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

• 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
• 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

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.

从诊断多形性胶质母细胞瘤（GBM）或IV期胶质瘤（最恶性的脑癌形式）开始的中位生存期约为1年，尽管目前的积极治疗结合了手术、放疗、化疗和贝伐单抗（阿瓦斯汀），一种靶向VEGF-A的中和抗体。需要新的治疗方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了许多与神经干细胞（NSCs）相似的特性，如通过中枢神经系统迁移、细胞外基质降解和向多谱系分化，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神经干细胞增殖所需的孤儿受体的第一个功能配体，并在脑室下区和齿状回选择性表达，其中发现了NSCs。在小鼠和人类患者中，受体过表达驱动胶质瘤的形成，胶质瘤中表达升高与生存率低高度相关。与许多参与干细胞功能的转录因子不同，这种受体在发现靶向GBM的药物方面具有双重优势。首先，它是