Metabolic vulnerabilities in cancers with impaired TCA cycle activity

TCA 循环活性受损的癌症的代谢脆弱性

基本信息

批准号：
10750296
负责人：
Abigail Xie
金额：
$ 5.27万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2027-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750296
关键词：
ATP Citrate (pro-S)-Lyase Adopted Anabolism Aspartate Cancer cell line Cell Line Cell Proliferation Cell Survival Cells Citric Acid Cycle Clear cell renal cell carcinoma Compensation Critical Pathways Data Dependence Development Effectiveness Enzymes Fumarate Hydratase Fumarate Hydratase Deficiency Functional disorder Generations Genes Genetic Germ-Line Mutation Goals Growth Human Hyperactivity Hypoxia Hypoxia Inducible Factor Impairment In Vitro Inherited Laboratories Lead Light Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Measures Mediating Memorial Sloan-Kettering Cancer Center Metabolic Metabolic Pathway Metabolism Neuroendocrine Tumors Output Oxaloacetates Pathway interactions Patients Physicians Predisposition Production Proliferating Protein Biosynthesis Renal Cell Carcinoma Route Scientist Signal Transduction Source Succinate Dehydrogenase Supporting Cell Syndrome Testing Therapeutic Tissues Training Tumor Suppressor Proteins VHL gene Work cancer cell cancer predisposition career cell growth cell type clinical training coping experimental study in vivo inhibitor loss of function mutation metabolic profile neoplastic cell novel strategies nucleotide metabolism pharmacologic pyruvate dehydrogenase reconstitution targeted cancer therapy tool tumor tumor growth tumor metabolism tumor xenograft

项目摘要

PROJECT SUMMARY Cancer cells exploit multiple metabolic strategies to generate biosynthetic precursors that fuel malignant proliferation. Such metabolic redundancy and plasticity hampers effectiveness of therapies that target cancer cell metabolism and underscores the importance of identifying tumor types most likely to respond to metabolic inhibitors. The goal of this proposal is to test the hypothesis that tumors with impaired metabolic pathways will have limited metabolic plasticity in generating critical biosynthetic intermediates, rendering them susceptible to metabolic inhibition. We focus on the tricarboxylic acid (TCA) cycle, which is a central metabolic hub that supports cell growth and yet is truncated or impaired in several forms of human renal cell cancer (RCC). A subset of RCC tumors arise from germline deficiencies in core TCA cycle enzymes succinate dehydrogenase (SDH) or fumarate hydratase (FH); more commonly, RCC tumors have hyperactive hypoxia-inducible factor (HIF) signaling that blunts TCA cycle metabolism. The goal of this proposal is to determine whether these RCC tumors with altered TCA cycle activity are dependent upon ATP citrate lyase (ACL) as an alternative source of critical metabolic intermediates. Aspartate, synthesized from TCA cycle intermediate oxaloacetate, supports nucleotide and protein synthesis and has emerged as a critical limitation for tumor growth. Nevertheless, how tumors with impaired TCA cycle flux sustain aspartate generation—and whether these compensatory pathways represent a targetable liability—remains largely unknown. My preliminary data demonstrate that SDH/FH-deficient or HIF-active RCC cells have reduced aspartate pools relative to their isogenic controls and that ACL inhibition selectively impairs survival of these cells with defective TCA cycle metabolism. In Aim 1, I will leverage a panel of isogenic RCC lines to test whether genetic and pharmacologic ACL inhibition specifically impairs growth of SDH-/FH-deficient RCC cells in vitro and in vivo. I will exploit genetic tools that supply intracellular aspartate to test the hypothesis that aspartate provision underlies the ACL requirement in SDH-/FH-deficient cells. In Aim 2, I will use RCC cells with hyperactive HIF driven by loss of the von Hippel Lindau tumor suppressor to determine whether cells with suppressed oxidative TCA cycle activity depend on ACL to produce aspartate and enable growth in vitro and in vivo. These studies will shed light not only on a potential metabolic Achilles heel in SDH-/FH-/VHL-null tumors but will also serve as proof of principle that cancer cells with TCA cycle dysfunction engage ACL as an alternative route of synthesizing anabolic precursors. The work and training plan outlined in this proposal will be completed in the laboratory of Dr. Lydia Finley with the co-advisement of Dr. Ross Levine at Memorial Sloan Kettering Cancer Center and will ideally prepare the applicant for further clinical training and a career as an independent physician-scientist.

项目摘要癌细胞利用多种代谢策略来产生生物合成前体，以增强恶性肿瘤增殖。这种代谢冗余和可塑性阻碍了针对癌症的疗法的有效性细胞代谢，并强调识别最有可能对代谢反应的肿瘤类型的重要性抑制剂。该提议的目的是检验以下假设：代谢途径受损的肿瘤将在产生关键的生物合成中间体时，代谢可塑性有限，使它们容易受到影响代谢抑制。我们专注于三核酸（TCA）周期，这是一个中央代谢枢纽支持细胞生长，但在几种形式的人肾细胞癌（RCC）中被截断或受损。一个 RCC肿瘤的子集来自核心TCA循环酶琥珀酸酯脱氢酶的种系缺乏症（SDH）或富马酸水平酶（FH）；更常见的是，RCC肿瘤具有多动缺氧诱导因子（HIF）信号表明钝TCA循环代谢。该提议的目的是确定这些是否是否 TCA循环活性改变的RCC肿瘤取决于ATP柠檬酸裂解酶（ACL）作为一个关键代谢中间体的替代来源。天冬氨酸，由TCA循环中间体合成草乙酸，支持核苷酸和蛋白质合成，并已成为肿瘤的关键限制生长。然而，TCA周期通量受损的肿瘤如何维持天冬氨酸的产生这些补偿性途径代表了有针对性的责任，这在很大程度上未知。我的初步数据证明SDH/FH缺乏或HIF活性的RCC细胞相对于它们的天冬氨酸池减少了等源性对照和ACL抑制选择性损害这些细胞的生存率有缺陷的TCA循环代谢。在AIM 1中，我将利用一系列等源性RCC线来测试遗传和药理 ACL抑制特异性会损害SDH-/FH缺陷型RCC细胞在体外和体内的生长。我会利用供应细胞内天冬氨酸以检验天冬氨酸提供的假设的遗传工具是 SDH-/FH缺陷细胞中的ACL需求。在AIM 2中，我将使用损失的RCC单元具有多动HIF驱动的RCC单元 von Hippel -Lindau肿瘤抑制剂的抑制剂，以确定抑制氧化TCA循环的细胞是否活性取决于ACL产生天冬氨酸并在体外和体内生长。这些研究将丢弃不仅在SDH-/fh-/vhl-null肿瘤中的潜在代谢性致命弱的脚跟上的光，还可以作为证明具有TCA循环功能障碍的癌细胞参与ACL作为合成的替代途径的原理合成代谢前体。该提案中概述的工作和培训计划将在实验室完成 Lydia Finley博士与Ross Levine博士在纪念Sloan Kettering Cancer Center的共同审议和威尔理想情况下，申请人为进一步的临床培训做好准备，并成为独立的身体科学家的职业。