Ioannou, Nikolaos (2013) Studies of biological significance and co-targeting of growth factor receptors in pancreatic cancer. (PhD thesis), Kingston University, .
Abstract
Despite many advances in cancer diagnosis and therapy in the last few decades, pancreatic cancer remains one of the most fatal types of human malignancies, with a 5-year survival rate of less than 6%. One of the major contributing factors for the poor prognosis of this malignancy is the lack of specific markers for its early detection. In addition, pancreatic tumours are highly resistant to conventional types of therapy. Of the numerous anti-cancer agents investigated during the last decade, only erlotinib, an EGFR tyrosine kinase inhibitor has been added to the weaponry against pancreatic cancer. However, the therapeutic benefit of this approach is limited since the majority of patients simply do not respond or eventually acquire resistance to this type of therapy. The aim of this study was to investigate the anti-tumour effect of chemotherapeutic agents such as gemcitabine and several HER and IGF-IR inhibitors, including the pan-HER inhibitor afatinib, when used alone or in combination or 'in vitro'. The expression levels of all HER family members and IGF-IR in a panel of human pancreatic cancer and their association with response to treatment with HER and IGF-IR inhibitors was also investigated. Furthermore, the expression levels of these receptors as well as several ABC transporters and putative pancreatic cancer cell variants developed by chronic treatment with escalating doses of targeted agents or chemotherapeutic agent gemcitabine, of their parental counterparts. All pancreatic cancer cell lines investigated were found to be positive for EGFR, HER-2 and IGF-IR, however, over-expression of these receptors was found to be uncommon. In addition, no correlation was found between the expression levels of HER family members or IGF-IR and sensitivity to their respective inhibitors. Growth inhibition studies revealed that the pan-HER inhibitor afatinib had greater anti-tumour efficacy compared to first generation TKIs erlotinib and gefinitib, supporting its utilization in the treatment of this malignancy. Most importantly, co-targeting of HER family members and IGF-IR was found to be superior to single treatment, providing a rationale for investigating the therapeutic potential of this combination 'in vivo' (animal models and in a clinical setting).
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