Pathology - Theses
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ItemUnderstanding melanoma progression and therapy response using in vivo modelling( 2015)A fundamental limitation to improving cancer outcomes is the lack of models that faithfully recapitulate the biological and molecular characteristics of human disease. In melanoma, with the emergence of immune based therapies and targeted therapies against defined oncogenic mechanisms, the development of clinically relevant models of melanoma progression and therapy response/resistance is a higher priority than ever. This thesis examines the key features of a particular type of cancer modelling called patient-derived xenografting (PDX), in which patient cancer cells (in this case melanoma cells) are injected into immunocompromised mice in order to form tumours whose biological and molecular features can be subsequently studied. Although PDX assays have some limitations, they are being increasingly used to study human cancer biology and to test the efficacy of new therapies. For example, PDX melanomas have been used to test whether hierarchical relationships exist amongst phenotypically distinct cells in patient melanomas, with surprisingly contrasting results obtained by different groups that used different PDX assays. An important implication of these studies is the possibility that differences in PDX assay methodology might result in different conclusions about underlying disease mechanisms. Chapters 3 and 4 will address this possibility by examining the effects of various modifications to PDX melanoma assays on the ability to reveal tumourigenic potential in melanoma cells, and to test theoretical models of disease progression. These studies and the work of others highlight a broader issue regarding cancer modelling and the degree to which individual approaches can be used to infer features of actual human disease, including disease-related outcomes of patients such as metastasis, survival and response/resistance to therapy. Although PDX melanoma assays may assist in the prediction of patient prognosis and therapy responses (Quintana, Piskounova et al 2012), extended testing of these possibilities is lacking. Chapter 5 will thus describe a series of direct comparisons of disease-related features of matched melanomas growing in patients and in PDX assays.