A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma.

Abstract

PURPOSE:

Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal-regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma.

EXPERIMENTAL DESIGN:

Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning.

RESULTS:

We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease.

CONCLUSIONS:

Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy.

• Authors: Dana Yip, Maithao N Le, Joseph L-K Chan, Jonathan H Lee, Janice A Mehnert, Anthony Yudd, Jeffery Kempf, Weichung J Shih, Suzie Chen, James S Goydos
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 11 Pg. 3896-902 (Jun 01 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19458050 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Excitatory Amino Acid Antagonists
• Ki-67 Antigen
• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor type 1
• Fluorodeoxyglucose F18
• Riluzole
• BRAF protein, human
• Oncogene Protein v-akt
• Proto-Oncogene Proteins B-raf
• Extracellular Signal-Regulated MAP Kinases
• Caspase 3
• ras Proteins

Topics

• Blotting, Western
• Caspase 3 (metabolism)
• Enzyme Activation (drug effects)
• Excitatory Amino Acid Antagonists (therapeutic use)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fluorodeoxyglucose F18
• Humans
• Immunohistochemistry
• Ki-67 Antigen (metabolism)
• Melanoma (drug therapy, genetics, metabolism)
• Mutation
• Neoplasm Staging
• Oncogene Protein v-akt (metabolism)
• Positron-Emission Tomography
• Proto-Oncogene Proteins B-raf (genetics)
• Receptors, Metabotropic Glutamate (metabolism)
• Riluzole (therapeutic use)
• ras Proteins (genetics)