DOI

https://doi.org/10.25772/SJA5-TQ96

Defense Date

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Human Genetics

First Advisor

Dr. David A. Gewirtz

Second Advisor

Dr. Hisashi Harada

Abstract

Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local, and distant metastasis and disease relapse as well as cisplatin-induced resistance are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in both p53 wild- type HN30 and p53 mutant HN12 head and neck cancer models. We also show that tumor cells can escape from senescence both in vitro and in vivo. We further established a cisplatin-resistant cell line from HN30 parental cell line that underwent brief senescence after cisplatin treatment. In this study, we evaluated the effectiveness of ABT-263 (Navitoclax) and ARV-825, in the elimination of senescent tumor cells after cisplatin treatment. Navitoclax increased apoptosis by 3.3-fold (p ≤ 0.05) at Day 7 compared to monotherapy by cisplatin in HN30 and HN12 cells, however, it did not sensitize HN30R cell line. Additionally, we show that ABT-263 interferes with the interaction between BCL-XL and BAX, anti- and pro-apoptotic proteins, respectively, followed by BAX activation, suggesting that ABT-263 induced apoptotic cell death is mediated through BAX. ARV-825 however, significantly induced apoptosis in both HN30 and HN30R cells. The mechanistic studies show that ARV-825 treatment in combination with cisplatin increased DNA double-strand breaks signals in-vitro and in-vivo. Our in vivo studies also confirm senescence induction in tumor cells by cisplatin, and the promotion of apoptosis coupled with a significant delay of tumor growth after sequential treatment with ABT-263 or ARV-825. Sequential treatment with cisplatin followed by ABT-263 extended the humane endpoint to ~130 days compared to cisplatin alone, where the mouse survived ~75 days. These results support the premise that secondary agents could be utilized to eliminate residual senescent tumor cells after chemotherapy and thereby potentially delay disease recurrence and resistance in head and neck cancer patients.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

1-12-2023

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