Development of Potent Estrogen Receptor Beta Agonists for Treating Glioblastoma

胶质母细胞瘤(GBM)是最常见的原发恶性脑肿瘤，生存时间约为19年。 5个月，5年生存率约为10%。GBM的标准治疗包括手术切除，外部 放射治疗(XRT)和替莫唑胺辅助化疗；然而，对XRT和 化疗是一个主要的临床问题。最近的研究表明，女性荷尔蒙起着保护作用 在GBM进展中。然而，使用雌激素作为治疗基底膜的效用是有限的，因为它与 发展新癌症的毒性和风险。雌激素的作用由两种雌激素受体(ER)介导。 亚型：作为肿瘤促进剂的ERα和作为肿瘤抑制因子的ERβ。最新研究 CRISPR KO在人基底膜模型中的应用证实，ERβ在基底膜中发挥肿瘤抑制作用。 然而，ERβ的治疗潜力还没有得到广泛的开发。目前可用 合成的ERβ激动剂(LY和ERB041)被证明对人类使用是安全的；然而，这些已经不再是 由于未能达到非肿瘤临床研究的临床终点，按行业划分的临床发展。低 合成ERβ激动剂的疗效部分归因于需要高浓度(10-100uM)导致 它们与ERα的交叉反应。因此，开发新型选择性ERβ激动剂，具有更高的 临床翻译需要选择性和高效性。与创新药物中心合作 发现(CIDD)：我们已经开发出领先的ERβ激动剂，具有更高的效力和特异性 对于ERβ，我们已经将其命名为CIDD-ERβ激动剂。这项提议的目标是将 利用新型CIDD-ERβ激动剂作为一种新的药物将ERβ作为肿瘤抑制因子的功能引入临床策略 治疗剂。假设是强大的ERβ特异性激动剂通过促进 抑制生长的途径，并使其对放射和化疗敏感。我们将使用以下工具验证这一假设 三个目标。在目标1，我们将进一步优化CIDD-ERβ激动剂导联的可译性，利用其结构- 基于设计、药物化学方法开发特异性、效价更高的CIDD-ERβ激动剂 和中枢神经系统(CNS)ADME特性。此外，我们将确定最大耐受量， 毒理学检查并建立PK、PD。在AIM2中，我们将确认CIDD-ERβ激动剂相互作用的特异性 用生物物理方法与ERβ结合，证实CIDD-ERβ激动剂对ERβ基因组和非基因组的影响 和DNA损伤反应功能。在AIM3中，我们将测试优化的CIDD-ERβ激动剂对 胶质瘤干细胞(GSCs)，使用患者异种移植的GBM测试其对肿瘤进展和生存的效果 模型，并测试结合放射和化疗的疗效。这一建议在临床上是 这些假说的成功测试将导致开发新的ERβ激动剂， 促进肿瘤抑制，可在当前化疗的同时很容易转化为临床使用 和放射疗法，为提高GBM患者的存活率提供了另一种工具。

Glioblastoma (GBM) is the most common primary malignant brain tumor with a survival time of approximately 19 months and the 5-year survival rate is ~10%. Standard treatment for GBM consists of surgical resection, external beam radiation therapy (XRT), and adjuvant chemotherapy with temozolomide; however, resistance to XRT and chemotherapy is a major clinical problem. Recent studies suggest female sex hormones play a protective role in GBM progression. However, the utility of using estrogen as a treatment for GBM is limited due to its associated toxicity and risks of developing new cancers. Estrogen functions are mediated by two estrogen receptor (ER)- subtypes: ERα that functions as a tumor promoter and ERβ that functions as a tumor suppressor. Recent studies using CRISPR KO in human GBM models have confirmed that ERβ functions as a tumor suppressor in GBM. Nonetheless, the therapeutic potential of ERβ have not been extensively exploited. Currently available synthetic ERβ agonists (LY and ERB041) are proven to be safe for human use; however, these are no longer in clinical development by industry due to failure to meet clinical endpoints in non-oncological clinical studies. Low efficacy of synthetic ERβ agonists is ascribed in part to requiring high concentrations (10-100 µM) resulting in their cross reactivity with ERα. Therefore, the development of novel selective ERβ agonists, with higher selectivity and high potency is needed for clinical translation. In collaboration with the Center for Innovative Drug Discovery (CIDD) at UTSA, we have developed lead ERβ agonists that deliver higher potency and specificity to ERβ, which we have branded as CIDD-ERβ agonists. The objective of this proposal to translate the functional role of ERβ as a tumor suppressor into a clinical strategy utilizing novel CIDD-ERβ agonists as a new therapeutic agent. The hypothesis is that potent ERβ specific agonists block GBM progression by promoting growth inhibitory pathways and sensitizes them to radiation and chemotherapy. We will test this hypothesis using three aims. In Aim 1, we will further optimize the translatability of CIDD-ERβ agonist leads by using its structure- based design, medicinal chemistry approaches and develop CIDD-ERβ agonists with higher specificity, potency and central nervous system (CNS) ADME properties. Further, we will determine maximum tolerated dose, toxicology and establish PK, PD. In Aim2, we will confirm the specificity of interaction of CIDD-ERβ agonists with ERβ using biophysical methods and confirm the effect of CIDD-ERβ agonists on ERβ genomic, non-genomic and DNA damage response functions. In Aim3, we will test the efficacy of optimized CIDD-ERβ agonists on glioma stem cells (GSCs), test their efficacy on tumor progression and survival using patient xenograft GBM models and also test the efficacy in conjunction with radiation and chemotherapies. This proposal is clinically significant as successful testing of these hypotheses will result in the development of novel ERβ agonists that promote tumor suppression, which can be readily translated into clinical use simultaneously with current chemo and radiation therapies, providing an additional tool for enhancing survival in GBM patients.