Nutrient Regulation of Cancer Cell Growth

癌细胞生长的营养调节

基本信息

批准号：
10607912
负责人：
Heather Christofk
金额：
$ 66.39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-06 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607912
关键词：
Acute Lymphocytic Leukemia Affect Amino Acids Anabolism Animals Asparagine Aspartate Aspartate-Ammonia Ligase Binding Biodistribution CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CRISPR/Cas technology Cancer Cell Growth Regulation Cell Proliferation Cells Clinical Complex Consumption Data Dependence Electron Transport Environment FDA approved FRAP1 gene Fibroblasts Genetic Genetic Transcription Genetically Engineered Mouse Genomics Growth Homing Immune Impairment Implant Kidney Knock-out Leucine Lymphoblastic Leukemia Lysosomes Macrophage Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measures Mediating Metabolic Metabolism Metformin Methods Mitochondria Modeling Molecular Mus NADH dehydrogenase (ubiquinone)Nutrient Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Population Production Proliferating Proteins Public Health Regulation Renal Cell Carcinoma Renal carcinoma Reporting Resistance Respiration Route Serum Signal Transduction T-Lymphocyte Testing Therapeutic Tissues Western Blotting Xenograft Model Xenograft procedure activating transcription factor 1 activating transcription factor 4 anticancer activity asparaginase cancer cell cancer cell subtype cancer therapy cell growth clinical translation detection of nutrient dietary extracellular immune activation immune checkpoint blockade in vitro activity in vivo inhibitor leukemia malignant breast neoplasm metabolomics mortality mouse model recruit sensor single-cell RNA sequencing standard of care subcutaneous therapeutic target tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

SUMMARY Renal cell cancer (RCC) is the most common type of kidney cancer, and despite therapeutic advances, mortality remains high. While there are over a dozen RCC subtypes with different genomic drivers, metabolic reprogramming is a shared feature of tumorigenesis and progression across most of the major forms of kidney cancer and represents a targetable vulnerability in RCC. Our preliminary results show that RCCs and other cancers rely on the amino acid asparagine for tumor mTORC1 activity and growth, and methods to deplete tumor asparagine levels impair cancer cell proliferation and block cancer growth. Cancers acquire asparagine through two main routes: 1) consumption from the environment, and 2) biosynthesis from aspartate via asparagine synthetase (ASNS). Over the last 5 years, we found that simultaneous reduction of tumor asparagine consumption and biosynthesis blocks growth of lung, breast, and pancreas cancers in mice. Tumor asparagine consumption can be targeted using L-Asparaginase (ASNase), which hydrolyzes serum asparagine, or dietary asparagine restriction, which reduces serum asparagine levels. Tumor asparagine biosynthesis can be targeted using metformin, which through inhibiting complex I of the electron transport chain (ETC), reduces cancer cell production of aspartate, an obligate substrate for ASNS biosynthesis of asparagine. In this renewal proposal, we will investigate kidney cancer asparagine dependency to determine whether asparagine depletion can be broadly applied to treat patients with various subtypes of RCC. We will also determine the mechanism by which asparagine is sensed in cancer cells to impact mTORC1 activity and whether asparagine depletion impacts immune cell activation within the RCC tumor microenvironment.

概括肾细胞癌 (RCC) 是最常见的肾癌类型，尽管治疗取得了进展，但死亡率仍然处于高位。虽然有十几种 RCC 亚型具有不同的基因组驱动因素，但代谢重编程是大多数主要肾脏形式肿瘤发生和进展的共同特征癌症，代表了 RCC 中的一个可针对的脆弱性。我们的初步结果表明，农村信用社和其他癌症依赖氨基酸天冬酰胺来促进肿瘤 mTORC1 活性和生长，以及消除肿瘤的方法天冬酰胺水平会损害癌细胞增殖并阻止癌症生长。癌症通过以下途径获取天冬酰胺两条主要途径：1）从环境中消耗，2）通过天冬酰胺从天冬氨酸生物合成合成酶（ASNS）。在过去的 5 年里，我们发现天冬酰胺同时减少肿瘤消耗和生物合成可阻止小鼠肺癌、乳腺癌和胰腺癌的生长。肿瘤天冬酰胺可以使用 L-天冬酰胺酶 (ASNase) 来确定消耗量，该酶可水解血清天冬酰胺，或者通过膳食天冬酰胺限制，可降低血清天冬酰胺水平。肿瘤天冬酰胺生物合成可靶向使用二甲双胍，通过抑制电子传递链 (ETC) 的复合物 I，减少癌细胞天冬氨酸的生产，天冬氨酸是 ASNS 生物合成天冬酰胺的必需底物。在这次更新提案中，我们将研究肾癌天冬酰胺依赖性，以确定天冬酰胺消耗是否可以广泛应用于治疗各种亚型肾细胞癌患者。我们还将确定机制癌细胞中检测到天冬酰胺会影响 mTORC1 活性以及天冬酰胺消耗是否会影响 RCC 肿瘤微环境中的免疫细胞激活。