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Title: Identification and validation of novel chemotherapeutic regulated tumour targets suitable for immunotherapeutic intervention
Author: Jaquin, Thomas Jean
ISNI:       0000 0004 2741 9020
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Cancer is the leading cause of death worldwide. Since the development of targeted therapy, the options to treat this disease have dramatically increased. Front line therapies consist of the combination of cytotoxic agents with targeted therapy such as monoclonal antibodies and tyrosine kinase inhibitors. These approaches have been efficacious but due to resistance mechanisms, many patients relapse. Accordingly, there is room for improvement. The aim of this project was to discover novel oncology targets over-expressed following chemotherapy treatment and suitable for immunotherapeutic intervention. The rational was that following chemotherapy, the expression of several surface or secreted proteins would be altered and that these variations of expression potentially participate in cancer cells resistance to treatments. The discovery of new targets was based on a microarray analysis of chemotherapy treated HCTl16 colorectal cancer xenograft tumours. Several targets were identified and characterised but the work presented in this thesis focuses on two related ligands of the ErbB family -amphiregulin (AREG) and heparin-binding-EGF (HB-EGF). Using siRNA knockdown, it was demonstrated that combined inhibition of AREG and HB-EGF synergistically inhibited cancer cell proliferation. We then hypothesised that targeting both ligands may be of therapeutic value. For this purpose, a neutralising dual targeting monoclonal antibody, 2F7, which specifically binds to both ligands, was developed. 2F7 has been shown to block cell proliferation of a wide range of cancer cell lines independently of K-Ras/B-Raf mutational status and to alter all the main hallmarks of cancer such as cell migration, invasion and angiogenesis. Furthermore, 2F7 enhanced the efficacy of conventional chemotherapies such as CPT-ll and 5-FU. 2F7 efficacy was also assessed in vivo, where it inhibited the growth of K-Ras mutant HCT116 xenograft tumours in combination with CPT -11. These promising data suggests that 2F7, with potentially broader efficacy than cetuximab, may represent a novel strategy for targeting the EGF-R pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available