NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

Oncotarget. 2016 Jul 5;7(27):41251-41264. doi: 10.18632/oncotarget.9275.

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.

Keywords: RO4929097 NOTCH inhibitor; glioblastoma; glioma stem cells; image guidance radiotherapy; temozolomide.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzazepines / administration & dosage*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Brain Neoplasms / therapy*
  • Cell Line, Tumor
  • Chemoradiotherapy / methods*
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives*
  • Glioblastoma / mortality
  • Glioblastoma / pathology
  • Glioblastoma / therapy*
  • Humans
  • Mice
  • Mice, Nude
  • Receptors, Notch / antagonists & inhibitors*
  • Survival Analysis
  • Temozolomide
  • Xenograft Model Antitumor Assays

Substances

  • 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide
  • Benzazepines
  • Receptors, Notch
  • Dacarbazine
  • Temozolomide