DOI

https://doi.org/10.25772/DE05-X210

Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology and Biophysics

First Advisor

Hisashi Harada

Second Advisor

Yue Sun

Third Advisor

Roland Pittman

Abstract

Non-small Cell Lung Cancer (NSCLC) originates from numerous different cell types in the lungs and is among the deadliest of cancers. Head and Neck Squamous Cell Carcinomas (HNSCC) are derived from the mucosal membranes of the oral cavity, pharynx, and larynx. Both NSCLC and HNSCC are predominately caused by tobacco smoke inhalation and as such mutations in the tumor suppressor gene TP53 are common. Since similarities exist in the root cause of NSCLC and HNSCC, they may also share similarities in treatment methods. Cisplatin is a platinum-based DNA damaging agent that has been used as a cancer chemotherapy for decades. While highly effective in the eradication of cancer cells, cisplatin also causes severe toxicity to patients when given in high doses. Previous research has shown that treatment with lower dosages of cisplatin can induce cancer cells into a state of senescence. In this state, the cancer cells are in growth arrest but remain metabolically active. Unfortunately, senescent cancer cells display a SASP (senescence associated secretory phenotype) that causes a prolonged inflammatory response in patients. The SASP is associated with angiogenesis and metastasis of the cancer cells. In addition, it has been shown that cancer cells can escape senescence and in doing so become more drug resistant and aggressive. A current field of cancer research involves selectively eradicating cancer cells that have first been induced into senescence using cisplatin or other traditional chemotherapies. Drugs that were once used to inhibit specific protein targets in the cancer cells are being repurposed as senolytics. The central idea of inducing cancer cells into senescence is that specific protein targets become upregulated upon treatment with cisplatin. The anti-apoptotic proteins BCL-XL and BCL-2 are two key proteins that promote cancer cell survival after exposure to DNA-damaging agents such as cisplatin. Once these proteins become overexpressed in the cancer cells, they make perfect targets for a class of drugs that act as BCL-XL and BCL-2 inhibitors. Previously research has shown that the dual BCL-XL/BCL-2 inhibitor ABT-263 is effective at selectively eradicating cancer cells that have been induced into senescence. However, ABT-263 was unable to pass clinical trials as it was shown to cause dose-limiting thrombocytopenia. Thrombocytopenia is a condition of low platelet counts in the blood. This is because platelets rely on BCL-XL for survival. For this reason, a new BCL-XL/BCL-2 inhibitor was formulated known as AZD-4320. AZD-4320 works in a similar manner to ABT-263 and only causes transient thrombocytopenia that can be managed. Here we show that AZD-4320 is a potent senolytic agent and is effective at eradicating both HNSCC and NSCLC cells in vitro and in vivo.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-11-2022

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