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

• 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
• 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

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 年 个月，5年生存率约为10%。 GBM 的标准治疗包括手术切除、外部治疗 束放射治疗 (XRT) 和替莫唑胺辅助化疗；然而，对 XRT 的抵抗力和 化疗是一个重大的临床问题。最近的研究表明女性性激素发挥保护作用 在 GBM 进展中。然而，使用雌激素治疗 GBM 的效用受到限制，因为其相关的 毒性和发生新癌症的风险。雌激素功能由两种雌激素受体 (ER) 介导 - 亚型：作为肿瘤促进剂发挥作用的ERα和作为肿瘤抑制因子发挥作用的ERβ。最近的研究 在人类 GBM 模型中使用 CRISPR KO 已证实 ERβ 在 GBM 中发挥肿瘤抑制因子的作用。 尽管如此，ERβ的治疗潜力尚未得到广泛开发。目前可用 合成 ERβ 激动剂（LY 和 ERB041）已被证明对人类使用是安全的；然而，这些已不再存在于 由于非肿瘤临床研究未能达到临床终点而导致行业进行临床开发。低的 合成 ERβ 激动剂的功效部分归因于需要高浓度 (10-100 µM)，从而导致 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 临床转化需要选择性和高效力。与创新药物中心合作 在 UTSA 的发现 (CIDD)，我们开发了先导 ERβ 激动剂，具有更高的效力和特异性 ERβ，我们将其命名为 CIDD-ERβ 激动剂。该提案的目标是翻译 ERβ 作为肿瘤抑制因子的功能作用进入利用新型 CIDD-ERβ 激动剂作为新药物的临床策略 治疗剂。假设有效的 ERβ 特异性激动剂通过促进 生长抑制途径并使它们对放射和化疗敏感。我们将使用以下方法来检验这个假设 三个目标。在目标1中，我们将利用其结构进一步优化CIDD-ERβ激动剂先导化合物的可翻译性—— 基于设计、药物化学方法并开发具有更高特异性、效力的 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 使用生物物理方法与 ERβ 进行研究，并确认 CIDD-ERβ 激动剂对 ERβ 基因组、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 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功效 模型并测试与放疗和化疗结合的疗效。这个建议在临床上 意义重大，因为这些假设的成功测试将导致新型 ERβ 激动剂的开发， 促进肿瘤抑制，可以与当前化疗同时转化为临床应用 和放射治疗，为提高 GBM 患者的生存提供了额外的工具。