Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo

Cancer Lett. 2020 Dec 1:494:73-83. doi: 10.1016/j.canlet.2020.08.028. Epub 2020 Sep 1.

Abstract

Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy, patient's survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed an immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.

Keywords: Endoplasmic reticulum; Glioblastoma; IRE1; Unfolded Protein Response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzopyrans / administration & dosage*
  • Benzopyrans / pharmacology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology
  • Brain Neoplasms / therapy*
  • Cell Line, Tumor
  • Combined Modality Therapy / methods*
  • Craniotomy
  • Drug Therapy
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics
  • Glioblastoma / immunology
  • Glioblastoma / therapy*
  • Humans
  • Immunocompetence
  • Injections, Intralesional
  • Mice
  • Morpholines / administration & dosage*
  • Morpholines / pharmacology
  • Neoadjuvant Therapy
  • Radiotherapy
  • Treatment Outcome
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Benzopyrans
  • MKC8866
  • Morpholines