Exploiting Metabolic Vulnerabilities in the PI3K and Akt Pathway in Cancer for Therapeutic Benefit

利用癌症 PI3K 和 Akt 通路中的代谢漏洞获得治疗效果

基本信息

批准号：
9903255
负责人：
Alex Toker
金额：
$ 39.57万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
2016-05-09 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903255
关键词：
Acute Anabolism Antioxidants Biological Markers Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Cell Line Cells Combined Modality Therapy Coupled Cysteine Data Dependence Development Enzymes Equilibrium Genes Genetic Glutathione Goals Growth Homocysteine In Vitro Interruption Lead Lesion Maintenance Malignant Neoplasms Mammary Neoplasms Measures Mediating Metabolic Metabolic Pathway Metabolism Methionine Monitor Mutation Newly Diagnosed Nutrient Oncogenic Oxidation-Reduction PTEN gene Pathway interactions Phenotype Phosphatidylinositols Phosphotransferases Play Process Production Protein Isoforms Proto-Oncogene Proteins c-akt Reduced Glutathione Regulation Role Shunt Device Signal Transduction Specificity Study models System Therapeutic Work addiction aerobic glycolysis breast cancer progression cancer initiation glucose metabolism in vivo Model interest malignant breast neoplasm metabolomics novel therapeutics patient subsets phosphoproteomics public health relevance response side effect targeted treatment therapeutic biomarker therapeutic target transcription factor tumor tumor growth tumor initiation tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): The central hypothesis of this application is that oncogenic PI3K/Akt signaling drives metabolic reprogramming to promote breast tumor initiation and progression, resulting in cancer-specific metabolic vulnerabilities that are therapeutically tractable. While there has been much interest in understanding how this pathway contributes to aerobic glycolysis in cancer, mechanisms by which PI 3-K/Akt signaling modulates other metabolic processes to synthesize metabolites required for tumor growth are not well defined. Using robust models for studying PI 3-K/Akt signaling in breast cancer, we propose a project to evaluate the metabolic changes mediated by PI3K/Akt to promote tumor initiation and progression, with a focus on two antioxidant pathways: (i) the synthesis of glutathione (GSH), the major cellular antioxidant, and (ii) the synthesis of cysteine, which is involved in multiple antioxidant systems, through the transsulfuration pathway. In Aim 1, we will extend our preliminary studies by evaluating the mechanisms by which oncogenic PI3K and Akt regulate GSH biosynthesis to modulate the cellular redox state. We will focus on the activation of Nrf2, a key transcription factor in the antioxidant defense system, as a major mechanism downstream of PI3K/Akt in GSH biosynthesis. We will evaluate the requirement for GSH biosynthesis in tumor initiation mediated by oncogenic PI3K/Akt and identify therapeutic strategies that exploit GSH dependence in tumor maintenance. In Aim 2, we will investigate the metabolic determinants for Akt2 specificity in the context of PTEN inactivation, with a focus on antioxidant metabolism. We will perform targeted metabolomics in PTEN-deficient cell lines coupled with SILAC phospho-proteomics to identify specific targets of Akt2, with prioritization focused on metabolic enzymes. We will also investigate the mechanistic basis for isoform-specific Akt2 substrate selection. These substrates may define potential therapeutic targets or biomarkers to guide specific therapies. In Aim 3, preliminary data indicate that a subset of breast cancer cells preferentially shunt the metabolite homocysteine away from methionine synthesis via the methionine cycle and towards the production of cysteine through the transsulfuration pathway. Cysteine, in turn, is involved in multiple antioxidant systems, including the synthesis of GSH. Oncogenic Akt is sufficient to confer this phenotype. We will assess how PI3K/Akt regulates transsulfuration pathway genes and assess pathway activity by metabolic analyses. Finally, we will evaluate the transsulfuration pathway genes CBS and CTH as potential therapeutic targets in breast cancer. Identifying these mechanisms as critical determinants for initiation and progression of breast cancers addicted to oncogenic PI3K/Akt will spur development of new antagonists to target antioxidant metabolism through GSH biosynthesis and the transsulfuration pathway. Our findings will provide an integrated, mechanistic understanding of how oncogenic signaling interfaces with metabolic reprogramming and expose cancer-specific metabolic vulnerabilities that constitute new therapeutic opportunities for breast cancer.

描述（由应用提供）：该应用的中心假设是致癌PI3K/AKT信号传导驱动代谢重编程以促进乳腺肿瘤的启动和进展，从而导致癌症特异性的代谢脆弱性，这些脆弱性在治疗上是可诱发的。尽管有很大的兴趣了解该途径如何有助于癌症中的有氧糖酵解，但PI 3-K/AKT信号传导调节其他代谢过程以合成肿瘤生长所需的代谢物的机制，但并未得到很好的定义。使用可靠的模型来研究乳腺癌中的PI 3-K/AKT信号传导，我们提出了一个项目，以评估PI3K/AKT介导的代谢变化以促进肿瘤的启动和进展，重点是两种抗氧化剂途径：（i）谷胱甘肽（GSH）的合成，该型含量是多种含量的静脉曲张（II）。抗氧化剂系统，通过过泄殖能途径。在AIM 1中，我们将通过评估致癌PI3K和AKT调节GSH生物合成以调节细胞氧化还原状态的机制来扩展初步研究。我们将重点关注NRF2的激活，NRF2是抗氧化剂防御系统中的关键转录因子，作为GSH生物合成中PI3K/AKT下游的主要机制。我们将评估由致癌PI3K/AKT介导的肿瘤倡议中GSH生物合成的需求，并确定利用GSH依赖性肿瘤维持的治疗策略。在AIM 2中，我们将在PTEN失活的背景下研究AKT2特异性的代谢决定剂，重点是抗氧化代谢。我们将在缺乏PTEN缺陷的细胞系中执行靶向代谢组学，并结合SILAC磷酸 - 蛋白质组学识别Akt2的特定靶标，而优先次序集中于代谢酶。我们还将研究同工型特异性AKT2底物选择的机理基础。这些底物可以定义潜在的治疗靶标或生物标志物来指导特定疗法。在AIM 3中，初步数据表明乳腺癌细胞的子集优先将代谢物同型半胱氨酸从蛋氨酸循环中脱离蛋氨酸的合成，并通过过硫化途径从蛋氨酸合成。半胱氨酸又参与了多种抗氧化剂系统，包括GSH的合成。致癌AKT足以赋予这种表型。我们将评估PI3K/AKT如何通过代谢分析调节剥离途径基因和评估途径活性。最后，我们将评估过丝途径基因CBS和CTH作为乳腺癌的潜在治疗靶标。将这些机制识别为关键的决定剂，以确定添加到致癌PI3K/AKT中的乳腺癌的启动和进展，将刺激新拮抗剂的发展，以通过GSH生物合成和透明途径靶向抗氧化剂代谢。我们的发现将提供对与代谢重编程的致癌信号传导如何与癌症特异性的代谢脆弱性构成新的乳腺癌治疗机会的综合机械理解。