# Phase IIA Trial of Dichloroacetate for Glioblastoma Multiforme, IND137007, 09172019

> **NIH FDA R01** · UNIVERSITY OF FLORIDA · 2023 · $660,372

## Abstract

Abstract:
 Glioblastoma multiforme (GBM), a grade IV glioma, is the most malignant form of an
astrocytoma and is the most common malignant brain tumor in adults. The cause of this primary
and highly aggressive cancer is unclear. The current treatment for glioblastoma is limited to
maximal safe surgical resection, followed by chemotherapy and radiation therapy. Unfortunately,
virtually all patients will have tumor recurrence and die of this disease. While survival without
treatment is approximately three months, survival following treatment is only 12 to 15 months.
Less than 5% of people survive longer than five years.
 A cardinal metabolic characteristic of tumorigenesis is a metabolic shift in which glycolysis,
even in the presence of adequate tissue oxygen, increases disproportionately relative to oxidative
phosphorylation (OXPHOS), a phenomenon known as the Warburg effect. This glycolytic shift
occurs in GBM and is mechanistically associated with post-translational inhibition of the
mitochondrial pyruvate dehydrogenase complex (PDC), which normally catalyzes the rate-limiting
step in the aerobic oxidation of glucose-derived pyruvate and lactate. PDC inhibition is due to
transcriptional upregulation of one or more of four pyruvate dehydrogenase kinase isoforms (PDK
1-4) that inhibit PDC by reversible phosphorylation. Dichloroacetate (DCA), the prototypic PDK
inhibitor, readily crosses the blood-brain barrier and represents an entirely new class of small
molecule metabolic modulators that act in mitochondria to reset cellular homeostasis in various
congenital and acquired metabolic disorders. Indeed, pharmacological inhibition of PDK in cancer
cells by DCA restores PDC activity, reverses the Warburg effect and induces a caspase-mediated
selective apoptosis of tumors. Extensive pre-clinical research and early clinical trials in patients
with recurrent GBM and other brain tumors indicate that DCA may be a safe and uniquely effective
metabolic therapy for GBM.
DCA inhibits its own metabolism and its only clinically limiting toxicity is reversible peripheral
neuropathy. To mitigate this adverse effect, we developed and validated a genotyping method
for genetics-based dosing of DCA that dichotomizes subjects into fast and slow drug
metabolizers, leading to safe, personalized DCA dosing.

## Key facts

- **NIH application ID:** 10693209
- **Project number:** 5R01FD007271-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** CHETAN BETTEGOWDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2023
- **Award amount:** $660,372
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693209

## Citation

> US National Institutes of Health, RePORTER application 10693209, Phase IIA Trial of Dichloroacetate for Glioblastoma Multiforme, IND137007, 09172019 (5R01FD007271-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693209. Licensed CC0.

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