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.