to its poor prognosis and limited therapeutic options. This thesis explores novel therapeutic strategies that integrate metabolic modulation, advanced radionuclide therapies, and lifestyle interventions to combat TNBC effectively.The first component investigates metabolic scaling and its implications for cancer metabolism. Gene and protein expression analyses across species reveal that metabolic processes, including oxidative metabolism and detoxification, scale inversely with body mass. This foundational insight underscores the importance of systemic metabolic regulation in understanding cancer progression. In the realm of cancer therapy, sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin, demonstrate potential as metabolic modulators. By reducing glucose uptake and insulin levels, these inhibitors enhance chemotherapy's efficacy, particularly in TNBC with specific genetic profiles. This research – to our knowledge, the first to apply precision medicine approaches to the use of metabolic therapy for breast cancer – highlights the promise of metabolism-targeting therapies tailored to individual tumor characteristics. Advances in targeted alpha therapy (TAT) are exemplified by the development of 225Ac-doped poly(lactic-co-glycolic acid) nanoparticles. These nanoparticles improve radionuclide retention and selectively deliver therapeutic doses to cancer cells, minimizing systemic toxicity. This innovation offers a new avenue for precise and effective radiotherapy in TNBC. Lifestyle interventions, particularly aerobic exercise, emerge as critical adjuncts in TNBC treatment. Exercise enhances systemic metabolism, reduces inflammation, and modulates the tumor microenvironment, improving immune infiltration and the efficacy of checkpoint inhibitors such as pembrolizumab. Exercise-induced metabolites, including beta-alanine and fish oil components, show potential as therapeutic adjuvants, further expanding the scope of non-pharmacological cancer therapies. Finally, this work emphasizes the impact of energy balance, exploring how obesity and related metabolic dysregulation influence TNBC progression and therapeutic responses. By addressing energy imbalance through caloric restriction and exercise, significant improvements in treatment outcomes and patient quality of life are achievable. This thesis integrates these interdisciplinary approaches, offering a comprehensive framework for advancing TNBC treatment. By uniting precision medicine, innovative therapies, and lifestyle modifications, it lays the groundwork for personalized and effective strategies against the most lethal form of breast cancer.  

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