Developing synergistic therapeutic strategies targeting deregulated nucleotide metabolism in MYC-driven lymphomas

开发针对 MYC 驱动的淋巴瘤中核苷酸代谢失调的协同治疗策略

基本信息

批准号：
10533261
负责人：
Chanel Alford
金额：
$ 3.97万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533261
关键词：
Adenosine Apoptosis Apoptotic Area B-Lymphocytes Biological Biological Assay Burkitt Lymphoma Cell Death Cell Line Cells Communities Coupled Cytidine Data Dependence Detection Diphosphates Disease Disease remission Dose Enzymes Gene Expression Gene Proteins Guanosine Guanosine Triphosphate Homeostasis In Vitro Investigation Isoenzymes Knowledge Literature Lymphoma Lymphoma cell Lymphomagenesis Malignant Neoplasms Mediating Messenger RNA Metabolic Metabolic Pathway Metabolism Methodology Mouse Cell Line Mus Normal Cell Nucleic Acids Nucleoside Transporter Nucleosides Nucleotide Biosynthesis Nucleotides Oncogenes Palpation Pathway interactions Pharmacogenomics Pharmacotherapy Phenotype Physiological Proliferating Protein Isoforms Proteins Purine Nucleotides Purines Pyrimidine Regimen Research Ribose-Phosphate Pyrophosphokinase Role Supplementation Testing Therapeutic Transcript Uridine Work addiction auxotrophy c-myc Genes cancer therapy cell growth combinatorial extracellular in vivo in vivo Model inhibitor loss of function mouse model new therapeutic target nucleoside analog nucleotide metabolism overexpression response targeted treatment therapeutic target uptake

项目摘要

Project Summary This project seeks to delineate the way in which PRPS2 (phosphoribosyl pyrophosphate synthetase) LOF results in selective, metabolic vulnerabilities in lymphoma with c-Myc overexpression. The isoforms of phosphoribosyl pyrophosphate synthetase (PRPS1 and PRPS2) are the rate limiting step in de novo nucleotide bio-synthesis as they are the enzymes responsible for the creation of 5-phosphoribosyl-1- pyrophosphate (PRPP) - a necessary component of all nucleotides including ATP, GTP, and IMP. In order to meet c-myc over-expressing cells’ demands for anabolic cellular components, they must have access to increased nucleoside pools. This provides a window of opportunity to use the increased levels of nucleotide bio-synthesis in B-cells with c-myc over-expression as a means of cancer therapy and therefore the focus of this investigation is the phosphoribosyl pyrophosphate synthetase enzyme. Recent studies have found inhibition of nucleotide bio-synthesis via loss of function (LOF) of PRPS2 induces apoptosis in a significant portion of Burkitt’s lymphoma cells. Elucidating the metabolic vulnerabilities demonstrated by PRPS2 LOF will inform the community as to what particular biological need is served by PRPS2 as well as underpin new strategies for combinatorial therapies that target nucleotide biosynthesis. Given the preliminary data generated by our lab, it is known that cell death upon PRPS2 LOF is cell intrinsic and selective- loss of PRPS1 does not result in activation of the apoptotic response. This result has remained consistent in in vitro and in vivo models and provides the basis for further study into ways to exploit this induced synthetic lethality. The most critical objectives of this proposal are to 1) Determine the mechanism by which some Myc overexpressing lymphoma cells evade PRPS2 LOF induced apoptosis and 2) Explore if and how dampened nucleotide biosynthesis sensitizes MYC over expressing malignancies to therapeutics that target nucleotide biosynthesis or nucleoside economy. We hypothesize that PRPS2 LOF produces a synthetic lethality that can be combined with pharmacogenomics approaches targeting de novo/ salvage nucleotide bio-synthetic pathways to induce selective and complete cell death and will analyze this objective through the use of standard dose response curves, cellular viability assays and metabolic fluxomics to determine uptake, rate, and utilization of adenosine through key metabolic pathways, and cellular viability assays to determine the degree of rescue achieved by supplementation. Second, we will determine to what extent does PRPS2 LOF, and therefore dampened nucleotide biosynthesis, combine with existing therapies to ablate lymphomagenesis in the Eμ- Myc mouse model.

项目概要该项目旨在描述 PRPS2（磷酸核糖焦磷酸合成酶）LOF 的方式导致 c-Myc 过度表达的淋巴瘤选择性代谢脆弱性。磷酸核糖焦磷酸合成酶（PRPS1 和 PRPS2）是从头合成的限速步骤核苷酸生物合成，因为它们是负责产生 5-磷酸核糖基-1- 的酶焦磷酸 (PRPP) - 所有核苷酸（包括 ATP、GTP 和 IMP）的必需成分。满足 c-myc 过表达细胞对合成代谢细胞成分的需求，它们必须能够获得增加的核苷库提供了使用增加的核苷酸水平的机会。 B 细胞中 c-myc 过度表达的生物合成作为癌症治疗的一种手段，因此是这项研究是最近研究发现的磷酸核糖焦磷酸合成酶。通过 PRPS2 功能丧失 (LOF) 抑制核苷酸生物合成可显着诱导细胞凋亡阐明 PRPS2 LOF 所表现出的代谢脆弱性将是伯基特淋巴瘤细胞的一部分。告知社区 PRPS2 满足哪些特定的生物需求并支持新的鉴于生成的初步数据，针对核苷酸生物合成的组合疗法的策略。我们的实验室已知 PRPS2 LOF 引起的细胞死亡是细胞固有的，而选择性丧失 PRPS1 则不会导致细胞凋亡反应的激活，该结果在体外和体内模型中保持一致。并为进一步研究利用这种诱导合成致死性的方法提供了基础。该提案的目标是 1) 确定某些 Myc 过表达淋巴瘤的机制细胞逃避 PRPS2 LOF 诱导的细胞凋亡，2) 探索是否以及如何抑制核苷酸生物合成使 MYC 过度表达恶性肿瘤对靶向核苷酸生物合成或核苷的治疗方法敏感我们发现 PRPS2 LOF 产生的合成杀伤力可以与经济相结合。药物基因组学方法靶向从头/挽救核苷酸生物合成途径以诱导选择性和完全的细胞死亡，并将通过使用标准剂量反应来分析这一目标曲线、细胞活力测定和代谢通量组学，以确定腺苷的摄取、速率和利用通过关键代谢途径和细胞活力测定来确定通过其次，我们将确定 PRPS2 LOF 达到什么程度，并因此受到抑制。核苷酸生物合成，与现有疗法相结合，消除 Eμ-Myc 小鼠淋巴瘤的发生模型。