Receptor tyrosine kinases (RTK) are key regulators of growth, differentiation and survival of epithelial cells and play a significant role in the development and progression of cancers derived from these tissues. In malignant cells, these receptors and their downstream signalling pathways are often deregulated, leading to cell hyper-proliferation, enhanced cell survival and increased metastatic potential. Furthermore, endothelial expressed RTKs regulate tumor angiogenesis allowing for tumor growth and maintenance by promoting their vascularization. Epithelial malignancies such as squamous cell carcinomas (SCC), non-small cell lung (NSCLC) and malignant mesotheliomas have very limited treatment options when presenting as metastatic disease. RTKs, particularly the epidermal growth factor (EGFR) and the vascular endothelial growth factor (VEGFR) receptors, have been shown to play significant roles in the pathogenesis of these tumor types. Statins are potent inhibitors of HMG-CoA reductase, the rate limiting enzyme of the mevalonate pathway, that are widely used as hypercholesterolemia treatments. The mevalonate pathway produces a variety of end products that are critical for many different cellular pathways, thus, targeting this pathway can affect multiple signalling pathways. Our laboratory has previously shown that lovastatin can induce tumor specific apoptosis especially in SCC and that 23% of recurrent SCC patients treated with lovastatin as a single agent showed disease stabilization in our Phase I clinical trial. Subsequently, our lab was able to demonstrate that lovastatin in combination with gefitinib, a potent inhibitor of the EGFR showed co-operative cytotoxicity when combined (Chapter 2). Furthermore, the pro-apoptotic and cytotoxic effects of these agents were found to be synergistic and to be manifested in several types of tumor cell lines including SCC, NSCLC and glioblastoma. I was able to expand upon these important findings and demonstrated that lovastatin, through its ability to disrupt the actin cytoskeleton, inhibited EGFR dimerization and activation (Chapter 3). This novel mechanism targeting this receptor has clinical implications as lovastatin treatment combined with gefitinib showed co-operative inhibitory effects on EGFR activation and downstream signalling. The RTK family of proteins share similar features with respect to activation, internalization and downstream signalling effectors. I further demonstrated that lovastatin can inhibit the VEGFR-2 in endothelial cells and mesotheliomas, where VEGF and its receptor are co-expressed driving their proliferation, and induces synergistic cytotoxicity in mesothelioma cells in combination with VEGFR-2 tyrosine kinase inhibitors (Chapter 4). These findings suggest that statins may augment the effects of a variety of RTK inhibitors in a similar fashion representing a novel combinational therapeutic approach in a wide repertoire of human cancers. More importantly, based on this work, we initiated a Phase I/II study evaluating high dose rosuvastatin and the EGFR inhibitor tarceva in SCC and NSCLC patients at our institute. This clinical evaluation will provide invaluable data that will play a role in developing this novel therapeutic strategy. Together, the work embodied in this thesis provides a model for the regulation of EGFR/VEGFR-2 activation and signalling by targeting the rho family of proteins that demonstrates a novel mechanism that can be exploited to refine current therapeutic paradigms.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU./en#10393/20334 |
| Date | 27 October 2011 |
| Creators | Zhao, Tong Tong |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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