DOI
https://doi.org/10.25772/T141-M989
Author ORCID Identifier
0000-0003-0350-9139
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biochemistry
First Advisor
David Gewirtz
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, and accounts for 15% of all breast cancer diagnoses. During cancer treatment, certain populations of cancer cells can become resistant to therapy and persist after treatment ends, resulting in tumor recurrence. Cancer cells can evade death by entering a state of replicative arrest called senescence. Senescent cells promote tumor aggressiveness and further senescence by excreting signals to surrounding cells. Senescent cells are ultimately harmful to the organism and must be eliminated to improve patient outcomes. Senolytics are used to selectively eliminate senescent cells and are in early clinical trials in ageing-related diseases including cancer. A new senolytic strategy called the “two-hit” approach involves purposefully inducing senescence and then treating with a senolytic to eliminate cells that persist after chemotherapy or radiation. One way to induce senescence is by eliminating the cell’s ability to repair DNA damage by using a poly (ADP-ribose) polymerase inhibitor (PARPi), which have been shown to enhance the response to radiation in cells that are both repair-deficient and repair-proficient. We used a combination strategy of radiation and the PARPi talazoparib to induce senescence in TNBC cells and followed with the senolytic ABT-263 to kill the senescent cells. We discovered that the combination of radiation and talazoparib is a potent inducer of growth arrest and senescence. However, ABT-263 did not improve upon the combination of radiation with talazoparib. In the clinical treatment of cancer, treatments are given repeatedly over multiple weeks, and not all at once, so we replicated that setting by repeating our treatments in a double-dose strategy. The double-dose of radiation with talazoparib produced a pronounced growth arrest compared to cells only treated once, and was accompanied by increased senescence measured by X-gal. The inclusion of ABT-263 with radiation and talazoparib revealed it is effective in the double-dose system. Even though we observe prolonged growth arrest in our double-dose system, the cells still recover if allowed to persist after the termination of treatment. Our findings suggest that an effective treatment for TNBC is the combination of talazoparib and radiation.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
2-12-2025