title: Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin.
abstract: 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.
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kegelman
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.|VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.|VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Talukdar
authors.affiliation: Department of Radiation Oncology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Beckta
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.|VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.|VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.|Department of Radiation Oncology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.|VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.|VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, CA 92093.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, CA 92093; wcavenee@ucsd.edu maurizio.pellecchia@medsch.ucr.edu paul.fisher@vcuhealth.org.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Angela
authors.initials: A
authors.lastname: Purves
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.|School of Medicine, University of California, Riverside, CA 92521.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037; wcavenee@ucsd.edu maurizio.pellecchia@medsch.ucr.edu paul.fisher@vcuhealth.org.|School of Medicine, University of California, Riverside, CA 92521.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298; wcavenee@ucsd.edu maurizio.pellecchia@medsch.ucr.edu paul.fisher@vcuhealth.org.|VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.|VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics*; D005910:Glioma / Q000235:genetics; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008545:Melanoma / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics*; D054731:PDZ Domains / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D053676:Syntenins / Q000235:genetics*; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D053676:Syntenins; D019061:src-Family Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: EGFR; MDA-9/Syntenin; PDZ1 inhibitor; glioblastoma multiforme; radiation