A Phase 0 Trial of Riluzole in Patients with Resectable Stage III and IV Melanoma

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...

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Published in:	Clinical cancer research Vol. 15; no. 11; pp. 3896 - 3902
Main Authors:	YIP, Dana, LE, Maithao N, CHAN, Joseph L.-K, LEE, Jonathan H, MEHNERT, Janice A, YUDD, Anthony, KEMPF, Jeffery, SHIH, Weichung J, CHEN, Suzie, GOYDOS, James S
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-06-2009
Subjects:	Antineoplastic agents Biological and medical sciences Blotting, Western Caspase 3 - metabolism Cell Surface Receptors Dermatology Enzyme Activation - drug effects Excitatory Amino Acid Antagonists - therapeutic use Extracellular Signal-Regulated MAP Kinases - metabolism Fluorodeoxyglucose F18 Glutamate Humans Immunohistochemistry Ki-67 Antigen - metabolism Medical sciences Melanoma Melanoma - drug therapy Melanoma - genetics Melanoma - metabolism Mitogen-Activated Protein Kinase Pathway Mutation Neoplasm Staging Oncogene Protein v-akt - metabolism Pharmacology. Drug treatments Phase 0 Trials Positron-Emission Tomography Proto-Oncogene Proteins B-raf - genetics ras Proteins - genetics Receptors, Metabotropic Glutamate - metabolism Riluzole - therapeutic use Tumors of the skin and soft tissue. Premalignant lesions Human Malignant melanoma Clinical trial Patient Advanced stage Locally advanced stage Malignant tumor Benzothiazole derivatives Riluzole Cancer
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-08-3303