Targeting glutamine metabolism slows soft tissue sarcoma growth

Pearl Lee, Dania Malik, Nicholas Perkons, Peiwei Huangyang, Sanika Khare, Seth Rhoades, Yao-Yu Gong, Michelle Burrows, Jennifer M. Finan, Itzhak Nissim, Terence P. F. Gade, Aalim M. Weljie and M. Celeste Simon ()
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Pearl Lee: University of Pennsylvania Perelman School of Medicine
Dania Malik: University of Pennsylvania
Nicholas Perkons: University of Pennsylvania
Peiwei Huangyang: University of Pennsylvania Perelman School of Medicine
Sanika Khare: University of Pennsylvania Perelman School of Medicine
Seth Rhoades: University of Pennsylvania
Yao-Yu Gong: University of Pennsylvania Perelman School of Medicine
Michelle Burrows: University of Pennsylvania Perelman School of Medicine
Jennifer M. Finan: University of Pennsylvania Perelman School of Medicine
Itzhak Nissim: Children’s Hospital of Philadelphia
Terence P. F. Gade: University of Pennsylvania Perelman School of Medicine
Aalim M. Weljie: University of Pennsylvania
M. Celeste Simon: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.

Date: 2020
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DOI: 10.1038/s41467-020-14374-1

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