Pre-clinical investigation and clinical development of E7080, a multi-targeted tyrosine kinase inhibitor: implications for melanoma

Glen, Hilary (2010) Pre-clinical investigation and clinical development of E7080, a multi-targeted tyrosine kinase inhibitor: implications for melanoma. PhD thesis, University of Glasgow.

Abstract

The basis for this PhD project was to investigate E7080, a novel multi-targeted tyrosine kinase inhibitor, both pre-clinically and clinically. Traditional early clinical trials of cytotoxic agents in cancer patients may not be the optimal way to develop new targeted agents, whose mechanism of action often means they are cytostatic, rather than cytotoxic, and have much less in the way of toxicity. For this reason, the use of biomarkers to aid early clinical development is becoming increasingly popular.
The initial aims of this PhD were to develop a pharmacodynamic biomarker of the activity of E7080 in patient peripheral blood mononuclear cells (PBMCs), and to gain a better understanding of its mechanism of action, while simultaneously performing a phase I clinical trial of E7080.
Two approaches were used to identify a pharmacodynamic biomarker of E7080’s activity, a candidate approach and a global phosphoproteomic approach. Neither approach was successful in identifying a biomarker in PBMCs, partly due to the finding that PBMCs were not an ideal candidate for a biomarker of E7080 activity as they lacked expression of some of the main receptor targets of E7080.
Inhibition of three of E7080’s main receptor targets, VEGFR-2, PDGFR-β and FGFR-1, was confirmed at concentrations of E7080 achieved in patients on the clinical trial. E7080 had no effect on basal proliferation of a number of different tumour cell lines, but caused a significant impairment of cellular migration and invasion in vitro, suggesting a potential role for E7080 in the adjuvant setting.
As the clinical trial of E7080 progressed, it became clear that patients with advanced malignant melanoma were deriving an unexpectedly high benefit from treatment with E7080, and our hypothesis was that this benefit was due to the inhibition fibroblast growth factor receptor-1 (FGFR-1) signalling, which has been implicated in the progression of malignant melanoma in vitro, and in mouse models in vivo. Therefore, a further investigation was undertaken to explore the relationship of FGFR-1 expression in human melanoma, and its impact on patient outcome. FGFR-1 expression was examined in a large human melanoma tumour tissue microarray, and was found to increase significantly as lesions progressed from benign naevi to primary malignant melanomas. FGFR-1 expression also significantly correlated with patient outcome. In patients with non-metastatic melanoma, low expression of FGFR-1 was an independent prognostic factor for poorer progression free and overall survival.
In conclusion, very encouraging evidence of efficacy was observed in patients treated on the phase I clinical trial of E7080, most notably with metastatic melanoma, with implications for future treatment. While it was not possible to identify a PBMC pharmacodynamic biomarker for the activity of E7080, pre-clinical investigation into the mechanism of action of E7080 has suggested a further role for E7080 in the adjuvant setting.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Due to copyright restrictions the full text of this thesis cannot be made available online. Access to the printed version is available once any embargo periods have expired.
• Keywords: tyrosine kinase inhibitor, biomarker, melanoma, fibroblast growth factor receptor-1, phase I clinical trial
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Frame, Prof. Margaret and Brunton, Dr. Valerie
• Date of Award: 11 August 2010
• Depositing User: Dr Hilary Glen
• Unique ID: glathesis:2010-2048
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 12 Aug 2010
• Last Modified: 05 Mar 2019 16:17
• URI: https://theses.gla.ac.uk/id/eprint/2048