Date of Award
Spring 5-6-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Sciences
First Advisor
Ming Luo
Second Advisor
Jenny J. Yang
Third Advisor
Leszek Ignatowicz
Abstract
Cancer has been one of the leading causes for decades. Conventional cancer treatments present several shortcomings, emphasizing the urgent need for more advanced therapies. This thesis aims to provide innovative strategies targeting different types of cancer. Focusing on pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), we com- bined oncolytic virus (OV) and immune checkpoint inhibitors (ICIs) to increase the efficacy of cancer treatment. In another approach, we also revealed how the inhibitor MA242 binds to the oncoprotein MDM2, generating valuable information for future drug design improve- ments. First, we investigate the efficacy of a novel genetically modified OV, vesicular stom- atitis virus expressing Smac protein (VSV-S), combining with ICIs. Through comprehensive in vitro and in vivo analyses, we demonstrate that the tumor microenvironment (TME) has been altered by VSV-S infection. Following with the programmed cell death protein-1 (PD- 1) antibody treatment, a more significant antitumor effect was observed. Next, we expand our combination therapy to NSCLC, which is traditionally considered resistant to anti-PD1 treatment due to mutations in oncogenic drivers such as EGFR, ALK, BRAF. We explored the transformative potential of VSV-S in sensitizing immunosuppressive TME to ICI treat- ment by eliciting inflammatory responses. The anticancer effect of combination is robust and TME is shifting towards ‘hot’ tumor phenotype. The combination remarkably inhibits tumor growth. Additionally, we delve into the molecular mechanism underlying the Mouse double minute 2 homolog (MDM2) inhibitor MA242. Through structural analysis and functional assays, we elucidated the inhibitory mechanism of MA242 on MDM2-mediated ubiquitina- tion. This study offered deeper insights of the mechanism of MA242 action, contributing to future structure improvement. In conclusion, the integration of OVs and immunotherapy, and the targeted molecular inhibitors represent advanced approaches in cancer therapy, and hold promises for improvement of cancer treatment.
DOI
https://doi.org/10.57709/37029878
Recommended Citation
Tang, Sijia, "Advanced Approaches in Cancer Therapy." Dissertation, Georgia State University, 2024.
doi: https://doi.org/10.57709/37029878