Novel ERbeta agonists for the treatment of gliomas

用于治疗神经胶质瘤的新型 ERbeta 激动剂

• 批准号: 8762188
• 负责人: Andrew Jacob Brenner
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762188
• 关键词: Adverse effects; Agonist; Apoptosis; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Cycle Progression; Cell Proliferation; Cells; Central Nervous System Neoplasms; Clinical; Clinical Trials; Development; Epidemiology; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Gene Expression; Genomics; Glioblastoma; Glioma; Glycyrrhiza; Glycyrrhiza uralensis; Goals; Growth; Hot flushes; In Vitro; Inflammation; Inflammatory; Ligand Binding Domain; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Neurons; Nuclear; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase; Plants; Play; Primary Brain Neoplasms; Protein Isoforms; Radiation; Radiation therapy; Research; Role; Sampling; Schizophrenia; Signal Transduction; Stem cells; Symptoms; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; Tumor Promoters; Tumor Suppression; Tumor Suppressor Proteins; Vasomotor; Work; Xenograft procedure; chemotherapy; equol; in vivo; innovation; insight; novel; novel therapeutics; prognostic; public health relevance; soy; stem cell differentiation; tool; tumor

DESCRIPTION (provided by applicant): Glioblastoma (GBM) are the most malignant primary brain tumor and patients with GBM (grade IV glioma) have a survival time of approximately 14 months. Estrogen plays a crucial role during brain development and differentiation. Epidemiological and experimental evidence suggests tumor suppressive role of estrogen on brain tumors. However, the molecular mechanisms by which estrogen mediate protection against GBM remains unknown. Estrogen functions are mediated by two ER-subtypes: ER¿ that functions as tumor promoter and ER¿ that functions as a tumor suppressor. Emerging evidence suggest that GBM cells express ER¿; however, the clinical utility of ER¿ is limited due to lack of mechanistic insights and agents that specifically target ER¿. Recent studies have identified liquiritigenin (LIQ) isolated from the plant Glycyrrhiza uralensis and synthetic compound LY500307 (LY) as selective ER¿ specific agonists. The objective of this proposal is to translate evolving scientific evidence and the functional role of ER¿ into a clinical strategy to suppress GBM by employing ER¿ specific agonists. Our central hypothesis is that ER¿ agonists inhibit the growth of GBM by enhancing tumor suppressive functions of ER¿ and that ER¿ agonists promote differentiation of glioma stem cells leading to increased therapeutic efficacy. The hypothesis is supported by our preliminary studies that (1) ER¿-mediated mechanisms play a tumor suppressive function; (2) ER¿ agonists suppress GBM cell proliferation in vitro and in vivo; (3) ER¿-agonists upregulate expression of ER¿ (4) ER¿-agonists inhibit growth of Glioma Stem Cells and promote their differentiation. To investigate the proposed hypotheses, in aim 1, we will test the significance and therapeutic efficacy of ER¿ agonists to inhibit the growth of GBM. In aim 2, we will determine the molecular mechanism(s) of ER¿ agonists in the suppression of GBM. In aim 3, we will investigate the role of ER¿ agonists in the differentiation of Glioma Stem Cells. Understanding how ER¿ functions as a tumor suppressor in GBM will be useful in maximizing treatment opportunities for GBM. The proposed research is innovative due to the novelty of the concepts involving ER¿ agonists and their therapeutic potential in the suppression of GBM. This proposal will establish the significance and therapeutic potential of ER¿ signaling in GBM progression and thus create a new paradigm for the use of ER¿ specific ligands (LIQ and LY) for curbing GBM progression. Since ER¿ agonists currently in clinical trials are well tolerated with limited side effects and good blood-brain barrier permeability, identification of ER¿ agonists as a therapeutic agent can be readily adapted to clinical use as a monotherpy or in combination with current chemotherapies and radiation, thereby providing an additional tool for enhancing survival in GBM patients. Further, the results from these studies have the potential to provide novel insights into the mechanisms of ER¿ mediated tumor suppression at the molecular level.

描述（由适用提供）：胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤，GBM（IV级胶质瘤）患者的生存时间约为14个月。雌激素在大脑发育和分化过程中起着至关重要的作用。流行病学和实验证据表明雌激素在脑肿瘤上的肿瘤作用。但是，雌激素介导对GBM的保护的分子机制仍然未知。雌激素功能是由两种ER辅助类型介导的：ER？er er ress tumor启动子和ER¿，可作为肿瘤抑制器。新兴的证据表明，GBM细胞表达ER？。然而，由于缺乏专门针对ER？的机械洞察力和药物，ER？的临床实用性受到限制。最近的研究已经确定从植物糖果素中分离出的液化素（LIQ）和合成化合物LY500307（LY）是选择性的特定激动剂。该提案的目的是将不断发展的科学证据和ER？通过采用ER研讨会的临床策略转化为抑制GBM的临床策略。我们的中心假设是，ER？激动剂通过增强ER的肿瘤抑制功能抑制GBM的生长，而ER？激动剂会促进神经胶质瘤干细胞的分化，从而提高治疗效率。我们的初步研究支持了这一假设，即（1）ER¿介导的机制起着肿瘤抑制功能。 （2）ER¿激动剂在体外和体内抑制GBM细胞增殖； （3）Er�-激动剂上调Er¿的表达（4）ER¿-激动剂抑制了神经胶质瘤干细胞的生长并促进其分化。为了研究提出的假设，在AIM 1中，我们将测试ERTOMONISTS抑制GBM生长的显着性和治疗效率。在AIM 2中，我们将在抑制GBM中确定Er eRMONISTS的分子机制。在AIM 3中，我们将研究ER？激动剂在神经胶质瘤干细胞分化中的作用。了解ER在GBM中充当肿瘤抑制剂的功能将有助于最大化GBM的治疗机会。拟议的研究具有创新性，这是因为涉及的概念的新颖性及其在抑制GBM中的治疗潜力。该提案将确定ER？在GBM进展中信号传导的重要性和治疗潜力，从而为使用ER¿特定的配体（LIQ和LY）创造了新的范式来遏制GBM进展。由于目前正在临床试验中的ER¿激动剂耐受性良好，副作用有限和良好的血脑屏障渗透性，因此可以很容易地将ER？激动剂鉴定为治疗剂，以单位或与当前的化学疗法和辐射结合使用临床用途，从而提供了一种增强GBM患者存活的工具。此外，这些研究的结果有可能提供有关分子水平介导的肿瘤抑制机理的新见解。