Oncogenic Signaling in Uveal Melanoma

Uveal melanoma (UM) is the most common eye cancer in adults, affecting approximately
6-7 individuals per million each year in Australia. Despite favourable outcomes after local
tumor control with either surgery or radiation therapy, up to 50% of patients develop
distant metastatic disease with over 90% of metastases occurring in the liver. Currently
there are no effective systemic treatments for metastatic UM. Chemotherapy has shown
limited activity in metastatic UM with no benefit in overall survival. Despite the success
of immunotherapy in treatment of advanced cutaneous melanoma, immunotherapy has
failed to translate its success in improving overall survival in advanced UM. Latest published
studies show patients with metastatic UM receiving immunotherapy, showed a response
rate of less than 5% and median overall survival of less than 8 months. Targeted therapy
has also shown limited success with the most recent phase III clinical trial using selumetinib
(MEK inhibitor) not meeting its primary and secondary end points with no difference in
progression free survival, overall survival and a response rate of less than 5%.
My PhD project investigates oncogenic signaling pathways in UM. It has 2 main components;
First, testing pre-clinical uveal melanoma cell models with small molecule inhibitors to
identify the critical survival pathways (including protein kinase and mitogen activated
protein kinase) in uveal melanoma. Second, is a translational research aim investigating
plasma and tissue samples from patients treated with a protein kinase C (PKC) inhibitor
(LXS196). We will explore circulating tumour (ct) DNA for resistance mutations, and
the utility of ctDNA in predicting patient responses to PKC inhibition. This clinical trial is
currently the only available clinical trial for metastatic UM in Australia and is currently
recruiting in Westmead Hospital, Sydney, NSW under Dr Matteo Carlino, my co-supervisor.