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Targeting glycolysis through inhibition of lactate dehydrogenase impairs tumor growth in preclinical models of Ewing sarcoma

  1. Author:
    Yeung, Choh
    Gibson, Anna E
    Issaq, Sameer H
    Oshima, Nobu
    Baumgart, Joshua T
    Edessa, Leah D
    Rai, Ganesha
    Urban, Daniel J
    Johnson, Michelle S
    Benavides, Gloria A
    Squadrito, Giuseppe L
    Yohe, Marielle E
    Lei, Haiyan
    Eldridge, Sandy [ORCID]
    Hamre,John [ORCID]
    Dowdy, Tyrone
    Ruiz-Rodado, Victor
    Lita, Adrian
    Mendoza, Arnulfo
    Shern, Jack F [ORCID]
    Larion, Mioara
    Helman, Lee J
    Stott,Gordon
    Krishna, Murali C
    Hall, Matthew D [ORCID]
    Darley-Usmar, Victor
    Neckers, Leonard M
    Heske, Christine M

  2. Author Address

    Pediatric Oncology Branch, National Cancer Institute., Urologic Oncology Branch, National Cancer Institute., National Center for Advancing Translational Sciences, National Institutes of Health., University of Alabama at Birmingham., Department of Pathology, University of Alabama at Birmingham., Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health., Center for Cancer Research, Pediatric Oncology Branch, National Cancer Institute., Division of Cancer Treatment and Diagnosis, National Cancer Institute., Laboratory of Investigative Toxicology, Frederick National Laboratory for Cancer Research., Neuro-Oncology Branch, National Institutes of Health., Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute., Pediatric Oncology Branch, National Institutes of Health., USC Norris Cancer Center, Children 39;s Hospital of Los Angeles., NCATS Chemical Genomics Center, National Center for Advancing Translational Sciences., Urologic Oncology Branch,CCR/NCI, NIH, National Institutes of Health., Pediatric Oncology Branch, National Cancer Institute christine.heske@nih.gov.,
    1. Year: 2019
    2. Date: OCT 1
    3. Epub Date: 2019 08 20
  2. Journal: Cancer research
    1. 79
    2. 19
    3. Pages: 5060-5073
  4. Type of Article: Article
  5. ISSN: 0008-5472
  1. Abstract:

    Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly a century ago, effective therapeutic targeting of glycolysis in cancer has remained elusive. One potentially promising approach involves targeting the glycolytic enzyme lactate dehydrogenase (LDH), which is overexpressed and plays a critical role in several cancers. Here, we used a novel class of LDH inhibitors to demonstrate, for the first time, that Ewing sarcoma (EWS) cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of EWS, regulated LDHA expression. Genetic depletion of LDHA inhibited proliferation of EWS cells and induced apoptosis, phenocopying pharmacological inhibition of LDH. LDH inhibitors impacted EWS cell viability both in vitro and in vivo by reducing glycolysis. Intravenous administration of LDH inhibitors resulted in the greatest intratumoral drug accumulation, inducing tumor cell death and reducing tumor growth. The major dose-limiting toxicity observed was hemolysis, indicating that a narrow therapeutic window exists for these compounds. Taken together, these data suggest that targeting glycolysis through inhibition of LDH should be further investigated as a potential therapeutic approach for cancers such as EWS that exhibit oncogene-dependent expression of LDH and increased glycolysis. Copyright ©2019, American Association for Cancer Research.

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External Sources

  1. View Full Text
  2. DOI: 10.1158/0008-5472.CAN-19-0217
  3. PMID: 31431459
  4. View record in Web of Science®
  5. WOS: 000489626000022
  6. PII : 0008-5472.CAN-19-0217

Library Notes

  1. Fiscal Year: FY2018-2019
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