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Understanding the AGL metastasis suppressor for therapeutic gain

了解 AGL 转移抑制因子的治疗效果

基本信息

批准号：
9030867
负责人：
DAN THEODORESCU
金额：
$ 42.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030867
关键词：
American Autophagocytosis Biological Assay Biological Markers Bladder Bladder Neoplasm Bladder Urothelium CD44 gene Cancer Biology Cancer Death Rates Cells Cessation of life Clinical Clinical Trials Data Death Rate Dependence Development Diagnosis Disease Enzymes Exhibits Federal Government Figs - dietary Foundations Future Gene Components Gene Targeting Genes Genomics Glucose Glycogen Glycolysis Goals Growth Guanosine Triphosphate Phosphohydrolases HMMR gene Human Hyaluronic Acid In Vitro Individual Knockout Mice Knowledge Lead Libraries Life Link Location Malignant Neoplasms Malignant neoplasm of urinary bladder Medicare Membrane Metabolic Modeling Molecular Target Mus Neoplasm Metastasis Pathway interactions Patients Phenotype Predictive Value Primary Neoplasm Production RNA Interference Receptor Inhibition Recurrence Resources Role SLC2A1 gene Signal Transduction Source Testing Therapeutic Translating Tumor Cell Line Tumor Suppressor Genes Urothelium Visceral Work Xenograft procedure biomarker panel biomarker-driven cancer cell cancer recurrence cancer type carcinogenesis cell growth chemical carcinogenesis cost expectation extracellular glucosidase glycogenolysis high risk in vivo inhibitor/antagonist innovation killings neoplastic cell new therapeutic target novel novel therapeutics outcome forecast pre-clinical prognostic assays prognostic value public health relevance receptor research clinical testing research study small hairpin RNA therapeutic development therapeutic target tumor tumor growth tumor initiation tumor metabolism tumor progression tumorigenesis whole genome

项目摘要

DESCRIPTION (provided by applicant): Bladder cancer kills 15,000 annually and because of few therapeutic advances there is a need for innovation. This project has discovered suppressors of bladder tumor growth and metastasis and shown that low expression of AGL, an enzyme involved in glycogenolysis, and RhoGDI2, an inhibitor of multiple GTPases, is associated with cancer recurrence and death. The Goal of this continuation project is to understand how reduced AGL levels result in aggressive bladder cancer and to translate this knowledge into novel therapies. We found bladder cancer cells with low AGL express elevated levels of Hyaluronic Acid (HA) synthase 2 (HAS2), and its extracellular product HA, and have activated RhoC and Rac1, known drivers of tumor progression. We demonstrated RhoC/Rac1 activity is suppressed by RhoGDI2, linking the actions of the two metastasis suppressors. Cells with low AGL also exhibit increased glycolysis, glucose import and autophagy. When either glucose import or autophagy are blocked, low AGL tumor cells show greater reduction of in vitro growth than cells with higher AGL levels, exposing a vulnerability of these aggressive cells. These data support an innovative Hypothesis: Tumor cells with low AGL generate growth and metastatic signals via production of HA, activation of its receptors CD44 and RHAMM, and downstream effectors such as RhoC and Rac1. For these signals to be actualized, sufficient energy needs to be provided via enhanced glucose import and autophagy. Three Specific Aims will test this hypothesis. 1) Evaluate impact of HA signaling on aggressiveness of bladder cancers with low AGL. We will determine if HA drives tumor progression via its receptors CD44 and RHAMM and effectors RhoC and Rac1 that are inhibited by RhoGDI2. Experiments will use RNAi and receptor inhibition in human xenografts. 2) Determine role of the AGL signaling network in bladder cancer development and progression. We will evaluate the independent predictive value of tumor suppressor genes and components of the AGL signaling network in a large panel of annotated human tumors, to define a predictive multigene biomarker signature and possible new therapeutic targets. We will use full and conditional (bladder urothelium) AGL knockout mice in a chemical carcinogenesis model that generates spontaneous visceral metastases to test whether lack of AGL makes urothelium more susceptible to carcinogenesis and resulting tumors more aggressive. 3) Target molecular vulnerabilities of bladder cancers with low AGL expression. Here we test whether blocking glucose import and/or autophagy reduces in vivo bladder tumor growth. We will use shRNA and pharmacologic agents already in preclinical/clinical testing. We will screen shRNA libraries to metabolic and autophagy genes in cells with low AGL to discover novel genes essential to the aggressive tumor phenotype, with the expectation that some of these will become therapeutic targets. We will evaluate combined inhibition of HA signaling and energy production pathways with the expectation this will have synergistic detrimental effects on tumor progression. Impact: This project will lay the foundation for future biomarker-driven personalized clinical trials that target critical vulnerabilities in bldder cancer while informing us on how AGL executes its unanticipated role in cancer.

描述（由申请人提供）：膀胱癌每年造成15，000人死亡，由于治疗进展很少，因此需要创新。该项目发现了膀胱肿瘤生长和转移的抑制因子，并表明参与糖原分解的酶AGL和多种GTP酶抑制剂RhoGDI 2的低表达与癌症复发和死亡相关。这个延续项目的目标是了解AGL水平降低如何导致侵袭性膀胱癌，并将这些知识转化为新的治疗方法。我们发现具有低AGL的膀胱癌细胞表达高水平的透明质酸（HA）合酶2（HAS 2）及其细胞外产物HA，并激活了RhoC和Rac 1，这是肿瘤进展的已知驱动因素。我们证明RhoC/Rac 1活性被RhoGDI 2抑制，连接两种转移抑制剂的作用。具有低AGL的细胞还表现出增加的糖酵解、葡萄糖输入和自噬。当葡萄糖输入或自噬被阻断时，低AGL肿瘤细胞比具有较高AGL水平的细胞显示出更大的体外生长减少，暴露出这些侵袭性细胞的脆弱性。这些数据支持了一个创新的假设：具有低AGL的肿瘤细胞通过产生HA、激活其受体CD 44和RHAMM以及下游效应物如RhoC和Rac 1来产生生长和转移信号。为了实现这些信号，需要通过增强的葡萄糖输入和自噬提供足够的能量。三个具体目标将检验这一假设。1)评估HA信号传导对具有低AGL的膀胱癌侵袭性的影响。我们将确定HA是否通过其受体CD 44和RHAMM以及受RhoGDI 2抑制的效应子RhoC和Rac 1驱动肿瘤进展。实验将在人类异种移植物中使用RNAi和受体抑制。2)确定AGL信号网络在膀胱癌发展和进展中的作用。我们将在大量注释的人类肿瘤中评估肿瘤抑制基因和AGL信号网络组分的独立预测价值，以定义预测性多基因生物标志物特征和可能的新治疗靶点。我们将在产生自发内脏转移的化学致癌模型中使用完全和条件性（膀胱尿路上皮）AGL敲除小鼠，以测试AGL的缺乏是否使尿路上皮更容易致癌并导致肿瘤更具侵袭性。3)AGL低表达膀胱癌的靶分子脆弱性。在这里，我们测试是否阻断葡萄糖输入和/或自噬减少体内膀胱肿瘤生长。我们将在临床前/临床试验中使用shRNA和药理学试剂。我们将筛选低AGL细胞中代谢和自噬基因的shRNA文库，以发现侵袭性肿瘤表型所必需的新基因，并期望其中一些基因将成为治疗靶点。我们将评估HA信号传导和能量产生途径的联合抑制，期望这将对肿瘤进展产生协同有害作用。影响：该项目将为未来生物标志物驱动的个性化临床试验奠定基础，这些试验针对膀胱癌的关键脆弱性，同时告诉我们AGL如何在癌症中发挥其意想不到的作用。