Heparan sulfate proteoglycans as critical regulators of brain cancer malignancy

硫酸乙酰肝素蛋白多糖作为脑癌恶性肿瘤的关键调节因子

基本信息

批准号：
8551786
负责人：
Joanna Phillips
金额：
$ 33.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8551786
关键词：
Abnormal Cell Anaplastic astrocytoma Astrocytoma Automobile Driving Behavior Binding Biological Availability Biology Brain Neoplasms Breast Carcinoma CXCL12 gene Cell membrane Cell surface Clinical Diffuse Disease Drug Targeting Environment Enzymes Extracellular Matrix FGF2 gene GDNF gene Glioblastoma Glucosamine Goals Growth Factor Heparan Sulfate Proteoglycan Heparitin Sulfate Human Immune response Immunocompetent Inorganic Sulfates Ligand Binding Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Microglia Modeling Mus Myelogenous Neoplasm Metastasis Oncogenic Outcome PDGFRB gene Pathway interactions Phase II Clinical Trials Primary carcinoma of the liver cells Proteins Proteoglycan Receptor Protein-Tyrosine Kinases Regulation Research Role Signal Pathway Signal Transduction Specimen Sulfatases Suppressor-Effector T-Lymphocytes Testing Translations Treatment outcome Tumor-Derived Unspecified or Sulfate Ion Sulfates Vascular Endothelial Growth Factors Xenograft procedure angiogenesis base carcinogenesis chemokine clinically relevant extracellular human disease improved innovation lung Carcinoma macrophage malignant breast neoplasm melanoma mimetics morphogens mortality neoplastic cell new therapeutic target novel novel strategies novel therapeutics outcome forecast pre-clinical preclinical study protein expression proteoglycan core protein response sulfation therapeutic target tumor tumor growth tumor microenvironment tumor progression versican

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways (1). Despite current therapies, the prognosis for GBM is poor and mean survival remains less than 2 years. An improved understanding of the mechanisms driving abnormal cell signaling is essential for improving treatment outcomes. The long-term goal of this innovative proposal is to define tumor-microenvironment interactions critical in brain cancer and identify clinically relevant, druggable therapeutic targets. Specifically, we focus on the role of extracellular heparan sulfate proteoglycans (HSPGs) as they regulate the activity of multiple ligand-mediated signaling pathways (2), are altered in malignant brain tumors (3, 4), and have the potential to influence both tumor cells and critical tumor-microenvironment interactions, including the tumor-associated microglia/macrophage response. HSPGs, present on the cell surface and in the extracellular matrix, regulate signaling via their ability to bind and alter the bioavailability of diverse ligands, including growth factors, morphogens, chemokines, and enzymes. SULF2, an extracellular heparan sulfate endosulfatase, actively regulates HSPG-dependent signaling by removing the sulfate from 6-O- of glucosamine (6OS) and liberating protein ligands from HSPG sequestration (5). Alterations in HSPG core protein expression and SULF2 expression are common in diverse cancers and the PI of this proposal has shown SULF2 can drive carcinogenesis in malignant astrocytoma through regulation of RTK signaling pathways. As extracellular enzymes that are both tethered to the cell membrane and secreted, the SULFs and their HSPG substrates are present in the extracellular environment and have great potential as novel therapeutic targets. Our Aims are: Aim 1: In human infiltrating astrocytomas, identify the alterations in HSPG expression and sulfation associated with tumor malignancy. Aim 2: Determine HSPG changes driving tumor biologic behavior, including microglia/macrophage response to tumor. Aim 3: Identify how HSPG alterations activate signaling pathways to promote GBM malignant behaviors. The proposed research will determine the mechanisms by which alterations in HSPGs drive oncogenic cell signaling pathways in malignant brain cancer and validate HSPGs as clinically relevant, novel therapeutic targets. Successful completion of these studies provides a preclinical basis to study agents that target HSPGs as a novel therapeutic option in malignant brain cancer.

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种均匀致命的脑癌，其特征是弥漫性侵袭和多个受体酪氨酸激酶（RTK）信号通路的异常激活（1）。尽管目前的疗法，GBM的预后较差，平均生存期仍然不到2年。对驱动异常细胞信号传导的机制的改进理解对于改善治疗结果至关重要。这项创新建议的长期目标是定义脑癌至关重要的肿瘤 - 微环境相互作用，并确定临床上相关的可药治疗靶标。 Specifically, we focus on the role of extracellular heparan sulfate proteoglycans (HSPGs) as they regulate the activity of multiple ligand-mediated signaling pathways (2), are altered in malignant brain tumors (3, 4), and have the potential to influence both tumor cells and critical tumor-microenvironment interactions, including the tumor-associated microglia/macrophage response. HSPG，存在于细胞表面和细胞外基质中，通过其结合和改变的能力来调节信号传导各种配体的生物利用度，包括生长因子，形态因子，趋化因子和酶。 Sulf2是一种细胞外硫酸盐内硫酸氢蛋白酶，通过从6-O-葡萄糖胺（6OS）中去除硫酸盐（6OS）和从HSPG序列化中释放蛋白质配体来积极调节HSPG依赖性信号传导（5）。 HSPG核心蛋白表达和SULF2表达的改变在不同的癌症中很常见，该提案的PI表明Sulf2可以通过调节RTK信号通路来驱动恶性星形胶质细胞瘤中的致癌作用。由于细胞外酶均被束缚在细胞膜上并分泌，因此硫及其HSPG底物存在于细胞外环境中，并且具有巨大的潜力作为新的治疗靶标。我们的目标是：目标1：在人类浸润的星形胶质细胞瘤中，确定HSPG表达的改变和与肿瘤恶性肿瘤相关的硫酸化的改变。 AIM 2：确定HSPG改变驱动肿瘤生物学行为的变化，包括对肿瘤的小胶质细胞/巨噬细胞反应。目标3：确定HSPG改变如何激活信号通路以促进GBM恶性行为。拟议的研究将确定HSPGS中的改变驱动恶性脑癌中的致癌细胞信号通路的机制，并将HSPG验证为临床相关的新型治疗靶标。这些研究的成功完成为研究HSPG作为恶性脑癌的一种新型治疗选择提供了临床前的基础。