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

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