The clinical and therapeutic significance of PI3K and MAPK signalling in epithelial ovarian cancer (EOC) and melanoma

© 2012 Dr. Despina HandoliasA common goal in the genetic and molecular characterization of tumours is to identify oncogenic mutations that drive cancer growth and to identify clinical subsets of patients most likely to display these and other genetic aberrations that are of clinical and therapeutic significance. Improved understanding of the molecular circuitry of cancers and the biological consequences of their signals enables the rational application of targeted agents against key effector molecules. Two important examples of this include the successful clinical application of imatinib an inhibitor of the KIT receptor tyrosine kinase in the management of gastrointestinal stromal tumours (GISTs) with activating mutations in the KIT gene and trastuzumab, the monoclonal antibody to the HER2 receptor tyrosine kinase in HER2 over expressing breast cancer. It is also becoming more apparent that applying targeted agents to large undefined groups of cancer patients is an ineffective clinical strategy. An understanding of the role of these molecules in the non cancer state is also of importance as therapies will only be successful in clinical practice if undue toxicity is avoided. Understanding parameters for patient selection and developing pharmacodynamic markers of response will therefore assist in improving the therapeutic index of targeted agents. This thesis focuses on two important and inter-related cell signalling pathways in cancer, the PI3K and MAPK pathways and describes genetic aberrations of critical molecules within these pathways in epithelial ovarian cancer (EOC) and melanoma. In EOC, the molecular pathogenesis is less clearly defined compared with melanoma, but a body of evidence is building that broadly suggests that low grade and high grade cancers arise from distinct pathways of cancer pathogenesis. I hypothesize that these differences can arise from the genetic and molecular alterations of PI3K and MAPK pathway substrates within the histological subtypes of ovarian cancer. In chapter two, I will focus on PI3K pathway activation in these subtypes as a proposed mechanism in the pathogenesis and progression of this cancer and in the potential response to agents targeting key molecules within this pathway. As these interconnecting pathways are considered important in the response to conventional cytotoxics and in the mechanism of platinum resistance I hypothesize that in activated tumour subtypes pathway attenuation with molecular inhibitors would lead to reversal of platinum resistance. In melanoma, more recent advances have been made with respect to identifying distinct molecular subtypes and consequently patients that are highly likely to respond to targeted therapies. In chapter three it will be demonstrated that KIT mutant melanomas are clinically and pathologically distinct from BRAF mutant melanomas and that oncogene dependence represents the underlying biological mechanism for this. I will describe the clinic-pathological characteristics of patients with KIT mutant melanoma and their responses to KIT kinase inhibition using available small molecule inhibitors. I hypothesize that for patients with cutaneous melanoma, stratifying patients for KIT mutation testing based on the identification of solar elastosis can identify those most likely to harbour KIT mutations and therefore suitability for KIT directed therapy. Additionally the selection of specific therapy can be determined by the exonic location of KIT mutations in melanoma as has been proven to be the case in the management of gastrointestinal stromal tumours. The understanding of molecular or physical mechanisms of resistance to therapy can also help to direct targeted biological therapies to enhance patient management. The work in this thesis contributes to the body of data describing the clinical and molecular differences of EOC and melanoma. It will contribute to the understanding of the molecular mechanisms associated with these cancers which in turn will assist in guiding the selection of patients best suited to the growing list of molecular targeted therapies