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

Abstract

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.

Keywords:

• brain
• glutamate
• GPCR
• melanoma
• metastasis
• radiation
• riluzole

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Melanoma is the most aggressive form of skin cancer, and its incidence has been on the rise worldwide in recent years.

• Although surgically curable at early stages, metastatic melanoma is relatively refractory to current therapies and has a poor prognosis.

• Cytotoxic chemotherapeutic agents such as dacarbazine have response rates of only 7–12% with few long-term survivors.

• Strong evidence has emerged implicating a role for glutamate receptors in cancer progression and maintenance.

• Here, we propose the use of a relatively safe nontoxic reagent, riluzole, as a radiosensitizer for the treatment of brain metastases from melanoma and other cancers.

• Tumor cells in general consume large amounts of glutamine, it is not explained by protein synthesis because it exceeds the need for essential amino acids by up to 10-fold.

• Normally there is bidirectional interconversion of glutamine and glutamate; however, in tumor cells the conversion to glutamate is favored. It is not surprising that receptors with glutamate as its natural ligand are involved in tumor cell proliferation in various human diseases.