USING ARGININE METABOLIC THERAPIES FOR SARCOMA

使用精氨酸代谢疗法治疗肉瘤

基本信息

批准号：
10471182
负责人：
Brian Andrew Van Tine
金额：
$ 36.05万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471182
关键词：
Ammonia Anabolism Antimetabolites Arginine Arginine deiminase Biological Markers Biopsy Blood Carbon Cell Cycle Arrest Cell Death Cell division Cells Cessation of life Chemoresistance Citrulline Clinical Clinical Trials Combined Modality Therapy Correlative Study Cytotoxic agent Data Development Enzymes Essential Amino Acids Excision Folic Acid Genetic Glucose Glutamine Goals Immunohistochemistry Knock-out Malignant Neoplasms Measures Mediating Metabolic Modeling Mus Neoplasm Metastasis Nucleotides Oncogenic Outcome Pathway interactions Patients Pattern Phase II Clinical Trials Preclinical Testing Principal Investigator Progression-Free Survivals Property Pyrimidine RRM2 gene Resistance Sampling Serine Serum Soft tissue sarcoma Starvation Steam Systems Biology TP53 gene Testing Therapeutic Therapeutic Agents Tissues Transgenic Mice Unresectable argininosuccinate synthase base biomarker development biomarker-driven cancer cell cell killing deprivation docetaxel extracellular gemcitabine improved metabolic profile metabolomics mouse model mutant neoplastic cell novel patient derived xenograft model phase II trial potential biomarker primary endpoint programs protein expression response sarcoma secondary endpoint therapy resistant tumor tumor growth tumor initiation tumor metabolism tumor progression tumorigenesis urea cycle

项目摘要

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.

项目总监/首席研究员：（Van Tine，Brian）项目概要我们最近证明精氨基琥珀酸合成酶 1 (ASS1) 的表达在 88% 的细胞中被沉默。肉瘤 (n=708)，这种损失与缺乏 ASS1、精氨酸的情况下总生存率降低有关。成为肿瘤细胞必须从血液中获取的必需氨基酸。精氨酸脱亚胺酶（ADI-PEG20，一种细胞外精氨酸消耗酶）诱导促生存代谢 ASS1 缺陷肉瘤中的重编程将葡萄糖重定向到丝氨酸/叶酸途径，从而将葡萄糖中的碳汇集到嘧啶生物合成中，代谢组学分析表明这应该是这样的。嘧啶抗代谢物吉西他滨此外，ADI-PEG20 和多西紫杉醇使细胞致敏致死。显着增加 SLC29A1（核苷酸/吉西他滨转运蛋白的组合）的表达。吉西他滨和多西他赛已被证明在治疗肉瘤方面优于单独使用吉西他滨。我们将进行一项 II 期临床试验，将 ADI-PEG20 与标准的吉西他滨和多西他赛结合起来软组织肉瘤的二线治疗药物，用于模拟 ASS1 缺陷的代谢后果在存在或不存在精氨酸饥饿的情况下，无进展生存期和总生存期是主要的。治疗前和 ADI-PEG20 后 21 天分别进行配对活检。为了进行相关研究，我们生成了第一个条件性小鼠基因敲除模型。我们还开发了在 p53 缺失的情况下形成肉瘤的 ASS1，这是肉瘤中常见的改变。肉瘤患者衍生的异种移植物 (PDX) 通过 ADI-PEG20 来模拟精氨酸剥夺。 ASS1沉默对转基因小鼠肿瘤发生的影响，并建立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对治疗的敏感性和耐药性模式。预计拟议的研究将导致精氨酸生物标志物驱动疗法的开发 ASS1 缺陷肉瘤中的剥夺。