Research Career Scientist Award

研究职业科学家奖

基本信息

批准号：
10454208
负责人：
Nissim Hay
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10454208
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 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

项目摘要

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.

癌细胞重新编程其新陈代谢，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法是劫持进化上保守的代谢 PI3K/Akt/mTORC1 信号通路的功能。另一种方法是显着提高表达己糖激酶同种型 HK2，催化葡萄糖代谢的第一个关键步骤。长期目标是该拨款申请旨在克服针对癌症代谢和 Akt 进行癌症治疗的挑战。虽然癌细胞因其高葡萄糖代谢而可以被选择性地检测到（FDG-PET扫描），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。我们通过证明己糖激酶 2 克服了这一障碍，该酶催化糖酵解的第一个关键步骤，在癌细胞中选择性表达，可以在小鼠体内被系统性删除且不会产生任何不良后果。该提案基于我的细胞和实验室实验室的研究结果生物体水平，并解决以下范式转变：（i）己糖激酶 2 的种系删除，这是在癌细胞中显着升高，对胚胎具有致命性。然而，我们发现它在成年小鼠中系统性缺失在多种小鼠癌症模型中具有良好的耐受性和治疗作用。该补助金申请将特别解决己糖激酶 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进行转移。 (ii) Akt 可能是人类中最常被激活的癌蛋白癌症。然而，我们发现，矛盾的是，小鼠肝脏中 Akt1 和 Akt2 的缺失会导致肝损伤，炎症和肝细胞癌的早期发作。我们将确定 HCC 细胞如何存活并在没有 Akt 的情况下增殖。 (iii) 我们发现成年小鼠中 Akt1 和 Akt2 的系统性缺失会引起快速死亡率，并且小鼠中的 Akt2 缺陷可能会促进肿瘤发生并增加化学物质的转移。诱发肝癌，可能是因为高胰岛素血症。因此，我们推出了一种综合方法，其中 Akt1 或 Akt2 或两者都可以在肿瘤发生后以细胞自主方式或系统性有条件地删除发病，跟随肿瘤生长和转移。我们的研究结果表明，两者之间存在显着且意想不到的差异 Akt 同种型的细胞自主缺失与系统性缺失与肿瘤发生和进展相关。（四） AMPK 的抑制被认为是促肿瘤发生的。矛盾的是，我们发现 AMPK 激活是必需的在实体瘤形成和可能的转移过程中细胞存活。我们将描述 AMPK 的作用乳腺癌和前列腺癌的人类细胞和小鼠模型中的转移。我们预计拟议的研究将揭示与癌症代谢相关的肿瘤发生的新机制，并产生策略利用癌症代谢进行癌症治疗，并揭示癌症过度激活的弱点 PI3K/Akt 信号传导。