Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.775170
Title: Renal cancer resistance to VEGF receptor tyrosine kinase inhibitors
Author: Sharpe, Kevin
ISNI:       0000 0004 7962 3664
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2015
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Abstract:
Aim: To investigates the molecular changes that occur in response to VEGFr TKI therapy to better understand the acquired resistance process. A further goal is to investigate the potential of SRC inhibitors to slow or prevent VEGFr TKI resistance. Methods: Work was conducted in in vitro assays (MTS assays, scratch and transwell migration assays), a preclinical in vivo model of resistance (786-O xenografts) and IHC was conducted in sequential RCC patient tissue taken before and after 12-16 weeks of VEGFr TKI therapy. Findings: 100% (n=15) of 786-O xenografts developed a resistant phenotype when continually exposed to VEGFr-TKI treatment. PCR with species-specific probes showed VEGFr-TKI induced significant up-regulation of several pro-angiogenic factors in both the tumour and host compartments. These factors included VEGF ligand, FGF-2, HGF, and MET receptor. In addition, genes associated with epithelial mesenchymal transition were up-regulated in treated xenografts. Interestingly, the pro-angiogenic factor PGF and the pro-metastatic gene s100a4 were up-regulated with time, independently of treatment. Gene pathway analysis suggested VEGFr-TKI treatment induced a process resembling fibrosis or wound healing. Furthermore, collagen was increased in treated xenografts. IHC in RCC patient tissue verified that some of the above pathways were affected in the clinical setting. VEGFr-TKI treatment caused a significant reduction in vessel density (CD31), and up-regulation of FGF-2 ligand and vessel-bound MET receptor. Collagen was also increased in VEGFr-TKI treated clinical samples. In vitro assays demonstrated that VHL gene mutation promoted resistance to SRC TKIs. Adding a SRC TKI to VEGFr-TKI therapy had a synergistic anti-tumour effect on 786-O xenografts. However, the combination could not prevent growth in tumours that had acquired a VEGFr TKI resistant phenotype. There was no evidence that the addition of a SRC TKI affected genes implicated in the resistance process. Interpretation: VEGFr-TKI treatment is associated with dynamic molecular changes to several relevant biomarkers. Targeting any one pathway in isolation may have an incremental anti-tumour effect, but because multiple pathways are affected, it is perhaps unlikely to result in a sustained improvement in tumour response. Heterogeneity of protein expression adds further complication to a targeted approach. Collagen deposition increases with VEGFr TKI therapy. Collagen has been shown to promote angiogenesis and metastasis. Further investigation is warranted to understand whether the addition of anti-fibrotic agents to anti-angiogenic therapy could have an incremental benefit on patient outcome.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.775170  DOI: Not available
Keywords: Medicine ; Renal Cancer
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