Khadka Sunada, Lin Yu-Hsi, Ackroyd Jeffrey, Chen Yi-An, Sheng Yanghui, Qian Wubin, Guo Sheng, Chen Yining, Behr Eliot, Barekatain Yasaman, Uddin Nasir, Arthur Kenisha, Yan Victoria, Hsu Wen-Hao, Chang Qing, Poral Anton, Tran Theresa, Chaurasia Surendra, Georgiou Dimitra K, Asara John M, Barthel Floris P, Millward Steve W, DePinho Ronald A, Muller Florian L
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
bioRxiv. 2023 Oct 19:2023.05.07.539744. doi: 10.1101/2023.05.07.539744.
Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition incurs extensive metabolic stress, prompting us to consider such metabolic stress as an to therapies targeting cancer metabolism. Metabolomic profiling of angiogenesis-inhibited intracranial xenografts showed universal decrease in tricarboxylic acid cycle intermediates, corroborating a state of anaplerotic nutrient deficit or stress. Accordingly, we show strong synergy between angiogenesis inhibitors (Avastin, Tivozanib) and inhibitors of glycolysis or oxidative phosphorylation through exacerbation of anaplerotic nutrient stress in intracranial orthotopic xenografted gliomas. Our findings were recapitulated in GBM xenografts that do not have genetically predisposed metabolic vulnerabilities at baseline. Thus, our findings cement the central importance of the tricarboxylic acid cycle as the nexus of metabolic vulnerabilities and suggest clinical path hypothesis combining angiogenesis inhibitors with pharmacological cancer interventions targeting tumor metabolism for GBM tumors.
肿瘤血管生成是癌症的一个标志，对其进行治疗性抑制虽能带来一定的临床益处，但作用有限。抗血管生成抑制剂使肿瘤无法获得氧气和必需营养物质，然而癌细胞会激活代谢适应性变化以降低治疗反应。尽管有这些适应性变化，但血管生成抑制会引发广泛的代谢应激，促使我们将这种代谢应激视为针对癌症代谢疗法的一个靶点。对血管生成受抑制的颅内异种移植瘤进行代谢组学分析显示，三羧酸循环中间体普遍减少，这证实了存在回补性营养物质缺乏或应激状态。因此，我们发现血管生成抑制剂（阿瓦斯汀、替沃扎尼）与糖酵解或氧化磷酸化抑制剂之间具有强大的协同作用，这种协同作用是通过加剧颅内原位异种移植胶质瘤中的回补性营养物质应激来实现的。我们的研究结果在基线时没有遗传易感性代谢弱点的胶质母细胞瘤异种移植瘤中得到了重现。因此，我们的研究结果巩固了三羧酸循环作为代谢弱点核心的重要地位，并提出了一个临床路径假设，即对于胶质母细胞瘤，将血管生成抑制剂与针对肿瘤代谢的药理学癌症干预措施联合使用。
