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Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy

  1. Author:
    Oshima, Nobu
    Ishida, Ryo
    Kishimoto, Shun
    Beebe, Kristin
    Brender, Jeffrey R
    Yamamoto, Kazutoshi
    Urban, Daniel
    Rai, Ganesha
    Johnson, Michelle S
    Benavides, Gloria
    Squadrito, Giuseppe L
    Crooks, Dan
    Jackson, Joseph
    Joshi, Abhinav
    Mott, Bryan T
    Shrimp, Jonathan H
    Moses, Michael A
    Lee, Min-Jung
    Yuno, Akira
    Lee, Tobie D
    Hu, Xin
    Anderson, Tamara
    Kusewitt, Donna
    Hathaway, Helen H
    Jadhav, Ajit
    Picard, Didier
    Trepel, Jane B
    Mitchell, James B
    Stott,Gordon
    Moore,Bill
    Simeonov, Anton
    Sklar, Larry A
    Norenberg, Jeffrey P
    Linehan, W Marston
    Maloney, David J
    Dang, Chi V
    Waterson, Alex G
    Hall, Matthew
    Darley-Usmar, Victor M
    Krishna, Murali C
    Neckers, Leonard M

  2. Author Address

    Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland., Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, MD 24060, USA., Ludwig Institute for Cancer Research, New York, NY 10017, USA; The Wistar Institute, Philadelphia, PA 19104, USA., Department of Chemistry, Vanderbilt University, Nashville, TN 37240, USA., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: neckersl@mail.nih.gov.,
    1. Year: 2020
    2. Date: Feb 11
  2. Journal: Cell reports
    1. 30
    2. 6
    3. Pages: 1798-1810.e4
  4. Type of Article: Article
  5. ISSN: 2211-1247
  1. Abstract:

    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. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2020.01.039
  3. PMID: 32049011
  4. View record in Web of Science®
  5. WOS: 000513920800012
  6. PII : S2211-1247(20)30054-1

Library Notes

  1. Fiscal Year: FY2019-2020
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