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有抑制作用。然而，雌激素介导抗GBM的分子机制尚不清楚。雌激素的功能是由两种ER亚型介导的：作为肿瘤促进因子的ER和作为肿瘤抑制因子的ER。新出现的证据表明GBM细胞表达ER；然而，由于缺乏机制见解和专门针对ER的药物，ER的临床应用受到限制。近年来的研究发现，从甘草中分离的利尿素（LIQ）和合成的化合物LY500307 （LY）是选择性ER特异性激动剂。本提案的目的是将不断发展的科学证据和ER -的功能作用转化为临床策略，通过使用ER -特异性激动剂来抑制GBM。我们的中心假设是，ER受体激动剂通过增强ER受体的肿瘤抑制功能来抑制GBM的生长，并且ER受体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了这一假设：(1)ER介导的机制具有肿瘤抑制功能；(2) ER受体激动剂抑制GBM细胞体外和体内增殖；(3) ER受体激动剂上调ER受体的表达；(4)ER受体激动剂抑制胶质瘤干细胞的生长，促进其分化。为了研究提出的假设，在目标1中，我们将测试ER受体激动剂抑制GBM生长的意义和治疗效果。在目标2中，我们将确定ER受体激动剂抑制GBM的分子机制。在目标3中，我们将研究ER受体激动剂在胶质瘤干细胞分化中的作用。了解ER在GBM中作为肿瘤抑制因子的作用将有助于最大化GBM的治疗机会。由于涉及ER激动剂的概念的新颖性及其在抑制GBM方面的治疗潜力，拟议的研究具有创新性。该建议将确立ER信号在GBM进展中的重要性和治疗潜力，从而为使用ER特异性配体（LIQ和LY）来抑制GBM进展创造新的范例。由于目前临床试验中的受体激动剂具有良好的耐受性，副作用有限，血脑屏障通透性好，因此确定受体激动剂作为一种治疗剂可以很容易地适应临床使用，作为单一疗法或与当前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。