Medicine (St Vincent's) - Theses
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ItemMolecular mechanisms regulating chemotherapy resistance in ovarian carcinomas( 2013)Epithelial ovarian cancer is the second most common and most lethal gynaecological malignancy. Due to lack of early diagnostic modalities this aggressive form of cancer is frequently diagnosed once it is at an advanced stage with a low 30% five year survival rate. Following primary cytoreductive surgery, ovarian cancer patients are treated with adjuvant or neo-adjuvant systemic administration of platinum and taxane based chemotherapy as part of first line chemotherapy regimens. A positive response to this form of treatment is seen in the majority of cases, with patients enjoying a short remission period. However, treatment is rarely curative and in nearly all cases within 16-22 months there is an emergence of fatal chemoresistant recurrent disease. It is believed that this phenomenon of chemoresistance and recurrence is attributed to the activation of specific cell signalling pathways associated with cancer cell survival and the emergence of cancer stem cell-like populations within the chemotherapy treated residual ovarian tumours. In order to increase the low 30% five year survival rate for this distressing disease, an understanding of the molecular processes that govern the enrichment of cancer stem cell-like cells and the activation of pro-survival signalling pathways in chemotherapy surviving residual cells is needed, as these are the ultimate source of the recurrent disease. Hence with the aim of elucidating such molecular processes, this thesis aimed to answer the following two critical questions: 1. Do first line taxane based chemotherapies facilitate the activation of pro-survival pathways such as the JAK2/STAT3 pathway which is involved in the enrichment of cancer stem cell-like characteristics and cancer cell survival in epithelial ovarian cancer? 2. Does targeting the JAK2/STAT3 pathway with small molecule inhibitors enhance the efficacy of current taxane based therapies? To answer the above question, this thesis diligently characterised the cancer stem cell-like profiles that emerged in response to taxane based chemotherapy of ovarian cancer cell lines as well as ovarian tumour cells isolated from the ascites of advanced stage ovarian cancer patients. Moreover, this thesis assessed the effects of inhibiting the JAK2/STAT3 pathway on chemoresistance and enrichment of cancer stem cell-like phenotypes. Finally, using an in vivo mouse xenograft model, this thesis validated the demonstrated results obtained from in vitro experimentations. The results of this thesis demonstrate that treatment with taxane and platinum based therapies does indeed activate the JAK2/STAT3 pathway in both ovarian cancer cell lines as well as tumour cells isolated from the ascites fluid of advanced stage ovarian cancer patients. Moreover, this thesis is the first to demonstrate that the activation of the JAK2/STAT3 pathway in response to taxane based therapies coincides with the enrichment of cancer stem cell-like phenotypes which was shown to contribute to cancer cell survival and the development of a significantly larger tumour burden in mice. Furthermore, this thesis is the first to demonstrate that inhibiting the JAK2/STAT3 pathway reduces the emergence of cancer stem cell-like populations and enhances the efficacy of current taxane based therapies resulting in the significant reduction of tumour burden in mice. The results demonstrated in this thesis have important implications for ovarian cancer patients who are being treated with taxane and or platinum based first line therapies. These findings warrant further pre-clinical investigation and may be used as a platform for the development of adjuvant therapies used in combination with the gold standard therapy that is currently offered to ovarian cancer patients.