DOI
https://doi.org/10.25772/0S5B-9085
Author ORCID Identifier
0000-0003-1856-7411
Defense Date
2023
Document Type
Thesis
Degree Name
Master of Science
Department
Biology
First Advisor
J. Chuck Harrell, PhD
Second Advisor
Tomasz Kordula, PhD
Third Advisor
Erich Damm, PhD
Fourth Advisor
Jason Newton, PhD
Abstract
Triple-negative breast cancer (TNBC), a highly metastatic breast cancer subtype, accounts for approximately 20% of all breast cancer diagnoses. Basal-like TNBC is notably difficult to treat due to the lack of actionable drug targets such as estrogen and progesterone receptors, as well as HER2. Due to the deficiency in TNBC-targeting drugs that are able to cross the blood-brain barrier (BBB) for breast-to-brain metastasis, there is a need to develop novel BBB-permeable treatments. After preliminary testing, KPT-330 (XPO1 inhibitor) and everolimus (FKBP1A/mTOR inhibitor) were selected as drug candidates for this study. Patient-derived xenograft (PDX) models for in vitro and in vivo studies were chosen based on the relative transcriptomic and proteomic expression of XPO1 and FKBP1A. KPT-330, everolimus, and KPT-330 + everolimus were assessed in NSG mice with mammary gland tumors or metastases. KPT-330 + everolimus significantly reduced an mTORC1-overactive PDX primary tumor burden compared to single agents and vehicle control, whereas an mTORC1-underactive PDX primary tumor burden was not significantly reduced upon treatment. Further testing of the affected PDX determined that the metastasis burden in the brain and ovaries was significantly reduced upon treatment with KPT-330 + everolimus. Therefore, the proposed treatment may be effective in improving the outcome of patients suffering from mTORC1-overactive TNBC surgically non-resectable metastases. FKBP1A expression could serve as a biomarker for future treatment selection for TNBC.
Rights
© Aaron D. Valentine 2023
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-10-2023