# Biguanide Sensitivity of Glioma Stem Cells

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $341,398

## Abstract

The biguanide metformin that inhibits mitochondrial complex I activity is now in over 200
oncology clinical trials. In this proposal we will determine how to enhance cancer cell sensitivity towards
metformin therapy. There are two principal modes of cellular energy production – glycolysis and mitochondrial
oxidation of glycose and fatty acids. Metformin inhibits mitochondrial energy production. Therefore, when
switched to a low glucose medium (that reduces glycolysis), cancer cells become sensitized to metformin.
Physiological glucose concentration in tissues is however significantly lower compared to that used in most cell
culture studies and glucose concentration is even lower in tumor tissues. At this physiological range of glucose,
cancer cells maintain high glycolytic rate and genes that regulate cancer cell glycolysis may resist biguanide
action by upregulating compensatory glycolysis when mitochondria is inhibited. Therefore, identification and
inhibition of such genes may enhance cancer cell liability towards biguanides. Despite promise in other
cancers, our data shows that glioma stem cells (GSCs) are resistant to biguanides at physiological glucose.
We discovered that the cellular energy sensor AMP kinase (AMPK) that augments glycolysis during stress in
cardiac and skeletal muscle is co-opted by GSCs for optimal glycolysis. We propose to test the mechanisms by
which AMPK regulates glycolysis in GSCs in vitro and in vivo. Through dose escalation pharmacological
studies in mice we will determine maximum tolerated metformin dose in brain tumor-bearing mice, quantitate
metformin plasma levels, and metformin concentrations attained in normal brain and tumor tissue. We will test
if genetic inhibition of AMPK in GSCs reduces glycolysis, suppress proliferation and tumor growth and
improves metformin sensitivity.

## Key facts

- **NIH application ID:** 9832214
- **Project number:** 5R01NS099162-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Biplab Dasgupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,398
- **Award type:** 5
- **Project period:** 2016-02-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832214

## Citation

> US National Institutes of Health, RePORTER application 9832214, Biguanide Sensitivity of Glioma Stem Cells (5R01NS099162-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9832214. Licensed CC0.

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