Identifying novel therapeutic strategies for brain metastatic and mucosal melanoma

Abstract

Melanoma encompasses a number of malignancies all originating from cells of melanocytic origin. Generally speaking, melanoma has a promising prognosis with a five-year survival rate of 91.3%, however two subtypes in particular – melanoma brain metastasis (MBM) and mucosal melanoma (MM) – have a high mortality and limited therapeutic options. Cancerous cells frequently have altered metabolic pathways in order to sustain their rapid growth. Cutaneous melanoma has previously been shown to be both arginine dependent and arginine auxotrophic due to silencing of the enzyme argininosuccinate synthase 1 (ASS1), which catalyses de novo arginine synthesis. As a result, arginine deprivation has demonstrated efficacy in the treatment of melanoma, however to date MBM have been excluded from trials. I hypothesised that MBM will be particularly sensitive to arginine deprivation due to it’s observed increased dependency on arginine metabolism and oxidative phosphorylation compared to primary cutaneous melanoma. Results show ASS1 is repressed in both MBM and extracranial melanoma metastasis (EMM), but that this is reversible in some cell lines upon arginine starvation with ADI-PEG20. Regardless of ASS1 upregulation, MBM and EMM were found to be sensitive to ADI-PEG20 via mitochondrial fragmentation followed by apoptotic cell death. The induction of autophagy and epigenetic remodeling of glutamate related pathways constitute two potential resistance mechanisms which were identified. MM is a rare and understudied cancer with very little known about it’s pathogenesis. Investigation of the mutational profile and immunology of disease was hypothesised to identify potentially novel therapeutic targets. Results show oncogeneic pathways similar to those activated in cutaneous melanoma are mutated in MM, however novel pathways unique to MM were also identified. All significantly mutated pathways were associated with MAPK signalling, PI3K/AKT signalling, and the Warburg effect, suggesting these to be potentially important therapeutic targets. Tumours were heavily infiltrated with immune cells in a site specific manner, with gastric and urogenetial tumours displaying infiltration of an anti-tumour immune population, and nasal tumours displaying mixed pro- and anti-tumour infiltration alongside epithelial-to-mesenchymal transition (EMT). Taken together, this study identifies suitable therapies and therapeutic targets for hard-to-treat MBM and MM.