Managing melanoma in the era of personalised therapy: more than one disease

Melanoma is the most aggressive form of skin cancer and its incidence has risen more than any other cancer in the United Kingdom. Surgery is the mainstay of treatment for localised and regional disease. Hitherto prognosis for metastatic melanoma has been poor, with a median life expectancy of less than 12 months. However, in the last decade there have been considerable molecular advances leading to greater understanding of tumour biology and molecular characterisation of tumours. These developments have highlighted the heterogeneous nature of melanoma and provided a basis for personalised therapy. This thesis presents the clinical use of surgical (sentinel lymph node biopsy) or molecular (genetic mutation screening) techniques in Oxford to stratify melanoma patients into subgroups. The use of sentinel lymph node biopsy for patients with thick (greater than 4mm) primary tumours predicted overall and recurrence free survival. Screening for BRAF and NRAS mutation in patients with metastatic melanoma demonstrated associations between clinical and genetic characteristics, and differences in clinical outcomes. Identifying subgroups through genetic screening enables targeted therapy. This thesis further investigated the role of phosphatidylinositol-3-kinase (PI3K) inhibitors in melanoma cell lines as pro-senescence therapy. Inhibition of the PI3K axis showed an increased in DNA damage; a marker for senescence. The PI3K pathway was shown to regulate the anti-senescent factors TBX2 and TBX3. Evaluation of transcriptional activity indicated cooperation between the T-box and Forkhead factors, raising the prospect of combination therapy in metastatic melanoma. The management of melanoma is evolving. Following substantial molecular advances, a new generation of targeted therapies have emerged, demonstrating clinical responses in patients that would have been inconceivable a decade ago with conventional therapies. In this progressive era of targeted therapies, it should not be assumed that all melanomas respond or progress in a similar manner. Therefore personalised investigations and therapies should be offered to melanoma patients in order to improve clinical outcomes.