Defense Date

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Dr. David A. Gewirtz

Abstract

Senescence is a unique cell state in which cells undergo a prolonged loss of proliferative capacity that is associated with various cytoskeletal, metabolic, and epigenetic alterations. Tumor cells can be induced into senescence by both genotoxic and targeted anti-cancer therapies. While it was long proposed that senescence was irreversible, more recent evidence has demonstrated that tumor cells, in particular those in a state of therapy-induced senescence, are capable of evading the growth arrest and re-entering a proliferative state. Additionally, the accumulation of senescent cells has been shown to contribute to deleterious outcomes, including chemotherapy-related toxicities and disease progression. In light of these observations, we and others have proposed that senescent tumor cells are keystone drivers of tumor progression and recurrence, and that the selective elimination of senescent cells following senescence-inducing chemotherapies may confer a benefit to patient outcome. To this end, we have tested here the effectiveness of the senolytic agent ABT-263 following therapy-induced senescence in both non-small cell lung cancer and prostate cancer. In etoposide-treated lung cancer, we demonstrate that the sequential combination of therapy-induced senescence and ABT-263 shifts the response to therapy towards apoptosis by interfering with the interaction between BCL-XL and BAX. Sequential administration of ABT-263 after etoposide also results in marked, prolonged tumor suppression in tumor-bearing animals. In a model of androgen-sensitive prostate cancer, we show that androgen-deprivation therapies promote a transient senescent response that likely contributes to the development of resistance via direct escape from the senescent growth arrest. Elimination of these senescent cells with ABT-263 mitigates the outgrowth of androgen-independent colonies in vitro and confers a survival benefit in mice following castration in vivo. Altogether, the data presented here support the premise that senolytic therapies following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

10-28-2021

Available for download on Tuesday, October 27, 2026

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