Neural Stem Cell-Selective Drug Target for Small Molecule Therapy of Brain Tumors

用于脑肿瘤小分子治疗的神经干细胞选择性药物靶点

基本信息

批准号：
8393572
负责人：
Scott McNear Thacher
金额：
$ 25.05万
依托单位：
ORPHAGEN PHARMACEUTICALS
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：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8393572
关键词：
Accounting Adhesions Adult Agonist Area Avastin Behavior Binding Bioavailable Biochemical Biological Assay Brain Brain Neoplasms Cell Culture Techniques Cell Cycle Cell Maintenance Cell Proliferation Cell physiology Clinical Combined Modality Therapy Cyclin-Dependent Kinase Inhibitor DNA biosynthesis DRPLA protein Development Diagnosis Drosophila genus Drug Delivery Systems Extracellular Matrix Degradation Family Family member Florida Fluorescence Resonance Energy Transfer Funding Gene Expression Gene Targeting Genetic Genetic Transcription Glioblastoma Glioma Goals Growth Homologous Gene Homology Modeling Hormones Human Immunocompromised Host Lead Ligand Binding Ligand Binding Domain Ligands Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Methods Modeling Molecular Mus Mutant Strains Mice Nodal Nuclear Orphan Receptor Nuclear Receptors Operative Surgical Procedures Orphan PTEN gene Pathway interactions Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Property Proteins Protocols documentation RXR RXRA gene Radiation therapy Regulation Retina Retinoids Role Sampling Screening procedure Signal Transduction Site Small Business Innovation Research Grant Specificity Staging Stem cells Steroid Receptors Structure-Activity Relationship Subgroup Technology Testing Thyroid Gland Time Transcription Repressor/Corepressor Tumor Suppressor Genes Tumor Suppressor Proteins Universities Vascular Endothelial Growth Factors adult neurogenesis analog angiogenesis base bevacizumab cell growth chemotherapy dentate gyrus drug discovery high throughput screening improved lateral line member migration neoplastic cell nerve stem cell neutralizing antibody novel outcome forecast overexpression receptor receptor binding selective expression small molecule small molecule libraries stem subventricular zone transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant) Median survival from time of diagnosis of glioblastoma multiforme (GBM) or stage IV glioma, the most malignant form of brain cancer, is about one year, despite the current aggressive treatment that combines surgery, radiotherapy, chemotherapy, and bevacizumab (Avastin), a neutralizing antibody targeting VEGF-A. Novel therapies are needed for controlling this aggressive cancer. Ongoing mechanistic and genetic studies of GBM find many properties in common with neural stem cells (NSCs), such as migration through the CNS, extracellular matrix degradation, and differentiation into multiple lineages, suggesting that mechanisms of NSC proliferation can provide clues for treatment of GBM. We propose here to identify and characterize the first functional ligands to an orphan receptor that is required for neural stem cell proliferation and is selectively expressed in the subventricular zone and the dentate gyrus, where NSCs are found. Receptor overexpression drives glioma formation in mice and, in human patients, elevated expression in glioma is highly correlated with poor survival. Unlike many of the transcription factors involved in stem cell function, this receptor has a dual advantage for the discovery of drugs to target GBM. First, it is primarily expressed in NSCs and appears to act at a nodal point for control of proliferation and differentiation; and second, it has the potential to be regulated by small molecule ligands. Ligands to this receptor thus have the potential to block GBM proliferation and suppress tumor growth. In Aim 1, we plan high throughput screening with a diverse small molecule library of 120,000 compounds utilizing a novel, rigorous specificity protocol that excludes the majority of false positive ligands and has been validated at Orphagen. More potent ligands (EC50 < 1.0 mM) will be identified from commercially available analogues and, in Aim 2, we develop a biochemical assay to detect ligand-induced changes in receptor interaction with a key functional interacting protein in order to confirm hits by a complementary receptor screen technology. In Aim 3, compounds will be tested for regulation of normal NSC gene expression and proliferation. Active compounds will be further examined in clinically-derived human GBM cell cultures to determine if they block tumor cell growth in a receptor-specific manner. If successful, an SBIR Phase 2-funded project would propose to discover and test ligands that suppress human GBM xenotransplant growth in immunocompromised mice. Our overarching goal is to commercialize a novel class of non-cytotoxic drug for treatment of GBM. PUBLIC HEALTH RELEVANCE: Glioblastoma (GBM) is the most common primary brain cancer in adults, accounting for more than half of the 22,000 malignant brain tumor cases expected to be diagnosed in the US in 2010. Treatment can delay cancer progression, but overall median survival remains roughly one year, despite efforts to introduce improved therapies over the past 30 years. We propose to identify the first ligands to a transcription facto that regulates neural stem cell (NSC) proliferation. High level expression of this factor is closel linked to poor prognosis in glioma patients. Our goal is to develop an orally bioavailable small molecule drug that inactivates this transcription factor and inhibits the aggressive clinical behavior of GBM.

描述（由申请人提供）尽管目前采用结合手术、放疗、化疗和化疗的积极治疗方法，但从诊断出多形性胶质母细胞瘤 (GBM) 或 IV 期胶质瘤（最恶性的脑癌形式）起，中位生存期约为一年。贝伐单抗（Avastin），一种针对 VEGF-A 的中和抗体。需要新的疗法来控制这种侵袭性癌症。正在进行的 GBM 机制和遗传学研究发现许多与神经干细胞 (NSC) 相同的特性，例如通过 CNS 迁移、细胞外基质降解和分化为多个谱系，这表明 NSC 增殖机制可以为 GBM 的治疗提供线索。我们在此建议鉴定和表征孤儿受体的第一个功能性配体，该配体是神经干细胞增殖所需的，并在神经干细胞所在的室下区和齿状回选择性表达。受体过度表达会促进小鼠神经胶质瘤的形成，而在人类患者中，神经胶质瘤中的表达升高与较差的生存率高度相关。与许多参与干细胞功能的转录因子不同，该受体对于发现靶向 GBM 的药物具有双重优势。首先，它是主要在 NSC 中表达，似乎在控制增殖和分化的节点上发挥作用；其次，它有可能受到小分子配体的调节。因此，该受体的配体有可能阻断 GBM 增殖并抑制肿瘤生长。在目标 1 中，我们计划利用一种新颖、严格的特异性方案对包含 120,000 种化合物的多样化小分子库进行高通量筛选，该方案排除了大多数假阳性配体，并已在 Orphagen 进行了验证。将从市售类似物中鉴定出更有效的配体（EC50 < 1.0 mM），并且在目标 2 中，我们开发了一种生化测定法来检测配体诱导的受体与关键功能相互作用蛋白相互作用的变化，以确认互补的命中受体筛选技术。在目标 3 中，将测试化合物对正常 NSC 基因表达和增殖的调节。活性化合物将在临床衍生的人类 GBM 细胞培养物中进行进一步检查，以确定它们是否以受体特异性方式阻止肿瘤细胞生长。如果成功的话， SBIR 第 2 期资助的项目将提议发现和测试抑制免疫受损小鼠中人类 GBM 异种移植物生长的配体。我们的首要目标是将一类用于治疗 GBM 的新型非细胞毒性药物商业化。公共卫生相关性：胶质母细胞瘤 (GBM) 是成人中最常见的原发性脑癌，占 2010 年美国预计诊断出的 22,000 例恶性脑肿瘤病例的一半以上。治疗可以延缓癌症进展，但总体中位生存期尽管在过去 30 年里努力引入改进的疗法，但仍大约需要一年的时间。我们建议鉴定调节神经干细胞（NSC）增殖的转录因子的第一个配体。该因子的高水平表达与神经胶质瘤患者的不良预后密切相关。我们的目标是开发一种口服生物可利用的小分子药物，使这种转录因子失活并抑制 GBM 的侵袭性临床行为。