Development of Novel ERRalpha Antagonists as Breast Cancer Therapeutics

项目总结/摘要 细胞代谢失调是癌症的一个既定标志，因此代谢途径的靶向 与肿瘤病理生物学有因果关系的肿瘤，已经并将继续成为癌症治疗的一个活跃领域， 发展在这方面特别重要的是观察到癌细胞利用 线粒体代谢损害化疗药物和一些靶向治疗的有效性， 这一发现加强了开发选择性靶向癌细胞线粒体代谢的策略的必要性。 这使我们的发现成为背景，即雌激素相关受体α（ERRa）的表达和/或活性， 一种专门调节线粒体代谢的可药用转录因子，在所有乳腺癌患者中均升高， 肿瘤亚型，最明显的是三阴性乳腺癌（TNBC），其表达和活性随 对患者产生负面影响。使用遗传学和药理学方法，我们已经验证了ERRa作为一种 有用的治疗靶点，其抑制允许选择性破坏线粒体代谢， 癌细胞重要的是，在正常细胞/动物中没有任何可观察到的毒性，证明了 使用工具化合物拮抗剂作为破坏线粒体功能的手段抑制ERRa导致 抑制乳腺癌动物模型中的肿瘤生长。我们假设ERRa拮抗剂将表现出 在TNBC患者中的单药活性，并将增加疗效（并降低所需剂量） 标准护理干预，其活性受到线粒体功能的负面影响。但 ERRa抑制剂的临床潜力的探索由于缺乏有效的和药物样的抑制剂而受到阻碍。 小分子ERRa抑制剂。因此，使用已建立的TNBC和患者来源的异种移植物模型， （PDX）我们将在目标1中评估ERRa拮抗剂如何影响对标准护理干预的反应; 这些研究将告知这些药物应该如何在临床上定位。在目标2中，我们将优化效力 以及我们已经确定开发小型ERRa靶向支架的新型药物样特性 ERRa的分子抑制剂，用于体内研究和未来的临床应用。此外，在试点研究中，我们确定 工具ERRa拮抗剂在已建立脑转移的小鼠模型中具有单一药剂功效， 这种化合物还增加了乳腺癌细胞对甲氨蝶呤的敏感性，甲氨蝶呤是目前用于治疗乳腺癌的药物， 癌症脑转移和软脑膜疾病。因此，我们将探索使用ERRa的实用性 拮抗剂作为单一药剂和与选择的化疗剂组合作为新的治疗方式， 这些使人衰弱的疾病。

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.