DOI
https://doi.org/10.25772/TNVG-FF70
Author ORCID Identifier
https://orcid.org/0000-0002-9422-830X
Defense Date
2023
Document Type
Thesis
Degree Name
Doctor of Philosophy
Department
Integrative Life Sciences
First Advisor
Dr. J. Chuck Harrell
Abstract
Breast cancer treatments have improved over time, but the diseases seeing the most benefit from these improvements have the estrogen receptor, progesterone receptor, or are positive for HER2. Basal-like breast cancer tends to not have these biomarkers, which necessitates their treatment to be traditional, untargeted therapeutics which are less effective and tend to have harsh adverse effect profiles – this is an important unmet need. These studies utilize a variety of techniques, including tissue culture, viability assays, high-throughput screening, in vivo drug treatments and imaging, pathway analyses, molecular techniques such as Western blot, antibody arrays, RNA sequencing, sc RNA sequencing, and many others. This project is divided into 4 studies, each with important findings. First, a characterization of the Glowing Head mouse model showed that the model is suitable for most metastatic settings, though the endogenous signal of the luciferase produced by the mouse will confound studies which study bone or brain metastasis. Then, a study in EGFR inhibitor resistance identified LCN2 as an upregulated marker of resistance which could reduce sensitivity to erlotinib by aiding in the recycling of EGFR. Another study discovered compounds that doxorubicin treated cells will become resistant to and which show a trend of reducing senescent cells’ viability. Finally, the core project identified three compounds when combined with BYL-719, a PIK3CA inhibitor, have synergistic activity in the reduction of tumor sizes of basal-like PI3K aberrant PDXs. It is my hope that these studies may be used as preliminary data for further study, both preclinical and clinical.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-4-2023