# Mechanisms of Biguanide Sensitivity in GBM

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $1

## Abstract

Project Summary/Abstract
The biguanide drug metformin that is widely used for the management of Type 2 diabetes is being evaluated as an anti-
neoplastic agent in cancer trials including GBM (NCT02780024, NCT03243851). The various mechanisms of action of
metformin as an anti-neoplastic agent is still being investigated, but recent studies have unequivocally demonstrated that
its therapeutic effects in tumor cell growth, cell death, gene expression, and signaling are dependent on inhibition of
mitochondrial complex I. Based on the success of metformin in combination therapy in some cancers, new generation of
mitochondrial complex I inhibitors (MCI-i) are currently under investigation. Diffusion of metformin across the plasma
membrane occurs slowly. Its entry is facilitated by two transporters OCT1 and OCT2 that are not well expressed outside
the liver and kidney. This presents a problem due its lack of accumulation in other tissues at therapeutic concentrations.
Therefore, identification of tumor subtypes that respond better to lower concentrations of metformin may be leveraged
for targeted metformin therapy. Metformin GBM trials may be unsatisfactory since there are no molecular markers to
distinguish metformin responders from non-responders. Identification of molecular markers may greatly improve
metformin and other MCI-i-based therapy in GBM. We identified that a pyruvate dehydrogenase subunit (PDHA1) is a
possible molecular beacon for MCI-i therapy in GBM. We will test this in vitro and in vivo. We also found that the cellular
energy sensor AMPK provides resistance to MCI-i therapy in a subset of GBM. We will test if a brain-penetrating AMPK
inhibitor restores MCI-i sensitivity in vivo. Lastly, our molecular analysis showed that ErbB activation is a likely mechanism
of resistance to AMPK inhibition. In mouse models we will test if a brain-penetrating ErbB inhibitor overcomes AMPK
inhibitor resistance in vivo.

## Key facts

- **NIH application ID:** 10833583
- **Project number:** 5R01NS099162-08
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Biplab Dasgupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2016-02-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833583

## Citation

> US National Institutes of Health, RePORTER application 10833583, Mechanisms of Biguanide Sensitivity in GBM (5R01NS099162-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10833583. Licensed CC0.

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