Novel experimental strategies to destroy oral cancer and precancer and residual disease

Abstract

Oral cancer is a major healthy problem, with about 400,000 new cases diagnosed annually worldwide. The disease is characterised by consistently low 5-year survival rate that related to the significant recurrence rate. The recurrence may correlate to the presence of genetically and histologically altered tissues with a higher risk of malignant transformation (Dysplasia) or the residual malignant cells may remain in the body after surgery to remove a tumour (Residual disease).This thesis examines the efficacy of conditionally replicating adenoviruses (CRAds), to lyse epithelia that show mild, moderate or severe dysplasia and the ability of angiogenesis inhibitor (ZD4190) to prevent the growth of malignant cells in a rodent model of residual cancer in muscle bed. Several primary and established keratinocytes derived lesions with dysplasia were grown in monolayer and organotypical culture (QC) to establish 3D model for oral epithelia with mild, moderate and severe dysplasia. The model was characterised and used to test the efficacy of CRAds to lyse these epithelia. This model showed the ability to the cells derived from dysplastic lesions when grown in QC to recapitulate the architectural and cytological features of the parent tissues. The results show that QC dysplastic epithelia can be lysed with topical application of d/922-947 being more lytic than wild type adenovirus or the retargeted CRAds, and that normal QC oral epithelia were very resistant to this treatment. This study also found that the lytic effect was determined by the grade of the dysplasia, and the presence of suprabasal cycling cells in the epithelium. The integrity of the G1-S checkpoint, expression of the coxsackie adenovirus receptor (CAR) and the transcription cofactor p300 may also be important. For residual disease, the studies showed that when 104 squamous tumour cells were implanted, mimicking the clinical scenario where low numbers of residual tumour cells persist at the operative site, immediate treatment with ZD4190 prevented outgrowth of these cells whereas the control groups developed large tumours. When more than 105 malignant cells were implanted the tumours that developed in ZD4190-treated animals contained more areas of necrosis and fewer blood vessels than the vehicle-treated controls and there was a significant reduction in the tumour area when treatment was maintained for 3 weeks. This project shows that it is possible to recapitulate the features of dysplastic oral lesions in vitro. Moreover, QC epithelial phenotype can be modulated by modifying the culture conditions. The CRAD d/922-947 may provide a "molecular scalpel" for oral dysplastic lesions and a means to selectively eliminate dysplastic oral keratinocytes. Finally, shows that angiogenesis inhibitors have an important role to play in preventing the outgrowth of any residual tumour cells and that treatment should commence immediately after surgery when the tumour burden is as low as possible to maximise the therapeutic effect.EThOS - Electronic Theses Online ServiceGBUnited Kingdo