Phosphoinositides and Cancer Metabolism

磷酸肌醇与癌症代谢

基本信息

批准号：
10454964
负责人：
LEWIS C. CANTLEY
金额：
$ 99.33万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-05 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454964
关键词：
1-Phosphatidylinositol 4-Kinase Affect Aldolase A B-Cell Lymphomas BRCA1 gene Biochemical Biological Markers Biopsy Cancer cell line Categories Cell Line Clinical Trials Combined Modality Therapy Cytoskeleton DNA Damage Drug Combinations Embryo Enzyme Inhibitor Drugs Enzymes Evaluation Family Genes Genetic Growth Human Impairment Intervention Knock-out Lipids Malignant Neoplasms Mammary Neoplasms Metabolic stress Metabolism Mus Mutation Nucleotides PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phosphatidylinositols Phosphotransferases Pre-Clinical Model Prostatic Neoplasms Proto-Oncogene Proteins c-akt Research S phase TP53 gene Tissues Toxic effect alpha Actin blood glucose regulation cancer cell cancer therapy cell growth cell growth regulation falls glucose metabolism in vivo inhibitor insight kinase inhibitor knock-down mutant nucleotide metabolism ovarian neoplasm phosphatidylinositol 5-phosphate pre-clinical predictive marker repaired resistance mechanism synergism therapeutic target tripolyphosphate tumor tumor growth tumor metabolism

项目摘要

Project Abstract: More than 25 years ago we discovered the phosphoinositide 3-kinases or PI3K. To date more than 30 PI3K inhibitors have entered clinical trials and an inhibitor (idelalisib) that targets PI3Kδ was recently approved for treating B cell lymphomas. Our research and research from other labs over the past 25 years has revealed that the PI3K pathway evolved to control cell growth, primarily through regulation of cellular metabolism. The focus of this application is to understand the biochemical mechanisms by which phosphoinositide kinases control cellular metabolism. We expect to uncover new targets for pharmaceutical intervention in cancers, new biomarkers for predicting patients who are likely to respond to pathway inhibitors, and new insight into mechanisms of resistance to pathway inhibitors. The proposed research falls into three categories: 1) Evaluate the mechanism by which PI3K controls glucose metabolism and nucleotide synthesis and develop biomarkers to identify patients who are likely to respond to PI3K inhibitors and predict drug combinations that are likely to be more effective than single agents. We have recently found that the major effect of activating PI3K on glucose metabolism is activation of Rac1 and consequent activation of aldolase A due to release of aldolase A from the actin cytoskeleton. Importantly we find that aldolase A activation is required for deoxy-nucleotide triphosphate synthesis at rates needed for S phase progression in tumors with p53 and BRCA1 or PTEN mutations, explaining why these tumors can be dramatically shrunk by PI3K plus PARP inhibitors but not by AKT plus PARP inhibitors. 2) Evaluation of phosphatidylinositol-5- phosphate 4-kinases (PIP4K2A and PIP4K2B) as therapeutic targets in cancers lacking p53 function and determination of the biochemical mechanism by which these kinases become essential for tumor growth when p53 is defective. PIP4K2A and B generate PI-4,5-P2 from the low abundant and poorly characterized lipid PI-5-P. Recently we made the surprising observation that PIP4K2B−/− TP53-/- mice die as early embryos. Importantly, PIP4K2A-/-, PIP4K2B+/-, TP53-/- mice are viable and rarely develop cancers, suggesting that PIP4K2A/B inhibitors might be effective for treating cancers with genetic aberrations in p53. Our studies show that knocking down PIP4K2A and B causes metabolic stress in p53 mutant cancer cells. We propose to determine the mechanism by which loss of PIP4K2A and B only causes metabolic stress in the context of loss of p53. 3) Identification and characterization of PIP4K2A and B inhibitors and evaluation of inhibitors in pre-clinical models in order to provide pre-clinical proof of concept studies that will allow these inhibitors to progress into human cancer trials. We have identified inhibitors of PIP4K2A and B and shown that they mimic the effects of knockout or knockdown of these enzymes in regard to affecting growth of p53 mutant cell lines. We will evaluate whether these inhibitors are on target and determine whether they have an efficacy/toxicity ratio in vivo that would make them useful for treating cancers with p53 mutations.

项目摘要：超过 25 年前，我们发现了磷酸肌醇 3-激酶或 PI3K 迄今为止，已有超过 30 种 PI3K。抑制剂已进入临床试验，针对 PI3Kδ 的抑制剂（idelalisib）最近被批准用于我们的研究和过去 25 年其他实验室的研究表明。 PI3K 通路主要通过调节细胞代谢来进化来控制细胞生长。该应用的重点是了解磷酸肌醇激酶的生化机制我们期望发现癌症药物干预的新靶点。用于预测可能对通路抑制剂产生反应的患者的生物标志物，以及对通路抑制剂的新见解所提出的研究分为三类：1) 评估 PI3K 控制葡萄糖代谢和核苷酸合成的机制，开发生物标志物来识别可能对 PI3K 抑制剂产生反应的患者并预测药物我们最近发现，组合药物可能比单一药物更有效。激活 PI3K 对葡萄糖代谢的主要影响是激活 Rac1 以及随后激活醛缩酶 A 由于从肌动蛋白细胞骨架中释放醛缩酶 A，重要的是我们发现醛缩酶 A。脱氧核苷酸三磷酸合成需要以 S 期进展所需的速率进行激活具有 p53 和 BRCA1 或 PTEN 突变的肿瘤，解释了为什么这些肿瘤可以通过以下方法显着缩小： PI3K 加 PARP 抑制剂，但不是 AKT 加 PARP 抑制剂 2) 磷脂酰肌醇-5- 的评估。磷酸 4-激酶（PIP4K2A 和 PIP4K2B）作为缺乏 p53 功能的癌症的治疗靶点并确定这些激酶对于肿瘤至关重要的生化机制当 p53 有缺陷时，PIP4K2A 和 B 会从低丰度且较差的状态生成 PI-4,5-P2。最近，我们做出了令人惊讶的观察，即 PIP4K2B−/− TP53−/− 小鼠死亡重要的是，PIP4K2A-/-、PIP4K2B+/-、TP53-/- 小鼠能够存活并且很少患癌症，表明 PIP4K2A/B 抑制剂可能有效治疗 p53 基因突变的癌症。我们的研究表明，敲低 PIP4K2A 和 B 会导致 p53 突变癌细胞产生代谢应激。提议确定 PIP4K2A 和 B 的损失仅导致代谢应激的机制 p53 丢失的背景。 3) PIP4K2A 和 B 抑制剂的鉴定和表征以及评估。临床前模型中的抑制剂，以提供临床前概念研究证明允许这些抑制剂进入人类癌症试验，我们已经鉴定出 PIP4K2A 和的抑制剂。 B 并表明它们模拟了这些酶的敲除或敲低的影响我们将评估这些抑制剂是否达到目标并确定是否有效。它们的体内功效/毒性比使其可用于治疗带有 p53 突变的癌症。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Evolution of host protease interactions among SARS-CoV-2 variants of concern and related coronaviruses.

所关注的 SARS-CoV-2 变体和相关冠状病毒之间宿主蛋白酶相互作用的演变。

DOI：
10.1101/2022.06.16.496428
发表时间：
2022
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Kastenhuber,EdwardR;Johnson,JaredL;Yaron,TomerM;Mercadante,Marisa;Cantley,LewisC
通讯作者：
Cantley,LewisC

SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication.

DOI：
10.1128/mbio.01007-23
发表时间：
2023-08-31
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry.

DOI：
10.7554/elife.77444
发表时间：
2022-03-23
期刊：
eLife
影响因子：
7.7
作者：
Kastenhuber ER;Mercadante M;Nilsson-Payant B;Johnson JL;Jaimes JA;Muecksch F;Weisblum Y;Bram Y;Chandar V;Whittaker GR;tenOever BR;Schwartz RE;Cantley L
通讯作者：
Cantley L

Regulation of folate and methionine metabolism by multisite phosphorylation of human methylenetetrahydrofolate reductase.

通过人亚甲基四氢叶酸还原酶的多位点磷酸化调节叶酸和蛋氨酸代谢。

DOI：
10.1038/s41598-019-40950-7
发表时间：
2019
期刊：
Scientific reports
影响因子：
4.6
作者：
Zheng,Yuxiang;Ramsamooj,Shivan;Li,Qian;Johnson,JaredL;Yaron,TomerM;Sharra,Klaus;Cantley,LewisC
通讯作者：
Cantley,LewisC

Membrane Lipids Speak to Histones.

膜脂质与组蛋白对话。