Data from Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma

• DOI: 10.1158/0008-5472.c.6511316.v1
• Publication Date: 2023-03-31T21:59:04Z
• Authors: Choh Yeung; Anna E. Gibson; Sameer H. Issaq; Nobu Oshima; Joshua T. Baumgart; Leah D. Edessa; Ganesha Rai; Daniel J. Urban; Michelle S. Johnson; Gloria A. Benavides; Giuseppe L. Squad...; Marielle E. Yohe; Haiyan Lei; Sandy Eldridge; John Hamre; Tyrone Dowdy; Victor Ruiz-Rodado; Adrian Lita; Arnulfo Mendoza; Jack F. Shern; Mioara Larion; Lee J. Helman; Gordon M. Stott; Murali C. Krishna; Matthew D. Hall; Victor Darley-Usmar; Leonard M. Neckers; Christine M. Heske

<div>Abstract<p>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 cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of Ewing sarcoma, regulated LDH A (LDHA) expression. Genetic depletion of LDHA inhibited proliferation of Ewing sarcoma cells and induced apoptosis, phenocopying pharmacologic inhibition of LDH. LDH inhibitors affected Ewing sarcoma cell viability both <i>in vitro</i> and <i>in vivo</i> 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 Ewing sarcoma that exhibit oncogene-dependent expression of LDH and increased glycolysis.</p>Significance:<p>LDHA is a pharmacologically tractable EWS-FLI1 transcriptional target that regulates the glycolytic dependence of Ewing sarcoma.</p></div>