Author ORCID Identifier
0000-0003-3957-8064
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
David Gewirtz
Second Advisor
Hisashi Harada
Third Advisor
Harry Bear
Fourth Advisor
Larisa Litovchick
Fifth Advisor
Lisa Shock
Abstract
Therapy-induce senescence (TIS) represents a major biological outcome of many anticancer treatments and is increasingly recognized as a strategic vulnerability in triple negative breast cancer, which is a highly aggressive subtype with limited therapeutic options and frequent relapse. Here, we probed TIS as a primary cellular response that may ultimately compromise long-term outcomes using standard chemotherapeutic agents in TNBC as well as the antibody-drug conjugate sacituzumab govitecan (SG). Both chemotherapy and SG reliably induced pronounced senescence across TNBC models, yielding durable growth arrest, however, also generating a persistent reservoir of viable tumor cells capable of eventual proliferative recovery, a hallmark challenge of TIS. Senolytic treatments with ABT-263 (navitoclax) produced only a transient clearance of senescent cells across the treatments with doxorubicin, hydroxy-peroxy-cyclophosphamide, 5-FU, paclitaxel and gemcitabine. Platinum-based agents yielded senescent populations that appeared to be significantly more susceptible to sequential treatment combined with ABT-263. These findings indicate that whereas TIS can suppress the growth of tumors, it simultaneously creates a population of therapy-persisting cells that may fuel recurrence. Collectively, our data highlights TIS as a central, conserved treatment response across cytotoxic chemotherapy and also in an advanced targeted treatment approach, such as SG, which underscores the clinical challenge presented by senescent tumor cell survival. These studies further support the development of optimized senolytic combination strategies along with platinum compounds, potentially using safer Bcl-2/Bcl-xL inhibitors to enhance the clearance of TIS cells and improve long-term outcomes in TNBC.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-9-2025