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（由申请人提供的）中位生存期是从诊断多形胶质母细胞瘤（GBM）或IV期神经瘤诊断为最恶性的脑癌形式的中位数，尽管目前的侵略性治疗方法结合了手术，放射疗法，化学疗法，化学疗法和贝伐氏蛋白酶和贝伐他米布（avastin），但中性抗体抗体靶向vegff-a。需要新的疗法来控制这种侵略性癌症。 GBM的正在进行的机械和遗传研究发现，与神经干细胞（NSC）相同的许多特性，例如通过CNS迁移，细胞外基质降解以及分化为多个谱系，这表明NSC增殖的机制可以为GBM治疗提供线索。我们在这里建议识别并表征对神经干细胞增殖所需的孤儿受体的第一个功能性配体，并在发现NSC的室内和齿状回中有选择性表达。受体过表达驱动小鼠的神经胶质瘤形成，在人类患者中，神经胶质瘤的表达升高与存活不良高度相关。与干细胞功能中涉及的许多转录因子不同，该受体在靶向GBM方面具有双重优势。首先，是主要在NSC中表达，并且似乎在控制和分化的节点点起作用。其次，它具有由小分子配体调节的潜力。因此，该受体的配体有可能阻断GBM增殖并抑制肿瘤生长。在AIM 1中，我们计划使用具有新颖的，严格的特异性方案的多样化的小分子库，这些分子库有120,000个化合物，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AIM 2中，我们开发了一种生化测定法，以检测配体诱导的受体相互作用的变化与关键功能相互作用蛋白质，以通过互补受体筛查技术来确认HITS。在AIM 3中，将测试化合物，以调节正常的NSC基因表达和增殖。活性化合物将在临床衍生的人类GBM细胞培养物中进一步检查，以确定它们是否以受体特异性方式阻断肿瘤细胞的生长。如果成功， SBIR 2期资助的项目将提议发现和测试抑制免疫功能低下小鼠中人类GBM自物质移植的配体。我们的总体目标是将一种新型的非毒性药物商业化，以治疗GBM。公共卫生相关性：胶质母细胞瘤（GBM）是成年人中最常见的原发性脑癌，在2010年，预计在美国预计将诊断出22,000例恶性脑肿瘤病例中有一半以上。尽管在过去30年中引入了改善的治疗疗法，但仍有大约一年的总中位生存期仍会延迟癌症的进展。我们建议将第一个配体识别为调节神经干细胞（NSC）增殖的事实的转录。该因素的高水平表达与神经胶质瘤患者的预后不良有关。我们的目标是开发一种可生物利用的小分子药物，该药物使这种转录因子失活并抑制GBM的侵袭性临床行为。