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Published on: July 31, 2016
A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma
Dana Yip1, Maithao N Le, Joseph L-K Chan
1Division of Surgical Oncology, Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, USA.
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.
Insights
Riluzole, a GRM1 blocker, showed potential in a phase 0 trial for melanoma patients. Blocking glutamate receptor 1 (GRM1) with riluzole inhibited key signaling pathways and suppressed tumor metabolic activity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ectopic expression of glutamate receptor 1 (GRM1) is implicated in melanoma development.
- GRM1 stimulation up-regulates extracellular signal-regulated kinase (ERK) signaling.
- A xenograft model showed reduced melanoma growth with GRM1 blockade by riluzole.
Purpose of the Study:
- To evaluate the effect of oral riluzole on melanoma patients in a phase 0 clinical trial.
- To assess the impact of GRM1 blockade on key signaling pathways (ERK, AKT) and tumor metabolic activity.
Main Methods:
- 12 melanoma patients received 200 mg/day of oral riluzole for 14 days.
- Pre- and post-treatment tumor biopsies were analyzed for pERK and pAKT levels.
- Fluorodeoxyglucose positron emission tomography (FDG-PET) scans assessed tumor metabolic activity before and after treatment.
Main Results:
- All 12 patients expressed GRM1.
- Four patients (34%) showed significant decreases in pAKT and/or pERK.
- These four patients also exhibited reduced FDG-PET intensity, indicating suppressed metabolic activity.
Conclusions:
- Glutamate blockade with riluzole inhibits MAPK and PI3K/AKT pathways in melanoma.
- Riluzole treatment suppressed melanoma metabolic activity.
- Targeting GRM1 may represent a viable therapeutic strategy for melanoma.
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