Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

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