DOI
https://doi.org/10.25772/GMSX-9M24
Defense Date
2025
Document Type
Thesis
Degree Name
Master of Science
Department
Microbiology & Immunology
First Advisor
Dr. Masoud H. Manjili
Abstract
Chemotherapy-induced tumor dormancy remains a major barrier to curative cancer therapy, as residual dormant tumor cells can evade treatment and drive metastatic relapse. However, the survival mechanisms that enable these dormant tumor cells to persist are poorly understood. In this study, we identify Bcl-xL, an anti-apoptotic protein, as a potential target to eliminate chemotherapy-induced dormant tumor cells in multiple breast cancer models. These dormant cells, especially in triple-negative breast cancer (TNBC) models 4T1 and MDA-MB-231, consistently exhibited sustained Bcl-xL expression as a dominant survival factor in chemotherapy-induced dormancy, while other anti-apoptotic proteins like Bcl-2 and Mcl-1 remained low or unchanged. Importance of Bcl-xL in facilitating dormant cell survival was seen by shRNA-mediated knockdown of Bcl-xL in neu-positive (neu+) MMC cells, which resulted in significantly enhanced chemotherapy-induced apoptosis and inhibited relapse both in vitro and in vivo. The selective Bcl-xL inhibitor A-1331852 replicated these effects in TNBC and neu+ MMC cells. A-1331852, when administered transiently during low-dose chemotherapy shows better efficacy than long term continuous administration, which results in activation of alternative escape strategies like rescue of anti-apoptotic protein, survivin. While systemic delivery suppressed tumor relapse, it was associated with high off target toxicity. In contrast, local delivery through intertumoral administration efficiently inhibited growth while mitigating off target toxicity but failed to prevent lung metastases. This highlights the need for tumor-targeted systemic delivery. These findings position Bcl-xL as a tractable therapeutic target in residual breast cancer and support the development of spatially selective, perioperative Bcl-xL inhibition strategies to eradicate dormant disease and prevent recurrence in aggressive subtypes like TNBC.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-8-2025