Targeting glutamine metabolism slows soft tissue sarcoma growth.,Nature Communications

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Targeting glutamine metabolism slows soft tissue sarcoma growth.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-020-14374-1
Pearl Lee ₁ , Dania Malik _{2,

3} , Nicholas Perkons ₄ , Peiwei Huangyang ₁ , Sanika Khare ₁ , Seth Rhoades _{2,

3} , Yao-Yu Gong ₁ , Michelle Burrows ₁ , Jennifer M Finan ₁ , Itzhak Nissim _{5,

6} , Terence P F Gade ₇ , Aalim M Weljie _{2,

3} , M Celeste Simon _{1,

8}

Affiliation

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.

中文翻译：

针对谷氨酰胺代谢可减缓软组织肉瘤的生长。

肿瘤细胞经常利用谷氨酰胺来满足细胞快速生长的生物能和生物合成需求。然而，基于周围微环境和对谷氨酰胺剥夺的复杂适应性反应，谷氨酰胺依赖性在体外和体内环境之间可能存在很大差异。软组织肉瘤 (STS) 是间叶性肿瘤，细胞毒性化疗仍然是治疗转移性或不可切除疾病的主要方法。因此，确定替代疗法以改善患者的治疗效果至关重要。使用本地 STS 小鼠模型和无偏代谢组学，我们证明谷氨酰胺代谢支持肉瘤发生。表达升高的谷氨酰胺酶 (GLS) 水平的 STS 亚型对谷氨酰胺饥饿高度敏感。与之前的研究相比，用口服生物可利用的 GLS 抑制剂 Telaglenastat (CB-839) 治疗原发肿瘤动物，可成功抑制未分化多形性肉瘤 (UPS) 肿瘤的生长。我们揭示谷氨酰胺代谢对于肉瘤发生至关重要，CB-839 表现出强大的治疗潜力。

更新日期：2020-01-24

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