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(申请人提供)：本申请的中心假设是致癌的PI3K/Akt信号驱动代谢重新编程，以促进乳腺癌的启动和进展，导致癌症特有的代谢脆弱性，这些脆弱性在治疗上是容易处理的。虽然人们很有兴趣了解这一途径如何在癌症的有氧糖酵解中起作用，但PI 3-K/Akt信号调节其他代谢过程以合成肿瘤生长所需代谢物的机制尚不清楚。利用稳健的模型研究PI3-K/Akt信号在乳腺癌中的作用，我们建议评估PI3K/Akt介导的促进肿瘤发生和发展的代谢变化，重点放在两条抗氧化途径上：(I)细胞内主要抗氧化剂谷胱甘肽(GSH)的合成和(Ii)半胱氨酸的合成，半胱氨酸通过跨硫途径参与多种抗氧化剂系统的合成。在目标1中，我们将通过评估致癌的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我们的初步研究。我们将重点关注Nrf2的激活，它是抗氧化防御系统中的关键转录因子，是GSH生物合成中PI3K/Akt下游的主要机制。我们将评估由致癌基因PI3K/Akt介导的肿瘤启动过程中对GSH生物合成的需求，并确定利用GSH依赖于肿瘤维持的治疗策略。在目标2中，我们将在PTEN失活的背景下研究Akt2特异性的代谢决定因素，重点是抗氧化剂代谢。我们将在PTEN缺陷的细胞系中进行靶向代谢组学，结合SILAC磷酸化蛋白质组学来确定Akt2的特定靶点，重点放在代谢酶上。我们还将研究异构体特异性Akt2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记物来指导特定的治疗。在目标3中，初步数据表明，乳腺癌细胞的一个子集 优先通过蛋氨酸循环将代谢产物同型半胱氨酸从蛋氨酸合成转移到半胱氨酸的合成，并通过硫化途径转向半胱氨酸的生产。半胱氨酸反过来又参与多种抗氧化系统，包括GSH的合成。致癌基因Akt足以赋予这种表型。我们将评估PI3K/Akt如何调节跨硫途径基因，并通过代谢分析评估途径的活性。最后，我们将评估跨硫途径基因CBS和Cth作为乳腺癌潜在的治疗靶点。确定这些机制是PI3K/Akt致癌成瘾乳腺癌发生和发展的关键决定因素，将刺激新的拮抗剂的开发，通过GSH生物合成和跨硫途径靶向抗氧化剂代谢。我们的发现将提供一个综合的，机械性的理解，了解致癌信号如何与代谢重新编程相结合，并揭示构成乳腺癌新治疗机会的癌症特异性代谢脆弱性。