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

• 批准号: 9270532
• 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
• 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/9270532
• 关键词: Acute; Adverse effects; Anabolism; Antioxidants; Biological Markers; Breast Cancer Cell; Breast Cancer cell line; Cancer Patient; 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; cancer initiation; glucose metabolism; in vivo Model; interest; malignant breast neoplasm; metabolomics; novel therapeutics; patient subsets; phosphoproteomics; public health relevance; response; targeted treatment; therapeutic biomarker; therapeutic target; transcription factor; tumor; tumor growth; tumor initiation; tumor progression; uptake

 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（由申请人提供）：本申请的中心假设是致癌PI 3 K/Akt信号传导驱动代谢重编程以促进乳腺肿瘤的发生和进展，导致治疗上易于处理的癌症特异性代谢脆弱性。虽然人们对理解该途径如何有助于癌症中的有氧糖酵解非常感兴趣，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尚未明确。我们使用研究乳腺癌中PI 3-K/Akt信号传导的稳健模型，提出了一个项目来评估由PI 3-K/Akt介导的促进肿瘤发生和进展的代谢变化，重点是两种抗氧化途径：（i）谷胱甘肽（GSH）的合成，主要的细胞抗氧化剂，和（ii）半胱氨酸的合成，其通过转硫途径参与多种抗氧化系统。 在目标1中，我们将通过评估致癌PI 3 K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我们的初步研究。我们将重点关注抗氧化防御系统中的关键转录因子Nrf 2的激活，作为GSH生物合成中PI 3 K/Akt下游的主要机制。我们将评估由致癌PI 3 K/Akt介导的肿瘤起始对GSH生物合成的需求，并确定利用GSH依赖性维持肿瘤的治疗策略。 在目标2中，我们将研究Akt 2特异性在PTEN失活背景下的代谢决定因素，重点是抗氧化剂代谢。我们将在PTEN缺陷细胞系中进行靶向代谢组学研究，结合SILAC磷酸化蛋白质组学，以确定Akt 2的特异性靶点，重点关注代谢酶。我们还将研究亚型特异性Akt 2底物选择的机制基础。这些底物可以定义潜在的治疗靶点或生物标志物，以指导特定的治疗。 在目标3中，初步数据表明，乳腺癌细胞的一个子集， 优先将代谢物高半胱氨酸从通过甲硫氨酸循环的甲硫氨酸合成中分流出来，并通过转硫途径向半胱氨酸的产生分流。半胱氨酸反过来又参与多种抗氧化系统，包括GSH的合成。致癌Akt足以赋予这种表型。我们将评估PI 3 K/Akt如何调节转硫途径基因，并通过代谢分析评估途径活性。最后，我们将评估转硫途径基因CBS和CTH作为乳腺癌潜在的治疗靶点。 将这些机制确定为对致癌PI 3 K/Akt成瘾的乳腺癌的起始和进展的关键决定因素，将刺激新拮抗剂的开发，以通过GSH生物合成和转硫途径靶向抗氧化剂代谢。我们的研究结果将提供一个综合的，机械的理解致癌信号如何与代谢重编程接口，并暴露癌症特异性代谢的脆弱性，构成乳腺癌的新的治疗机会。