Glioblastoma multiforme (GBM) is a deadly brain cancer, and a major challenge to its treatment with radiation is that the approach often leads to an even more aggressive form of the cancer. Kegelman et al. report that targeting a scaffolding protein called MDA-9 or syntenin (encoded by melanoma differentiation-associated gene 9) with a small-molecule inhibitor may prevent this outcome. The drug targets a protein interaction domain (PDZ1) in MDA-9, blocking key signaling pathways that promote invasiveness and proliferation in cultured glioblastoma cells. The drug also boosted tumor sensitivity to radiation and improved survival in a mouse model of GBM. The results suggest a possible path to targeted brain cancer therapy.