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：
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
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/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

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（申请人证明）：这一假设的中心假设是，致癌PI3K/AKT信号传导驱动代谢G促进呼吸肿瘤的启动和程序，并且有很大的兴趣了解如何理解如何途径有助于有氧糖酵解在癌症中，哪个PI 3-- K/AKT信号传导其他代谢物所需的代谢物的代谢，我们预定了乳腺癌。谷胱甘肽（GSH），主要的细胞抗氧化剂和（ii）伴有与多氧化剂系统的chysteine的合成，通过评估JICH OLFURATION途径。我们将重点介绍NRF2的激活，NRF2是抗氧化剂防御系统中的关键转录因子，作为PI3K生物合成的主要机制。在PTEN中，肿瘤维持的依赖性。这些底物可以在AIM 3中定义特定的疗法。偏好的分流蛋白循环的代谢物同型半胱氨酸远离甲基菌株，并在跨硫化途径中产生了半胱氨酸的产生硫化途径基因CBS作为乳腺癌的potitic靶标。致癌界面如何重新编程和暴露癌症特异性的代谢脆弱性，构成了乳腺癌的新治疗性差异。