Research Career Scientist Award

研究职业科学家奖

• 批准号: 10618282
• 负责人: Nissim Hay
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618282
• 关键词: AKT Signaling Pathway; AKT inhibition; Ablation; Acceleration; Address; Adipose tissue; Adult; Affect; Applications Grants; Attention; Award; Binding; Breast Cancer Model; Breast cancer metastasis; Cancer Model; Cell Proliferation; Cell Survival; Cell model; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Clinical Trials; Coupled; Dedications; Development; Dose; Embryo; Enzymes; Genes; Genetic; Genetically Engineered Mouse; Germ Lines; Glucose; Glucose Transporter; Glucose-6-Phosphate; Glycolysis; Goals; Growth; Growth Factor; Growth Factor Receptors; Heart; Hepatic; Hepatocarcinogenesis; Hexokinase 2; Human; Hyperinsulinism; Individual; Inflammation; Inhibition of Cancer Cell Growth; Insulin; Intestines; K-ras mouse model; Knockout Mice; Laboratories; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mammary gland; Mediating; Mediator; Metabolic; Metabolism; Mitochondria; Mus; NADP; Nature; Neoplasm Metastasis; Normal Cell; Oncoproteins; PIK3CG gene; Paper; Pathway interactions; Pharmacologic Substance; Pharmacotherapy; Phenotype; Phosphorylation; Physiological; Population; Positron-Emission Tomography; Primary carcinoma of the liver cells; Process; Proliferating; Property; Prostate; Prostate carcinoma; Protein Isoforms; Protein-Serine-Threonine Kinases; PubMed; Publications; Publishing; Reporting; Research; Rest; Role; Scientist; Serine; Signal Pathway; Signal Transduction; Skeletal Muscle; Solid Neoplasm; Systemic Therapy; Therapeutic; Therapeutic Effect; Time; Tissues; Veterans; adverse outcome; aerobic glycolysis; analog; breast cancer progression; cancer cell; cancer therapy; career; early onset; embryo tissue; feasibility testing; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; hepatocellular carcinoma cell line; hexokinase; high risk; in vivo; inhibitor; liver injury; malignant breast neoplasm; mortality; mouse genetics; mouse model; neoplastic cell; novel; programs; prostate cancer progression; recruit; selective expression; targeted cancer therapy; tumor; tumor growth; tumor initiation; tumor metabolism; tumor progression; tumorigenesis; tumorigenic

Cancer cells reprogram their metabolism to fuel anabolic processes required for their proliferation and survival. One way by which cancer cells reprogram metabolism is by hijacking the evolutionarily conserved metabolic function of the PI3K/Akt/mTORC1 signaling pathway. Another way is by markedly elevating the expression of the hexokinase isoform, HK2, which catalyzes the first committed step in glucose metabolism. The long-term goal of this grant application is to overcome challenges in targeting cancer metabolism and Akt for cancer therapy. Although cancer cells can be selectively detected because of their high glucose metabolism (FDG-PET scan), exploiting this property for selective targeting is challenging because interference with glucose metabolism could have adverse consequences. We overcame this roadblock by showing that hexokinase 2, which catalyzes the first committed step in glycolysis, and is selectively expressed in cancer cells, can be systemically deleted in mice without any adverse consequences. The proposal is based on findings made in my laboratory at the cellular and organismal levels, and address the following paradigm shifts: (i) Germ-line deletion of hexokinase 2, which is markedly elevated in cancer cells, is embryonic lethal. However, we found that its systemic deletion in adult mice is well tolerated, and therapeutic in several mouse models of cancer. This grant application will specifically address the role of hexokinase 2 in metastasis. We will investigate the role of hexokinase 2 in EMT and metastasis through a novel mechanism. (ii) Akt is perhaps the most frequently activated oncoprotein in human cancer. However, we found that, paradoxically, hepatic deletion of Akt1 and Akt2 in mice induces liver injury, inflammation, and early onset of hepatocellular carcinoma. We will determine how the HCC cells survive and proliferate in the absence of Akt. (iii) We found that systemic deletion of Akt1 and Akt2 in adult mice elicits rapid mortality, and that Akt2 deficiency in mice could be pro-tumorigenic and increased metastasis of chemically- induced HCC, possibly because of hyperinsulinemia. Therefore, we launched a comprehensive approach in which Akt1 or Akt2 or both can be conditionally deleted either in a cell autonomous manner or systemically, after tumor onset, to follow tumor growth and metastasis. Our findings showed marked and unexpected differences between cell autonomous versus systemic deletions of Akt isoforms with respect to tumor initiation and progression. (iv) The inhibition of AMPK is considered pro-tumorigenic. Paradoxically, we found that AMPK activation is required for cell survival during solid tumor formation and possibly metastasis. We will delineate the role of AMPK during metastasis in human cells and mouse models of breast and prostate cancer. We anticipate that the proposed studies will uncover new mechanisms of tumorigenesis associated with cancer metabolism, yield strategies that exploit cancer metabolism for cancer therapy, and uncover vulnerabilities of cancers displaying hyperactivation of PI3K/Akt signaling.

癌细胞将其新陈代谢重新编程以促进其增殖和生存所需的合成代谢过程。 癌细胞重编代谢的一种方法是劫持进化保守的代谢 PI3K/AKT/MTORC1信号通路的功能。另一种方法是明显提升 己糖酶同工型HK2，它催化了葡萄糖代谢的第一步。长期目标 该赠款的应用是要克服针对癌症代谢和AKT癌症治疗的挑战。 尽管由于其高葡萄糖代谢（FDG-PET扫描），可以选择性地检测到癌细胞，但 利用此属性进行选择性靶向是具有挑战性的，因为干扰葡萄糖代谢可能 有不利的后果。我们通过表明己糖2催化了己糖酶2来克服这一障碍 在糖酵解中首先提交的步骤，并在癌细胞中有选择地表达，可以在小鼠中系统地删除 没有任何不利后果。该提案是基于我在蜂窝的实验室中提出的发现， 生物水平，并解决以下范式转移：（i）己糖酶2的种系缺失，即 癌细胞中明显升高的是胚胎致死。但是，我们发现其在成年小鼠中的系统缺失 在几种癌症的小鼠模型中耐受性且治疗性。该赠款申请将专门 探讨己糖酶2在转移中的作用。我们将研究己糖激酶2在EMT和 通过一种新型机制转移。 （ii）AKT可能是人类中最常激活的癌蛋白 癌症。但是，我们发现，矛盾的是，小鼠中Akt1和Akt2的肝缺失会诱导肝损伤， 炎症和肝细胞癌的早期发作。我们将确定HCC细胞如何存活和 在没有AKT的情况下扩散。 （iii）我们发现成年小鼠中Akt1和Akt2的全身缺失引起快速 死亡率，小鼠中的Akt2缺乏症可能是促肿瘤的，化学的转移增加 诱导的HCC，可能是由于高胰岛素血症。因此，我们启动了一种全面的方法 AKT1或AKT2或两者都可以在肿瘤后以自主方式或系统地有条件地删除 发作，跟随肿瘤生长和转移。我们的发现显示出明显的和意外的差异 Akt同工型的细胞自主性与全身缺失相对于肿瘤的启动和进展。 （iv） AMPK的抑制作用被认为是促肿瘤的。矛盾的是，我们发现需要AMPK激活 用于实体瘤形成和可能转移的细胞存活。我们将描述AMPK在 人类细胞和乳腺癌和前列腺癌小鼠模型中的转移。我们预计提议 研究将发现与癌症代谢相关的肿瘤发生的新机制，产生策略 利用癌症代谢进行癌症治疗，并发现癌症的脆弱性 PI3K/AKT信号。