Development of Potent Estrogen Receptor Beta Agonists for Treating Glioblastoma

开发用于治疗胶质母细胞瘤的有效雌激素受体β激动剂

基本信息

批准号：
10594832
负责人：
Andrew Jacob Brenner
金额：
$ 54.85万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594832
关键词：
Adjuvant Chemotherapy Adult Agonist Apoptosis Binding Biological Assay Biological Availability Brain CRISPR/Cas technology Cells Central Nervous System Chemotherapy and/or radiation Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Combined Modality Therapy DNA Damage Data Development Diagnosis Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Evaluation Excision External Beam Radiation Therapy Failure Fluorescence Resonance Energy Transfer Genomics Glioblastoma Glioma Gliomagenesis Growth Histone Deacetylase Inhibitor Human Hydroxyl Radical In Vitro Industry Knock-out Lead Ligands Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Mediating Modality Modeling Molecular Operative Surgical Procedures Oximes Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Play Process Property Radiation therapy Reporter Research Proposals Resistance Risk Role Specificity Structure Structure-Activity Relationship Survival Rate Testing Tetralones Therapeutic Therapeutic Agents Time Toxic effect Toxicology Translating Tumor Promoters Tumor Promotion Tumor Suppression Tumor Suppressor Proteins Validation Xenograft procedure biophysical techniques chemotherapy clinical development clinical translation clinically significant cross reactivity design drug discovery efficacy testing female sex hormone improved in vitro Assay in vivo innovation meter non-genomic novel novel therapeutics pre-clinical response standard care standard of care stem cells stemness temozolomide tool tumor tumor initiation tumor progression xenoestrogen

项目摘要

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.

胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，生存时间约为19 月份和5年生存率约为10％。 GBM的标准治疗包括手术切除，外部梁辐射疗法（XRT），并用替莫唑胺调节化学疗法；但是，对XRT的抵抗力和化学疗法是一个主要的临床问题。最近的研究表明，女性马匹发挥了保护作用在GBM进展中。但是，将雌激素用作GBM治疗的实用性由于其相关毒性和发展新癌症的风险。雌激素功能由两个雌激素受体（ER） - 亚型：充当肿瘤启动子的ERα，充当肿瘤抑制器的ERβ。最近的研究在人类GBM模型中使用CRISPR KO已证实ERβ在GBM中起抑制肿瘤。但是，ERβ的治疗潜力尚未得到广泛利用。目前可用事实证明，合成的ERβ激动剂（LY和ERB041）是安全使用的。但是，这些不再存在由于未能在非综合临床研究中满足临床终点而导致的临床开发。低的合成ERβ激动剂的功效部分分配给需要高浓度（10-100 µm），从而导致它们与ERα的交叉反应性。因此，新型选择性ERβ激动剂的发展，较高临床翻译需要选择性和高效力。与创新药物中心合作 UTSA的发现（CIDD），我们开发了ERβ激动剂，这些激动剂具有更高的效力和特异性到ERβ，我们已经将其命名为CIDD-ERβ激动剂。该提议翻译的目的 ERβ作为肿瘤抑制器的功能作用，利用新型CIDD-ERβ激动剂作为新的临床策略治疗剂。假设是潜在的ERβ特异性激动剂通过促进GBM的进展生长抑制途径并将其感知到放射和化学疗法。我们将使用三个目标。在AIM 1中，我们将通过使用其结构 - 基于设计，药物化学方法并发展具有更高特异性的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剂量，毒理学和建立PK，PD。在AIM2中，我们将确认CIDD-ERβ激动剂相互作用的特异性使用生物物理方法使用ERβ，并确认CIDD-ERβ激动剂对ERβ基因组非基因组的影响和DNA损伤响应功能。在AIM3中，我们将测试优化的CIDD-ERβ激动剂在神经胶质瘤干细胞（GSC），使用患者异种移植GBM测试其对肿瘤进展和存活的有效性模型并与辐射和化学疗法结合测试效率。该建议在临床上是重要的是，由于这些假设的成功检验将导致新型ERβ激动剂的发展促进抑制肿瘤，可以简单地将其简单地转化为临床用途和辐射疗法，为增强GBM患者的生存提供了额外的工具。