Development of Novel ERRalpha Antagonists as Breast Cancer Therapeutics

新型 ERRα 拮抗剂作为乳腺癌治疗药物的开发

• 批准号: 10510732
• 负责人: Donald P McDonnell
• 金额: $ 25.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510732
• 关键词: Address; African American; Animal Model; Animals; Area; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Carbon; Catabolism; Cells; Chemoresistance; Clinical; Clinical Management; Data; Development; Disease; Disease model; Dose; ERR1 protein; Effectiveness; Estrogen Nuclear Receptor; Exhibits; FRAP1 gene; Future; Genetic; Glutaminase; Glutamine; Glycolysis; Goals; Histidine; Intervention; Intervention Studies; Link; Malignant Neoplasms; Mammary Neoplasms; Medical; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Central Nervous System; Metastatic malignant neoplasm to brain; Methotrexate; Mitochondria; Modality; Modeling; Molecular Target; Neuraxis; Normal Cell; Nuclear; Outcome; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Play; Positioning Attribute; Pre-Clinical Model; Property; Role; Solid Neoplasm; Source; Therapeutic; Toxic effect; Treatment Efficacy; Work; antagonist; cancer cell; cancer subtypes; clinical development; cytotoxic; drug discovery; flexibility; improved outcome; in vivo; inhibitor; leukemia; malignant breast neoplasm; mitochondrial metabolism; mouse model; novel; optimism; overexpression; oxidation; programs; response; scaffold; small molecule; small molecule inhibitor; standard of care; targeted treatment; therapeutic development; therapeutic target; tool; transcription factor; treatment guidelines; triple-negative invasive breast carcinoma; tumor; tumor growth; Address; African American; Animal Model; Animals; Area; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Carbon; Catabolism; Cells; Chemoresistance; Clinical; Clinical Management; Data; Development; Disease; Disease model; Dose; ERR1 protein; Effectiveness; Estrogen Nuclear Receptor; Exhibits; FRAP1 gene; Future; Genetic; Glutaminase; Glutamine; Glycolysis; Goals; Histidine; Intervention; Intervention Studies; Link; Malignant Neoplasms; Mammary Neoplasms; Medical; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Central Nervous System; Metastatic malignant neoplasm to brain; Methotrexate; Mitochondria; Modality; Modeling; Molecular Target; Neuraxis; Normal Cell; Nuclear; Outcome; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Play; Positioning Attribute; Pre-Clinical Model; Property; Role; Solid Neoplasm; Source; Therapeutic; Toxic effect; Treatment Efficacy; Work; antagonist; cancer cell; cancer subtypes; clinical development; cytotoxic; drug discovery; flexibility; improved outcome; in vivo; inhibitor; leukemia; malignant breast neoplasm; mitochondrial metabolism; mouse model; novel; optimism; overexpression; oxidation; programs; response; scaffold; small molecule; small molecule inhibitor; standard of care; targeted treatment; therapeutic development; therapeutic target; tool; transcription factor; treatment guidelines; triple-negative invasive breast carcinoma; tumor; tumor growth

Project Summary/Abstract Dysregulated cellular metabolism is an established hallmark of cancer and thus targeting of metabolic pathways that are causally linked to tumor pathobiology has, and continues to be, an active area of cancer therapeutic development. Of particular importance in this regard is the observation that the ability of cancer cells to utilize mitochondrial metabolism compromises the effectiveness of chemotherapeutics and some targeted therapies, a finding that reinforces the need to develop strategies to selectively target cancer cell mitochondrial metabolism. This puts into context our discovery that the expression and/or activity of estrogen related receptor alpha (ERRa), a druggable transcription factor that specifically regulates mitochondrial metabolism, is elevated in all breast tumor sub-types, most notably in triple negative breast cancer (TNBC) and its expression and activity tracks with a negative outcome in patients. Using genetic and pharmacological approaches we have validated ERRa as a useful therapeutic target the inhibition of which allows the selective disruption of mitochondrial metabolism in cancer cells. Importantly, absent any observable toxicities in normal cells/animals, it was demonstrated that inhibition of ERRa using tool compound antagonists as a means to disrupt mitochondrial function results in the inhibition of tumor growth in animal models of breast cancer. We hypothesize that ERRa antagonists will exhibit single agent activity in patients with TNBC and will increase the efficacy (and reduce the doses required) of standard of care interventions whose activity is negatively impacted by mitochondrial function. However, the exploration of the clinical potential of ERRa inhibitors has been hampered by the lack of potent and drug-like small-molecule ERRa inhibitors. Thus, using established models of TNBC and patient-derived xenografts (PDXs) we will evaluate in Aim 1, how ERRa antagonists impact response to standard of care interventions; studies that will inform how these drugs should be positioned clinically. In Aim 2 we will optimize the potency and drug-like properties of the novel ERRa targeting scaffolds we have already identified to develop small molecule inhibitors of ERRa for in vivo studies and future clinical use. Further, in pilot studies we have determined that a tool ERRa antagonist has single agent efficacy in a mouse model of established brain metastasis and that this compound also increases breast cancer cell sensitivity to methotrexate, a drug currently used to treat breast cancer brain metastasis and leptomeningeal disease. Therefore, we will explore the utility of using ERRa antagonists as single agents and in combination with select chemotherapeutics as new treatment modalities for these debilitating diseases.

项目摘要/摘要 细胞代谢失调是癌症的既定标志，因此靶向代谢途径 与肿瘤病理生物学有关的因果关系，并且继续是癌症治疗的活性领域 发展。在这方面，特别重要的是癌细胞使用的能力 线粒体代谢损害了化学治疗剂和某些靶向疗法的有效性，A 发现强大的需要制定策略，以选择性地靶向癌细胞线粒体代谢。 这使我们发现，雌激素相关受体α（ERRA）的表达和/或活动， 特异性调节线粒体代谢的可药物转录因子在所有乳房中均升高 肿瘤亚型，最著名的是三重阴性乳腺癌（TNBC）及其表达和活性轨迹 患者的负面结果。使用遗传和药理学方法，我们已将ERRA验证为 有用的治疗靶标的抑制作用允许选择性破坏线粒体代谢 癌细胞。重要的是，没有正常细胞/动物的任何可观察到的毒性，证明 使用工具化合物拮抗剂抑制ERRA作为破坏线粒体功能的手段 乳腺癌动物模型中肿瘤生长的抑制作用。我们假设Erra拮抗剂将表现出来 TNBC患者的单一药物活性，并将提高功效（并降低所需剂量） 活性受线粒体功能负面影响的护理干预措施。但是， 缺乏有效和类似药物样的ERRA抑制剂临床潜力的探索受到了阻碍 小分子ERRA抑制剂。因此，使用已建立的TNBC和患者衍生异种移植的模型 （PDXS）我们将在AIM 1中评估ERRA拮抗剂如何影响对护理干预措施的反应； 研究将告知这些药物应如何临床定位。在AIM 2中，我们将优化效力 新型Erra靶向脚手架的类似药物样特性，我们已经确定为发展小型 ERRA的分子抑制剂用于体内研究和未来的临床用途。此外，在试点研究中，我们已经确定 工具ERRA拮抗剂在已建立的脑转移的小鼠模型中具有单一药物的功效，并且 该化合物还增加了乳腺癌细胞对甲氨蝶呤的敏感性，甲氨蝶呤目前用于治疗乳房 癌症脑转移和钩脑性疾病。因此，我们将探索使用ERRA的实用性 拮抗剂作为单个药物，并与精选的化学治疗剂一起作为新的治疗方式 这些使人衰弱的疾病。