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: 9326814
• 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/9326814
• 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; 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; Xenograft procedure; chemotherapy; equol; in vivo; innovation; insight; novel; novel drug class; novel therapeutics; prognostic significance; 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（由申请人提供）：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对脑肿瘤具有肿瘤抑制作用。然而，雌激素介导对GBM的保护作用的分子机制仍然未知。雌激素的功能由两种ER亚型介导：作为肿瘤促进剂的ER β和作为肿瘤抑制剂的ER β。新出现的证据表明，GBM细胞表达ER β;然而，由于缺乏专门针对ER β的机制见解和药物，ER β的临床用途有限。最近的研究已经确定从植物甘草中分离的甘草素（LIQ）和合成化合物LY 500307（LY）是选择性ER β特异性激动剂。该提案的目的是将不断发展的科学证据和ER β的功能作用转化为通过采用ER β特异性激动剂抑制GBM的临床策略。我们的中心假设是ER β激动剂通过增强ER β的肿瘤抑制功能来抑制GBM的生长，并且ER β激动剂促进胶质瘤干细胞的分化，从而提高治疗效果。我们的初步研究支持这一假设：（1）ER β介导的机制发挥肿瘤抑制作用;（2）ER β激动剂抑制GBM细胞的体外和体内增殖;（3）ER β激动剂上调ER β的表达;（4）ER β激动剂抑制胶质瘤干细胞的生长并促进其分化。为了研究所提出的假设，在目标1中，我们将测试ER β激动剂抑制GBM生长的意义和治疗效果。在目标2中，我们将确定ER β激动剂抑制GBM的分子机制。在目标3中，我们将研究ER β激动剂在胶质瘤干细胞分化中的作用。了解ER如何在GBM中作为肿瘤抑制因子发挥作用将有助于最大限度地增加GBM的治疗机会。由于涉及ER β激动剂及其抑制GBM的治疗潜力的概念的新奇，拟议的研究是创新的。该提案将确立ER β信号在GBM进展中的意义和治疗潜力，从而为使用ER β特异性配体（LIQ和LY）抑制GBM进展创造新的范例。由于目前在临床试验中的ER β激动剂耐受性良好，副作用有限，血脑屏障通透性良好，因此ER β激动剂作为治疗剂的鉴定可以很容易地适用于临床使用，作为单一疗法或与目前的化疗和放疗联合使用，从而为提高GBM患者的生存率提供了额外的工具。此外，这些研究的结果有可能在分子水平上为ER介导的肿瘤抑制机制提供新的见解。