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dc.contributor.authorBernardi, Maria-Pia
dc.date.accessioned2018-02-22T22:37:19Z
dc.date.available2018-02-22T22:37:19Z
dc.date.issued2017en_US
dc.identifier.urihttp://hdl.handle.net/11343/198358
dc.description© 2017 Dr. Maria-Pia Bernardi
dc.description.abstractAnal squamous cell carcinoma is a human papilloma virus–related disease for which definitive treatment comprises chemoradiotherapy that has not changed substantially for forty years. Few advances in treatment have been made since then, especially for those patients who develop disease relapse and for whom no surgical options exist. Predicting responses in patients for whom conventional treatment will fail remains elusive and is a significant clinical problem. As anal cancer is reasonably described as a rare cancer, innovative approaches are required to address this pressing clinical issue as large clinical trials are exceptionally challenging and are unlikely to be undertaken. This thesis describes a range of research strategies to identify potential avenues to predict and improve patient responses to existing and novel therapies. It comprises a combination of clinical and translational research. Using our institutional database I have assessed the utility of post-treatment imaging with FDG-PET as it may serve as a means of early detection of poor response to treatment. I found that a complete metabolic response on post-treatment PET scan was predictive of overall survival and disease-free survival. The database, which spans a thirty year period, was also interrogated to explore patterns of treatment failure, subsequent salvage treatment and outcomes. I found that multiple treatment modalities have been utilised to treat patients with persistent or recurrent disease, with satisfactory survival benefit in carefully selected patients. I also evaluated the literature that investigated the molecular biology of anal cancer finding that no clinically valuable biomarkers have emerged. Some suggestions have been reported that regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, might offer opportunities for targeted therapy. Additionally, antibody therapy targeting epidermal growth factor receptor may prove efficacious although the safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. In the laboratory, next generation RNA sequencing was utilised in eleven anal SCC patient samples. Through stratification of the tumours into clinically relevant groups and Bioinformatic analysis, eight genes with differential expression were chosen for further validation. One of these genes was identified as a novel target which could ultimately lead to expanding therapeutic options in anal cancer management. Due to a lack of pre-clinical models, including cell lines and mouse models for testing new therapies, I developed a new anal cancer model based upon patient-derived tumour xenografts. I used this model in a pilot experiment to assess the novel drug target identified by RNA-seq. The outcomes were promising with stand-alone efficacy of the novel drug observed with statistical significance, while also validating the feasibility of using xenografts for anal SCC. This thesis builds upon the clinical experience of decades of management of patients with anal cancer identifying both clinical and laboratory approaches to advance assessment and identify novel treatment possibilities for this group of patients. en_US
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dc.subjectanal squamous cell carcinomaen_US
dc.subjectanal SCCen_US
dc.subjectanal canceren_US
dc.subjectmolecular biologyen_US
dc.subjectnovel targetsen_US
dc.subjectpatient-derived tumour xenograftsen_US
dc.titlePrediction and prognosis in anal cancer: developing models to improve patient outcomeen_US
dc.typeDoctorateen_US
dc.typethesis
melbourne.affiliation.departmentSurgery (St Vincent's)
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.affiliation.facultyMelbourne Medical School
dc.identifier.orcid0000-0002-9833-2892en_US
melbourne.thesis.supervisornameHeriot, Alexander
melbourne.thesis.supervisoremailAlexander.Heriot@petermac.orgen_US
melbourne.contributor.authorBernardi, Maria-Pia
melbourne.accessrightsOpen Access


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