USING ARGININE METABOLIC THERAPIES FOR SARCOMA

使用精氨酸代谢疗法治疗肉瘤

• 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
• 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

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.

计划主任/首席研究员：（范·蒂，布莱恩） 项目摘要 我们最近证明了精氨酸核酸合成酶1（ASS1）表达在所有的88％中被沉默 肉瘤（n = 708），并且这种损失与降低的总生存率有关。在没有ASS1的情况下，精氨酸 成为必须从血液中获得的必需氨基酸。我们证明了这一点 精氨酸脱节酶（ADI-PEG20，一种细胞外精氨酸耗尽酶）诱导生存代谢 重新编程的缺陷肉瘤，将葡萄糖重定向到串行/叶酸途径中，从而 来自葡萄糖到嘧啶生物合成的有趣碳。代谢组学分析表明，这应该 通过嘧啶抗代谢物吉西他滨将细胞致死。此外，ADI-PEG20和多西他赛 动态增加核苷酸/吉西他滨转运蛋白的SLC29A1的表达。结合 吉西他滨和多西他赛已被证明在肉瘤中仅优于吉西他滨。所以， 我们将进行II期临床试验，该试验将ADI-PEG20与吉西他滨和多西他赛相结合，这是标准 软组织肉瘤的二线热剂，以建模ASS1缺乏症的代谢后果 在存在和不存在精氨酸饥饿的情况下。无进展的生存和整体生存是主要的 和次要终点。治疗前的配对活检和ADI-PEG20之后的21天将是 获得矫正研究。对于临床前测试，我们生成了第一个有条件的鼠敲除模型 在p53损失的背景下发展肉瘤的ASS1，这是肉瘤的常见改变。我们也发展了 肉瘤患者衍生的Xenographictics（PDXS）通过ADI-PEG20模拟精氨酸剥夺。我们将确定 ASS1沉默对转基因小鼠肿瘤发生的影响，并建模自适应代谢重编程 对吉西他滨和多西他赛的反应，以确定敏感性和对治疗的抗性模式。我们 预计拟议的研究将导致精氨酸开发生物标志物驱动的疗法 Ass1缺陷肉瘤的剥夺。