Abstract
Ovarian cancer is the leading cause of cancer death among all gynaecological cancers. Its aggressive nature is partly due to genetic heterogeneity and the lack of effective treatments strategies. Standard treatment involves cytoreductive surgery followed by chemotherapy using a platinum-based agent. Although initially, patients response well to this treatment, the majority will relapse and develop recurrent disease, predominantly due to the emergence of platinum resistance. Further understanding of the molecular changes which occur during ovarian ontogenesis and in the development of platinum resistance is essential to design new targeted drugs to improve patient prognosis. HOX gene are a family of homeodomain-containing transcription factors that determine cell and tissue identity in the early embryo and are found to be aberrantly expressed in cancer. HOX gene expression in ovarian cancer of different histological subtypes and in primary ovarian tumours were evaluated here. This is the first comprehensive study of HOX gene expression in a cohort of primary ovarian tumours, including statistical analysis of HOX gene expression profiles along with clinic-pathological data of each patient. HOX genes were found to be profoundly dysregulated in ovarian cancer cell lines and primary ovarian tumours, with very little to no expression found in normal ovarian and fallopian tube tissue. A 5-HOX gene signature which predicts poor overall survival in ovarian cancer patients was identified. Platinum resistant disease displayed an overall higher level of HOX gene expression, significantly HOXB4 and HOXB9. This dysregulated HOX expression reported could therefore act as a set of targets for therapeutic intervention. The novel peptide, HXR9, has been developed to block the interaction between HOX proteins and their co-factor, PBX, and therefore subsequent target gene expression. The efficacy of HXR9 treatment of ovarian cancer cells was explored. HXR9 treatment was shown to induce cell death via apoptosis in ovarian cancer cells shown by an increase in apoptotic cells identified by flow cytometric analysis, and increase in caspase-3 activity and the upregulation of pro-apoptotic gene cFos. Enhanced cell cytotoxicity was observed when combining HXR9 with cisplatin to treat platinum resistant cells, revealing a new therapeutic option for drug resistant disease that should be explored further for potential clinical trial investigation. A limiting factor towards the development of new treatment strategies is the lack of a reliable animal model of ovarian cancer. Common methods used to test new drugs involve in vitro investigation and the use of engineered animal models. However, these models do not represent the true heterogeneity and complexity of human ovarian tumours. Therefore, the use of the chicken chorioallontoic membrane (CAM) as a model of ovarian cancer for the testing of anti-cancer drugs was assessed. Cell lines grafted onto the CAM successfully and developing into micro-tumours. Cell cultured from ascites samples of ovarian cancer patients also grafted, but with a less success rate. Morphological and tumour retardation was detected after treatment with HXR9. This demonstrated the potential of this model to be developed for future personalised drug screening.