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Updated: Jul 24, 2025

Generation of Microtumors Using 3D Human Biogel Culture System and Patient-derived Glioblastoma Cells for Kinomic Profiling and Drug Response Testing
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Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma

Evan K Noch1,2, Laura N Palma2, Isaiah Yim2

  • 1Division of Neuro-oncology, Department of Neurology, Weill Cornell Medicine, New York, New York, USA.

Neuro-Oncology
|July 3, 2023
PubMed
Abstract

Insights

Combining metformin with PI3K inhibitors improves glioblastoma treatment in mice. Hyperglycemia, or high blood sugar, is linked to worse outcomes in glioblastoma patients receiving PI3K inhibitors.

Area of Science:

  • Oncology
  • Metabolism
  • Immunology

Background:

  • Insulin feedback limits phosphatidylinositol 3-kinase (PI3K) inhibitor efficacy in cancer.
  • Hyperglycemia is an independent poor prognostic factor in glioblastoma (GBM).

Purpose of the Study:

  • To investigate combination anti-hyperglycemic therapy with PI3K inhibition in a GBM mouse model.
  • To evaluate the association of glycemic control with GBM patient outcomes in clinical trial data.

Main Methods:

  • Assessed metformin and ketogenic diet effects with PI3K inhibition in GBM cells and mouse models.
  • Retrospectively evaluated insulin feedback and immune microenvironment in GBM patient blood and tumor tissue from a clinical trial.

Main Results:

  • PI3K inhibition induced hyperglycemia and hyperinsulinemia in mice.
  • Metformin combined with PI3K inhibition improved GBM xenograft model efficacy.
  • Hyperglycemia independently correlated with poor progression-free survival in GBM patients.
  • PI3K inhibition increased insulin receptor activation and immune cell abundance in tumors.

Conclusions:

  • Reducing insulin feedback enhances PI3K inhibitor efficacy in preclinical GBM models.
  • Hyperglycemia is a resistance mechanism to PI3K inhibition in GBM.
  • Anti-hyperglycemic therapy may improve PI3K inhibitor efficacy in GBM patients.
Keywords:
glioblastomahyperglycemiainsulinmetforminphosphatidylinositol 3-kinase

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