Combination of an anti-EGFRvIII antibody CH12 with Rapamycin synergistically inhibits the growth of EGFRvIII+PTEN-glioblastoma in vivo

Oncotarget. 2016 Apr 26;7(17):24752-65. doi: 10.18632/oncotarget.8407.

Abstract

There are still unmet medical needs for the treatment of glioblastoma (GBM), the most frequent and aggressive brain tumor worldwide. EGFRvIII, overexpressed in approximately 30% of GBM, has been regarded as a potential therapeutic target. In this study, we demonstrated that CH12, an anti-EGFRvIII monoclonal antibody, could significantly suppress the growth of EGFRvIII+ GBM in vivo; however, PTEN deficiency in GBM reduced the efficacy of CH12 by attenuating its effect on PI3K/AKT/mTOR pathway. To overcome this problem, CH12 was combined with the mTOR inhibitor rapamycin, leading to a synergistic inhibitory effect on EGFRvIII+PTEN- GBM in vivo. Mechanistically, the synergistic antitumor effect was achieved via attenuating EGFR and PI3K/AKT/mTOR pathway more effectively and reversing the STAT5 activation caused by rapamycin treatment. Moreover, the combination therapy suppressed angiogenesis and induced cancer cell apoptosis more efficiently. Together, these results indicated that CH12 and rapamycin could synergistically suppress the growth of EGFRvIII+PTEN- GBM, which might have a potential clinical application in the future.

Keywords: CH12; EGFRvIII+PTEN– GBM; STAT5; rapamycin.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Synergism
  • ErbB Receptors / immunology*
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology
  • Glioblastoma / pathology
  • Humans
  • Mice
  • PTEN Phosphohydrolase / metabolism
  • Sirolimus / administration & dosage
  • Sirolimus / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Anti-Bacterial Agents
  • Antibodies, Monoclonal
  • CH12 monoclonal antibody
  • epidermal growth factor receptor VIII
  • ErbB Receptors
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Sirolimus