Characterizing treatment induced alterations of the tumor microenvironment towards optimizing therapeutic regimens in cancer

Bloom, Meghan Jean
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It is well recognized that the tumor microenvironment plays a key role in cancer initiation, progression, and response to treatment. Therapies targeted towards the tumor microenvironment are being introduced in the clinic to be administered alongside chemotherapy and radiation, however, not every patient responds to treatment. The purpose of this dissertation is to characterize modulation of the tumor microenvironment induced by targeted therapies, and build a better understanding of how to exploit these alterations to increase efficacy of developing combination treatments. Our objective is addressed in three parts. First, we quantified temporal alterations in nuclear factor kappa B signaling and downstream gene expression to a small-molecule pathway inhibitor and demonstrated the complexity of altering pathway dynamics for therapeutic gain. Secondly, we characterized changes in innate immune cell infiltration in human epidermal growth factor receptor 2 positive (HER2+) breast cancer after targeted antibody treatment and identified mechanisms of vascular alterations and windows of reduced immune suppression. Lastly, we quantified the effects of radiation and targeted antibody therapy in HER2+ breast cancer and elucidated a potential to reduce radiation dose in this combination regimen. Collectively, the results presented provide valuable insight of how the tumor microenvironment can dictate treatment response and the potential to modulate the tumor microenvironment to enhance therapeutic efficacy