Reversed metabolic reprogramming as a measure of cancer treatment efficacy in rat C6 glioma model.

Abstract

BACKGROUND:

Metabolism in tumor shifts from oxidative phosphorylation to inefficient glycolysis resulting in overproduction of lactate (Warburg effect), and cancers may be effectively treated if this imbalance were corrected. The aim of this longitudinal study of glioblastoma in a rat model was to determine whether the ratio of lactate (surrogate marker for glycolysis) to bicarbonate (for oxidative phosphorylation), as measured via in vivo magnetic resonance imaging of hyperpolarized 13C-labeled pyruvate accurately predicts survival.

METHODS:

C6 Glioma implanted male Wistar rats (N = 26) were treated with an anti-vascular endothelial growth factor antibody B20.4.1.1 in a preliminary study to assess the efficacy of the drug. In a subsequent longitudinal survival study, magnetic resonance spectroscopic imaging (MRSI) was used to estimate [1-13C]Lactate and [1-13C]Bicarbonate in tumor and contralateral normal appearing brain of glioma implanted rats (N = 13) after injection of hyperpolarized [1-13C]Pyruvate at baseline and 48 hours post-treatment with B20.4.1.1.

RESULTS:

A survival of ~25% of B20.4.1.1 treated rats was noted in the preliminary study. In the longitudinal imaging experiment, changes in 13C Lactate, 13C Bicarbonate and tumor size measured at baseline and 48 hours post-treatment did not correlate with survival. 13C Lactate to 13C Bicarbonate ratio increased in all the 6 animals that succumbed to the tumor whereas the ratio decreased in 6 of the 7 animals that survived past the 70-day observation period.

CONCLUSIONS:

13C Lactate to 13C Bicarbonate ratio (Lac/Bic) at 48 hours post-treatment is highly predictive of survival (p = 0.003). These results suggest a potential role for the 13C Lac/Bic ratio serving as a valuable measure of tumor metabolism and predicting therapeutic response.

• Authors: Keshav Datta, Mette H Lauritzen, Milton Merchant, Taichang Jang, Shie-Chau Liu, Ralph Hurd, Lawrence Recht, Daniel M Spielman
• Journal: PloS one (PLoS One) Vol. 14 Issue 12 Pg. e0225313 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 31830049 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Immunological
• Bicarbonates
• Biomarkers
• Vascular Endothelial Growth Factor A
• Lactic Acid

Topics

• Animals
• Antineoplastic Agents, Immunological (therapeutic use)
• Bicarbonates (metabolism)
• Biomarkers (metabolism)
• Brain (diagnostic imaging, metabolism)
• Brain Neoplasms (diagnostic imaging, drug therapy, metabolism)
• Glioma (diagnostic imaging, drug therapy, metabolism)
• Glycolysis
• Lactic Acid (metabolism)
• Magnetic Resonance Spectroscopy
• Male
• Neoplasm Transplantation
• Oxidative Phosphorylation
• Prognosis
• Rats
• Rats, Wistar
• Survival Rate
• Treatment Outcome
• Vascular Endothelial Growth Factor A (immunology)