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，其生存时间约为19 5个月，5年生存率约为10%。GBM的标准治疗包括手术切除、外部治疗和局部治疗。 射线放射治疗（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，女性性激素起着保护作用， GBM进展然而，使用雌激素作为GBM的治疗的效用是有限的，这是由于其相关的 毒性和发展新癌症的风险。雌激素功能由两种雌激素受体（ER）介导- 亚型：作为肿瘤促进剂的ERα和作为肿瘤抑制剂的ERβ。最近的研究 在人GBM模型中使用CRISPR KO的研究证实了ERβ在GBM中作为肿瘤抑制因子发挥作用。 然而，ERβ的治疗潜力尚未被广泛开发。当前可用 合成ERβ激动剂（LY和ERB 041）已被证明对人类使用是安全的;然而，这些已不再存在 由于未能满足非肿瘤临床研究中的临床终点，行业进行了临床开发。低 合成ERβ激动剂的疗效部分归因于需要高浓度（10-100 µM）， 与ERα的交叉反应。因此，开发新的选择性ERβ激动剂， 临床翻译需要选择性和高效力。与创新药物中心合作 在UTSA的Discovery（CIDD），我们已经开发出具有更高效力和特异性的领先ERβ激动剂 ERβ，我们称之为CIDD-ERβ激动剂。本提案的目的是将 将ERβ作为肿瘤抑制剂的功能作用纳入利用新型CIDD-ERβ激动剂作为新的 治疗剂假设有效的ERβ特异性激动剂通过促进GBM的进展来阻断GBM的进展。 生长抑制途径，并使它们对放疗和化疗敏感。我们将测试这个假设， 三个目标。在目标1中，我们将通过使用其结构- 基于药物化学的设计方法，开发出特异性、效价更高的CIDD-ERβ激动剂 和中枢神经系统（CNS）ADME性质。此外，我们将确定最大耐受剂量， 毒理学并确定PK、PD。在Aim 2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进行比较，并证实CIDD-ERβ激动剂对ERβ基因组、非基因组 和DNA损伤反应功能。在Aim 3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测试它们对肿瘤进展和存活的功效 模型，并结合放射和化学疗法测试疗效。该建议在临床上 这些假设的成功测试将导致开发新的ERβ激动剂， 促进肿瘤抑制，这可以很容易地转化为临床使用的同时，目前的化疗 和放射治疗，提供了一个额外的工具，提高生存GBM患者。