The current management of brain metastasis in melanoma: a focus on riluzole

Brain metastasis is a common endpoint in human malignant melanoma, and the prognosis for patients remains poor despite advancements in therapy. Current treatment for melanoma metastatic to the brain is grouped into those providing symptomatic relief such as corticosteroids and antiepileptic agents, to those that are disease modifying. Related to the latter group, recent studies have demonstrated that aberrant glutamate signaling plays a role in the transformation and maintenance of various cancer types, including melanoma. Glutamate secretion from these and surrounding cells have been found to stimulate regulatory pathways that control tumor growth, proliferation and survival in vitro and in vivo. The antiglutamatergic actions of an inhibitor of glutamate release, riluzole, have been detected by its ability to clear glutamate from the synapse, and it has been shown to inhibit glutamate release rather than directly inhibiting glutamate receptors. Preclinical studies have demonstrated the ability of riluzole to act as a radiosensitizing agent in melanoma. The effect of riluzole on downstream glutamatergic signaling has pointed to cross talk between the metabotropic G-protein-coupled glutamate receptors implicated in a subset of human melanomas with other signaling pathways, including apoptotic, angiogenic, ROS and cell invasion mechanisms, thus establishing its potential to be further explored in combination therapy regimens for both primary human melanoma and melanoma metastatic to the brain.