Targeting metabotropic glutamate receptors in the treatment of primary brain tumors

In spite of the recent advancement in the molecular characterization of malignant gliomas and medulloblastomas, the treatment of primary brain tumors remains suboptimal. The use of small molecule inhibitors of intracellular signaling pathways, inhibitors of angiogenesis, and immunotherapic agents is limited by systemic adverse effects, limited brain penetration, and, in some cases, lack of efficacy. Thus, adjuvant chemo-therapy and radiotherapy still remain the gold standard in the treatment of grade-IV astrocytoma (glioblastoma multiforme) and medulloblastoma. We review evidence that supports the development of mGlu3 receptor antagonists as add-on drugs in the treatment of malignant gliomas. These drugs appear to display pleiotropic effect on tumor cells, affecting proliferation, differentiation, and response to chemotherapy. mGlu1 and mGlu4 receptors could also be targeted by potential anticancer agents in the treatment of malignant gliomas and medulloblastoma, but extensive research is required for target validation.