Targeting BCAT1 and branched-chain amino acid metabolism for the detection and prevention of SCLC

靶向 BCAT1 和支链氨基酸代谢用于检测和预防 SCLC

• 批准号: 10241289
• 负责人: Kwon-Sik Park
• 金额: $ 45.87万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241289
• 关键词: Affect; Anabolism; Biochemical; Biogenesis; Biological Markers; Branched-Chain Amino Acids; Cancer Patient; Cause of Death; Cells; Chemoprevention; Chronic; Clinic; Clinical; Cytotoxic Chemotherapy; Data; Dependence; Detection; Development; Diagnosis; Diet; Disease; Drug toxicity; Early Diagnosis; Enzymes; Essential Amino Acids; Eukaryotic Initiation Factors; Family; Genes; Genetically Engineered Mouse; Glioblastoma; Glutamates; Goals; Growth; Homeostasis; Human; Individual; Intervention; Isoleucine; Keto Acids; Kinetics; Knock-out; Knowledge; Leucine; Literature; Lung Adenocarcinoma; Malignant neoplasm of lung; Measurable; Mediating; Metabolic; Metabolic stress; Metabolism; Modeling; Molecular; Monitor; Mus; Nitrogen; Nutrient; Oncogenic; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Physiology; Plasma; Prevention; Prevention strategy; Protein Biosynthesis; Proteins; Publishing; Reaction; Resistance; Ribosomes; Role; Route; Sampling Studies; Smoker; Stress; TP53 gene; Testing; Therapeutic; Toxic effect; Translations; Tumor stage; United States; Validation; Valine; Woman; alpha ketoglutarate; amino acid metabolism; amino group; biological adaptation to stress; branched-chain-amino-acid transaminase; cancer diagnosis; cancer type; cell transformation; detection method; early detection biomarkers; endoplasmic reticulum stress; genetic signature; high risk; high risk population; improved; in vivo; inhibitor/antagonist; insight; knock-down; lung cancer cell; lung small cell carcinoma; men; minimally invasive; mortality; mouse development; novel; novel strategies; nutrient deprivation; nutrition; patient derived xenograft model; potential biomarker; premalignant; prevent; prospective; public health relevance; small hairpin RNA; small molecule inhibitor; tumor; tumor growth; tumor metabolism; tumorigenic

Summary The high mortality of small cell lung cancer (SCLC) is largely due to its invariable resistance to current cytotoxic therapies. Chemoprevention has been considered as an alternative to existing therapeutics on the basis of long tumor latency and the well-defined high-risk population (e.g. smokers). Identification of tractable targets for prevention and early detection requires an understanding of molecular changes underlying early- stage tumor development. We found that enhanced ribosome biogenesis and protein synthesis are critical for MYC family-driven transformation of precancerous precursors (preSC) into fully tumorigenic cells. Both human and mouse SCLC cells are extremely sensitive to a specific inhibitor of ribosome biogenesis that has also been shown to reduce tumor growth in a genetically engineered mouse model. Analysis of the MYC-driven oncogenic gene signature revealed branched-chain aminotransferase 1 (BCAT1) as a potential modulator of both metabolic adaptation and related stress response to promote cellular homeostasis. BCAT1 is an enzyme that catalyzes transfer of the α-amino nitrogen from branched-chain amino acids (BCAAs including leucine) to α-ketoglutarate to produce branched-chain α-keto acids (BCKAs) and glutamate. This enzyme routes BCAAs into multiple metabolite pools for biosynthesis and regulates levels of BCAAs, specifically leucine, that stimulate protein synthesis by acting as indicators of nutrient availability. BCAT1 has recently been implicated in multiple types of cancers, including glioblastoma and mouse Kras/p53-driven lung adenocarcinoma. In this application, we will test the hypotheses that enhanced BCAT1 promotes SCLC development by controlling protein synthesis and stress response, and that altered levels of BCAA metabolites inform early BCAT1- dependent SCLC development. To test these hypotheses, we propose the following Aims. Aim 1: To determine the necessity of BCAT1 for SCLC development, we will evaluate the tumor suppressive effects of knocking out Bcat1 and examine the effects of pharmacological inhibition of BCAT1 on SCLC development and long-term survival in vivo. Aim 2: To determine the role of BCAT1 in protein synthesis and stress response during SCLC development, we will manipulate BCAT1 and determine the resulting impact on biochemical interactions among related proteins and pathways that influence proliferation and survival of L-Myc-induced transforming cells, a model of early stage SCLC. We will also determine the significance of BCAA metabolism in tumor development in vivo by setting up variable conditions that mimic different outcomes of the metabolic reaction using a BCAA-defined diet. Aim 3: To test alterations in BCAA metabolites as biomarkers for BCAT1- dependent SCLC development, we will monitor changes in plasma BCAA and BCKA levels during SCLC development in vivo and examine the clinical correlation of plasma levels of these metabolites with a SCLC diagnosis. The expected outcome of this proposal will provide critical insights into novel strategies for targeted prevention using minimally invasive detection methods and intervention using low-toxicity drugs or nutrition.

摘要 小细胞肺癌(SCLC)的高死亡率在很大程度上是由于其对电流的恒定抵抗。 细胞毒疗法。化学预防一直被认为是现有治疗方法的替代方案 肿瘤潜伏期长和明确界定的高危人群(如吸烟者)的基础。易驯服的鉴定 预防和早期发现的目标需要了解早期- 肿瘤发展分期。我们发现，增强核糖体的生物发生和蛋白质合成对 MYC家族驱动的癌前体细胞向完全致瘤细胞的转化。都是人类 小鼠SCLC细胞对一种特定的核糖体生物发生抑制物非常敏感，这种抑制物也是 在基因工程小鼠模型中显示了减少肿瘤生长的作用。对MYC驱动的分析 致癌基因特征显示支链氨基转移酶1(BCAT1)是一种潜在的调节因子 代谢适应和相关的应激反应，以促进细胞内稳态。BCAT1是一种酶 它催化α-氨基氮从支链氨基酸(包括亮氨酸)转移到 α-酮戊二酸生产支链α-酮酸(BCKA)和谷氨酸。这种酶将支链氨基酸 进入多个代谢物库进行生物合成，并调节支链氨基酸的水平，特别是亮氨酸， 通过充当营养可获得性的指示器来刺激蛋白质合成。BCAT1最近被牵连 在多种类型的癌症中，包括胶质母细胞瘤和小鼠Kras/P53驱动的肺腺癌。在这 应用程序中，我们将检验增强的BCAT1通过控制 蛋白质合成和应激反应，以及支链氨基酸代谢物水平的变化通知早期BCAT1- 依赖小细胞肺癌的发展。为了检验这些假设，我们提出了以下目标。目标1：确定 BCAT1在小细胞肺癌发展中的必要性，我们将评估基因敲除对肿瘤的抑制作用 并检测BCAT1的药理抑制对小细胞肺癌发生和长期疗效的影响 活体内存活。目的2：探讨BCAT1在小细胞肺癌蛋白质合成和应激反应中的作用 在开发过程中，我们将操作BCAT1并确定其对生化相互作用的影响 影响L-Myc诱导转化细胞增殖和存活的相关蛋白及途径 细胞，早期小细胞肺癌的模型。我们还将确定支链氨基酸代谢在肿瘤中的意义 通过设置模拟不同代谢反应结果的可变条件在体内发育 使用BCAA定义的饮食。目的3：测试BCAA代谢物作为BCAT1生物标志物的变化 依赖于小细胞肺癌的发展，我们将监测小细胞肺癌期间血浆支链氨基酸和BCKA水平的变化 体内发育并检测这些代谢物水平与小细胞肺癌的临床相关性 诊断。这项提案的预期结果将为有针对性的新战略提供关键的见解 使用微创检测方法进行预防，并使用低毒药物或营养进行干预。