Cell Reports (Feb 2020)
Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy
- Nobu Oshima,
- Ryo Ishida,
- Shun Kishimoto,
- Kristin Beebe,
- Jeffrey R. Brender,
- Kazutoshi Yamamoto,
- Daniel Urban,
- Ganesha Rai,
- Michelle S. Johnson,
- Gloria Benavides,
- Giuseppe L. Squadrito,
- Dan Crooks,
- Joseph Jackson,
- Abhinav Joshi,
- Bryan T. Mott,
- Jonathan H. Shrimp,
- Michael A. Moses,
- Min-Jung Lee,
- Akira Yuno,
- Tobie D. Lee,
- Xin Hu,
- Tamara Anderson,
- Donna Kusewitt,
- Helen H. Hathaway,
- Ajit Jadhav,
- Didier Picard,
- Jane B. Trepel,
- James B. Mitchell,
- Gordon M. Stott,
- William Moore,
- Anton Simeonov,
- Larry A. Sklar,
- Jeffrey P. Norenberg,
- W. Marston Linehan,
- David J. Maloney,
- Chi V. Dang,
- Alex G. Waterson,
- Matthew Hall,
- Victor M. Darley-Usmar,
- Murali C. Krishna,
- Leonard M. Neckers
Affiliations
- Nobu Oshima
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Ryo Ishida
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Shun Kishimoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Kristin Beebe
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Jeffrey R. Brender
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Kazutoshi Yamamoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Daniel Urban
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Ganesha Rai
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Michelle S. Johnson
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Gloria Benavides
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Giuseppe L. Squadrito
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Dan Crooks
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Joseph Jackson
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Abhinav Joshi
- Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland
- Bryan T. Mott
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Jonathan H. Shrimp
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Michael A. Moses
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Min-Jung Lee
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Akira Yuno
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Tobie D. Lee
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Xin Hu
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Tamara Anderson
- University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- Donna Kusewitt
- University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- Helen H. Hathaway
- University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- Ajit Jadhav
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Didier Picard
- Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland
- Jane B. Trepel
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- James B. Mitchell
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Gordon M. Stott
- Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, MD 24060, USA
- William Moore
- Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, MD 24060, USA
- Anton Simeonov
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Larry A. Sklar
- University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- Jeffrey P. Norenberg
- University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- W. Marston Linehan
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- David J. Maloney
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Chi V. Dang
- Ludwig Institute for Cancer Research, New York, NY 10017, USA; The Wistar Institute, Philadelphia, PA 19104, USA
- Alex G. Waterson
- Department of Chemistry, Vanderbilt University, Nashville, TN 37240, USA
- Matthew Hall
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
- Victor M. Darley-Usmar
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Murali C. Krishna
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Leonard M. Neckers
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Corresponding author
- Journal volume & issue
-
Vol. 30,
no. 6
pp. 1798 – 1810.e4
Abstract
Summary: The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo. : Oshima et al. use hyperpolarized magnetic resonance spectroscopy to dynamically monitor tumor glycolysis and oxidative phosphorylation. LDH inhibition slows tumor growth but rapidly redirects pyruvate to support mitochondrial metabolism. Inhibiting both mitochondrial complex 1 and LDH suppresses metabolic plasticity of glycolytic tumors in vivo, significantly prolonging tumor growth inhibition. Keywords: lactate dehydrogenase, pyruvate metabolism, metabolic flux, cancer, metabolic imaging, hyperpolarized magnetic resonance spectroscopic imaging
