Glioblastoma multiforme (GBM) is an intractable
tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified
melanoma differentiation-associated gene 9 [MDA-9/
Syntenin;
syndecan-
binding protein (SDCBP)] as a differentially regulated gene associated with aggressive
cancer phenotypes in
melanoma. MDA-9/
Syntenin, a highly conserved double-PDZ domain-containing scaffolding
protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with
tumor grade and correlating with shorter survival times and poorer response to
radiotherapy. Knockdown of MDA-9/
Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and
EGFRvIII signaling, which is abrogated through MDA-9/
Syntenin down-regulation. A specific inhibitor of MDA-9/
Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/
Syntenin binding to
EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/
Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR,
EGFRvIII, and abrogated gains in secreted
proteases, MMP-2 and MMP-9, following radiation. In an in vivo
glioma model, PDZ1i resulted in smaller, less invasive
tumors and enhanced survival. When combined with radiation, survival gains exceeded
radiotherapy alone. MDA-9/
Syntenin (SDCBP) provides a direct target for
therapy of aggressive
cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted
brain cancer therapy.