DOI
https://doi.org/10.25772/NE20-RN41
Defense Date
2022
Document Type
Thesis
Degree Name
Master of Science
Department
Physiology and Biophysics
First Advisor
Hisashi Harada
Second Advisor
Charles Anderson
Third Advisor
Jiong Li
Abstract
TARGETING CHEMOTHERAPY-INDUCED SENESCENT HNSCC WITH SENOLYTICS
Head and Neck squamous cell carcinoma (HNSCC) are cancers derived from the mucosal membranes of the oral cavity, larynx and pharynx. Cisplatin, a chemotherapeutic DNA damaging agent used in the treatment of HNSCC has proven to be effective but cytotoxic to normal cells if used in high doses. Additionally, chemotherapy can induce HNSCC cells into a state of growth arrest called cellular senescence. Senescence is often a response to chemotherapy treatment and cellular stress, and senescent cells have been found to secrete inflammatory cytokines, so called senescence associated secretory phenotypes (SASP). We and others have found that chemotherapy-induced senescent tumor cells are not in eternal growth arrest and have the capacity to re-emerge and recover as stronger proliferating cells. Our study aims to eliminate these cells to suppress tumor growth, minimize the risk of recurrence and extend survival. The upregulated expression of pro-survival BCL-2 family proteins such as BCL-2 and BCL-XL has been found in tumor cells and are highly associated with resistance to chemotherapy. ABT-263 (Navitoclax) is a dual inhibitor of BCL-2 and BCL-XL that has been used in a two-step approach to eliminate cisplatin-induced senescent tumor cells. Although our data supports ABT-263’s capacity to effectively eliminate senescent cells, there are drawbacks with this senolytic agent in clinical settings. It was found that ABT-263 induces dose-limiting thrombocytopenia in patients due to its on-target specificity to platelets. To reduce this toxicity in patients, a PROTAC, DT2216 was developed that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation; the VHL E3 ligase is minimally expressed in platelets. The primary objective of our study is to better understand the mechanism of DT2216, determine the frequency and dose for optimal efficacy in sequential combination with chemotherapeutic drugs, limit toxicity and improve overall survival in vitro and in vivo mouse models.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-9-2022