Investigating the Therapeutic Efficacy of Aspirin and Oseltamivir Phosphate in Combination with Gemcitabine for the Treatment of Pancreatic Cancer
Loading...
Authors
Qorri, Bessi
Date
Type
thesis
Language
eng
Keyword
cancer research , drug repurposing , multistage tumorigenesis , targeted therapy , aspirin , oseltamivir phosphate , osmotic pump , continuous perfusion
Alternative Title
Abstract
Pancreatic cancer is one of the most lethal malignancies and is often referred to as the “silent killer.” In addition to its advanced-stage detection, there have been no significant improvements in patient survival rates or in the development of effective therapies, highlighting the urgent need for therapeutic options that target the aggressive nature of the disease. Several clinical challenges remain in the treatment of pancreatic cancer, attributed to the adaptive, self-sustaining, and invasive cancer cell program, whereby more aggressive phenotypes will survive and metastasize despite therapeutic intervention. Repeat instability emerges first, followed by more significant aberrations, with compensatory effects leading to robust tumor fitness maintained throughout tumor progression. Future studies must not rely on targeting a single oncogenic pathway but must suppress the multiple enabling hallmark(s) capabilities of pancreatic cancer cells. In the work presented in this thesis, a novel treatment approach targeting mammalian neuraminidase-1 (Neu-1) is hypothesized to ablate the compensatory effects of pancreatic cancer. Neu-1 plays critical roles in ligand-induced activation of several receptor tyrosine kinases (RTKs) and TOLL-like receptors (TLRs), all of which are upregulated and implicated in multistage tumorigenesis.
Here, we investigate the efficacy of repurposing non-steroidal anti-inflammatory drug aspirin (acetylsalicylic acid; ASA) and anti-viral agent oseltamivir phosphate (OP) in combination with clinical standard chemotherapeutic agent gemcitabine (GEM) that may open a novel and promising clinical treatment approach for patients with pancreatic cancer. For the first time, we show that ASA targets Neu-1, representing a potential link between cancer, inflammation, and glycosylation. Furthermore, OP has been reported to target Neu-1 and shut down several tumorigenic pathways. In this work, the combination of ASA+OP in addition to GEM is proposed as a horizontal approach to target several key cancer-promoting pathways including epithelial-to-mesenchymal transition (EMT), chemoresistance, hypoxia, cell signaling via the MAPK/Akt/mTOR pathway, cancer stem cell (CSC) enrichment, tumor progression, and metastases. The studies presented in this thesis stress the importance of the role of drug repurposing ASA and OP for cancer therapy that simultaneously targets multiple hallmarks of pancreatic cancer, highlighting the role that mammalian Neu-1 plays in cancer pathogenesis.
Description
Citation
Publisher
License
Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NoDerivs 3.0 United States
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NoDerivs 3.0 United States