Novel ERbeta agonists for the treatment of gliomas

描述(申请人提供)：胶质母细胞瘤(GBM)是最恶性的原发脑肿瘤，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的保护的分子机制仍不清楚。雌激素的作用由两种ER亚型介导：作为肿瘤促进剂的ER�和作为肿瘤抑制因子的ER�。新的证据表明，基底膜细胞表达ER�；然而，由于缺乏针对ER�的机械性见解和药物，ER�的临床应用受到限制。最近的研究发现，从植物甘草中分离得到的甘草素(LIQ)和合成的化合物LY500307(LY)是选择性ER�特异性激动剂。该建议的目的是将不断发展的科学证据和ER�的功能作用转化为一种临床策略，通过使用ER�特异性激动剂来抑制基底膜。我们的中心假设是ER�激动剂通过增强ER�的肿瘤抑制功能来抑制基底膜的生长，ER�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说：(1)ER�介导的机制发挥肿瘤抑制作用；(2)ER�激动剂在体内外抑制基底细胞增殖；(3)ER�激动剂上调ER�的表达；(4)ER�激动剂抑制胶质瘤干细胞的生长并促进其分化。为了验证提出的假设，在目标1中，我们将测试ER�激动剂抑制基底膜生长的意义和治疗效果。在目标2中，我们将确定ER�激动剂抑制基底膜的分子机制(S)。在目标3中，我们将研究ER�激动剂在胶质瘤干细胞分化中的作用。了解ER�在基底膜中作为肿瘤抑制因子的作用，将有助于最大限度地增加基底膜的治疗机会。这项拟议的研究具有创新性，因为涉及ER�激动剂的概念及其在抑制基底膜方面的治疗潜力具有新颖性。这一建议将确立ER�信号在基底膜进展中的意义和治疗潜力，从而为使用ER�特异性配体(LIQ和LY)抑制基底膜进展创造一个新的范例。由于目前在临床试验中的ER�激动剂耐受性良好，副作用有限，且具有良好的血脑屏障通透性，因此将ER�激动剂鉴定为治疗剂可以很容易地适应临床使用，或者与目前的化疗和放射治疗相结合，从而为提高基底膜患者的存活率提供另一种工具。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。

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.