Targeting glutamine metabolism slows soft tissue sarcoma growth

Area of Science:

• Oncology
• Metabolic pathways
• Cancer biology

Background:

• Tumor cells, including soft tissue sarcomas (STSs), often depend on glutamine metabolism for energy and biosynthesis.
• Glutamine dependence varies significantly between in vitro and in vivo environments, influenced by microenvironment and adaptive responses to deprivation.
• Current treatments for advanced STSs primarily rely on cytotoxic chemotherapy, highlighting the need for alternative therapeutic strategies.

Purpose of the Study:

• To investigate the role of glutamine metabolism in sarcomagenesis.
• To evaluate the therapeutic potential of targeting glutaminase (GLS) in STSs.
• To assess the efficacy of Telaglenastat (CB-839), a GLS inhibitor, in preclinical STS models.

Main Methods:

• Utilized autochthonous soft tissue sarcoma (STS) murine models.
• Employed unbiased metabolomics to analyze metabolic profiles.
• Administered Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, to tumor-bearing animals.

Main Results:

• Demonstrated that glutamine metabolism is crucial for STS development (sarcomagenesis).
• Identified specific STS subtypes with elevated glutaminase (GLS) levels that are sensitive to glutamine starvation.
• Showed that Telaglenastat (CB-839) treatment successfully inhibited undifferentiated pleomorphic sarcoma (UPS) tumor growth in vivo.

Conclusions:

• Glutamine metabolism is a critical driver of sarcomagenesis.
• Telaglenastat (CB-839) demonstrates significant therapeutic potential for treating soft tissue sarcomas, particularly UPS.
• Targeting glutaminase offers a promising alternative or complementary strategy to existing STS therapies.