USING ARGININE METABOLIC THERAPIES FOR SARCOMA

项目总监/首席调查员：(van Tine，Brian) 项目摘要 我们最近证实在88%的ALL中精氨酸琥珀酸合成酶1(ASS1)的表达是沉默的 肉瘤(n=708)，这种丧失与总存活率的降低有关。在没有ASS1的情况下，精氨酸 成为肿瘤细胞必须从血液中获取的必需氨基酸。我们证明了聚乙二醇化 精氨酸脱亚胺酶(ADI-PEG20，一种胞外精氨酸耗竭酶)诱导生存代谢 在ASS1缺陷的肉瘤中重编程，从而将葡萄糖重定向到丝氨酸/叶酸途径 将葡萄糖中的碳转化为嘧啶的生物合成。代谢组学分析表明，这应该是 用嘧啶类抗代谢药吉西他滨使细胞致死。此外，ADI-PEG20和多西紫杉醇 显著增加核苷酸/吉西他滨转运蛋白SLC29A1的表达。这两种技术的结合 吉西他滨和多西紫杉醇已被证明优于单独使用吉西他滨治疗肉瘤。因此， 我们将进行ADI-PEG20联合吉西他滨和多西他赛的第二阶段临床试验，这是标准的 软组织肉瘤的二线治疗药物，模拟ASS1缺乏的代谢后果 在精氨酸饥饿存在和不存在的情况下。无进展生存和总体生存是主要的 和次要端点。治疗前和ADI-PEG20后21天的配对活检将 以供相关研究使用。在临床前测试中，我们建立了第一个有条件的小鼠基因敲除模型 在发生肉瘤的ASS1中，P53缺失是肉瘤中的一种常见变化。我们还开发了 肉瘤患者来源的异种移植物(PDX)建立精氨酸剥夺模型。我们将确定 ASS1沉默对转基因小鼠肿瘤发生的影响及适应性代谢重编程模型 对吉西他滨和多西他赛的反应以确定治疗的敏感性和耐药性模式。我们 预期拟议的研究将导致精氨酸生物标记物驱动疗法的发展 ASS1缺陷肉瘤中的缺失。

Program Director/Principal Investigator: (Van Tine, Brian) Project Summary We recently demonstrated that argininosuccinate synthetase 1 (ASS1) expression is silenced in 88% of all sarcomas (n=708), and this loss is associated with reduced overall survival. In the absence of ASS1, arginine becomes an essential amino acid that tumor cells must obtain from blood. We demonstrated that PEGylated arginine deiminase (ADI-PEG20, an extracellular arginine-depleting enzyme) induces prosurvival metabolic reprogramming in ASS1-deficient sarcomas that redirects glucose into the serine/folate pathway, thereby funneling carbons from glucose into pyrimidine biosynthesis. Metabolomics analyses suggested that this should sensitize cells to death by the pyrimidine antimetabolite gemcitabine. In addition, ADI-PEG20 and docetaxel dramatically increase the expression of SLC29A1, the nucleotide/gemcitabine transporter. The combination of gemcitabine and docetaxel has been demonstrated to be superior to gemcitabine alone in sarcoma. Therefore, we will perform a Phase II clinical trial combining ADI-PEG20 with gemcitabine and docetaxel, which are standard second-line therapeutic agents for soft tissue sarcoma, to model the metabolic consequences of ASS1 deficiency in the presence and absence of arginine starvation. Progression-free survival and overall survival are the primary and secondary endpoints, respectively. Paired biopsies before treatment and 21 days after ADI-PEG20 will be obtained for correlative studies. For preclinical testing, we generated the first conditional murine knockout model of ASS1 that develops sarcomas in the context of p53 loss, a common alteration in sarcomas. We also developed sarcoma patientderived xenografts (PDXs) to model arginine deprivation by ADI-PEG20. We will determine the effect of ASS1 silencing on tumorigenesis in transgenic mice, and model the adaptive metabolic reprograming response to gemcitabine and docetaxel to determine patterns of sensitivity and resistance to therapy. We anticipate that the proposed studies will lead to the development biomarker-driven therapy for arginine deprivation in ASS1-deficient sarcomas.