Research Career Scientist Award

研究职业科学家奖

• 批准号: 10265395
• 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/10265395
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; AKT inhibition; Ablation; 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; 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; 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 of activation protein; Metabolic; Metabolism; Mitochondria; Mus; NADP; Nature; Neoplasm Metastasis; Normal Cell; Oncoproteins; 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; Signal Pathway; Signal Transduction; Skeletal Muscle; Solid Neoplasm; Systemic Therapy; Therapeutic; Therapeutic Effect; Time; Tissues; Veterans; adverse outcome; aerobic glycolysis; analog; base; 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/antagonist; liver injury; malignant breast neoplasm; mortality; mouse genetics; mouse model; neoplastic cell; novel; 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.

癌细胞重新编程其代谢，以促进其增殖和生存所需的合成代谢过程。 癌细胞重新编程代谢的一种方式是劫持进化上保守的代谢， PI 3 K/Akt/mTORC 1信号通路。另一种方法是通过显著提高 己糖激酶亚型，HK 2，催化葡萄糖代谢的第一个关键步骤。的长期目标 这项拨款申请是为了克服靶向癌症代谢和Akt用于癌症治疗的挑战。 虽然癌细胞由于其高葡萄糖代谢（FDG-PET扫描）而可以被选择性地检测， 利用这种特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 会产生不良后果我们克服了这一障碍，证明了己糖激酶2，它催化 糖酵解的第一个关键步骤，并在癌细胞中选择性表达，可以在小鼠中全身删除 没有任何不良后果。该建议是基于我在细胞和生物技术实验室的发现， 生物体水平，并解决以下范式转变：（i）己糖激酶2的种系缺失，其是 在癌细胞中显著升高，是胚胎致死的。然而，我们发现，在成年小鼠中， 在几种小鼠癌症模型中耐受性良好且具有治疗性。本申请将特别 探讨己糖激酶2在转移中的作用。我们将研究己糖激酶2在EMT中的作用， 通过新的机制转移。(ii)Akt可能是人类中最常被激活的癌蛋白 癌然而，我们发现，自相矛盾的是，小鼠肝脏Akt 1和Akt 2的缺失会诱导肝损伤， 炎症和早期肝细胞癌。我们将确定HCC细胞如何存活， 在没有Akt的情况下增殖。(iii)我们发现，成年小鼠Akt 1和Akt 2的系统性缺失可以快速地 死亡率，并且小鼠中的Akt 2缺陷可能是促肿瘤发生的，并且增加了化学- 诱发HCC，可能是由于高胰岛素血症。因此，我们启动了一个全面的办法， 在肿瘤发生后，Akt 1或Akt 2或两者可以以细胞自主方式或全身性地条件性缺失 发病，以跟踪肿瘤生长和转移。我们的研究结果显示， Akt同种型的细胞自主性缺失与系统性缺失在肿瘤发生和进展方面的差异。（四） AMPK的抑制被认为是促肿瘤发生的。巧合的是，我们发现AMPK激活是必需的， 在实体瘤形成和可能的转移期间用于细胞存活。我们将描述AMPK的作用， 转移的人细胞和小鼠模型的乳腺癌和前列腺癌。我们预计， 研究将揭示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，并揭示癌症的脆弱性， PI 3 K/Akt信号转导。