2. Academic Validation
  3. Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

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

  • Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):370-375. doi: 10.1073/pnas.1616100114.
Timothy P Kegelman 1,  Bainan Wu 2,  Swadesh K Das 1 3 4,  Sarmistha Talukdar 1,  Jason M Beckta 5,  Bin Hu 1,  Luni Emdad 1 3 4,  Kristoffer Valerie 4 5,  Devanand Sarkar 1 3 4,  Frank B Furnari 6,  Webster K Cavenee 7,  Jun Wei 2,  Angela Purves 2,  Surya K De 2 8,  Maurizio Pellecchia 9 8,  Paul B Fisher 10 3 4
Affiliations

Affiliations

  • 1 Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
  • 2 Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
  • 3 VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • 4 VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • 5 Department of Radiation Oncology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • 6 Ludwig Institute for Cancer Research, University of California, San Diego, CA 92093.
  • 7 Ludwig Institute for Cancer Research, University of California, San Diego, CA 92093; wcavenee@ucsd.edu maurizio.pellecchia@medsch.ucr.edu paul.fisher@vcuhealth.org.
  • 8 School of Medicine, University of California, Riverside, CA 92521.
  • 9 Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037; wcavenee@ucsd.edu maurizio.pellecchia@medsch.ucr.edu paul.fisher@vcuhealth.org.
  • 10 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.
PMID: 28011764 DOI: 10.1073/pnas.1616100114
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.

Keywords

EGFR; MDA-9/Syntenin; PDZ1 inhibitor; glioblastoma multiforme; radiation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124813
    99.29%, MDA-9/Syntenin抑制剂
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