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Structural-Transcriptional Relationships that Improve Y537S Estrogen Receptor Antagonism

改善 Y537S 雌激素受体拮抗作用的结构转录关系

基本信息

批准号：
10636229
负责人：
Sean William Fanning
金额：
$ 35.79万
依托单位：
LOYOLA UNIVERSITY CHICAGO
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：
2023-05-11 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636229
关键词：
Address Adopted Affect Binding Breast Cancer Cell Breast Cancer Model Breast Cancer therapy CDK4 gene Cancer Etiology Cessation of life Clinical Data Development Dimerization Disease Progression Drug Kinetics Drug resistance ESR1 gene Emergency Department patient Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogen receptor positive Fulvestrant Genes Genetic Transcription Genome Genomics Growth Hormones Hydrogen Bonding In Vitro Legal patent Libraries Ligand Binding Ligand Binding Domain Ligands MCF7 cell Missense Mutation Modeling Molecular Conformation Mutation Neoplasm Metastasis Oral Pathology Patients Pharmaceutical Preparations Population Pre-Clinical Model Proliferating Proteins Resistance Resolution Roentgen Rays Route Selective Estrogen Receptor Modulators Series Shapes Somatic Mutation Structure Structure-Activity Relationship Tamoxifen Therapeutic Tissues Transcription Coactivator Transcriptional Regulation Treatment Efficacy United States antagonist anticancer activity appropriate dose breast cancer genomics breast cancer progression genome-wide hormone therapy improved in vivo inhibitor insight malignant breast neoplasm mortality mutant next generation novel novel therapeutics overexpression patient derived xenograft model pharmacologic pressure prevent programs protein protein interaction receptor response side effect small molecule therapeutic target transcriptome tumor tumor growth tumor xenograft

项目摘要

Summary This proposal studies how drug-induced structural changes to Y537S estrogen receptor alpha (ERα) impact anti- tumoral activities in hormone-resistant breast cancer cells. Breast cancer is the second leading cause of cancer death in the United States. Acquired resistance to hormone therapies is a leading contributor to mortality. In approximately 40% of progressive ER+ patients, prolonged selective pressure by antiestrogenic therapies gives raise to tumors bearing activating somatic ESR1 (the gene for ERα) mutations. These mutations resist inhibition by clinically approved hormone therapies and engage new transcriptional programs that boost metastatic potential. Y537S missense mutation is among the most common and enables the greatest hormone-free transcriptional activities and resistance to antiestrogen. Next generation selective estrogen receptor degraders (SERDs) have been clinically deployed to address this mechanism of drug resistance. However, they show variable activities in Y537S ESR1 breast cancers and possess common side-effects that will limit their long-term use. We recently studied how a panel of 17 selective estrogen receptor modulators (SERMs) and SERDs bind to and affect Y537S ERα activities in breast cancer cells. We identified structurally distinct SERMs and SERDs with improved activities in this setting. While structurally distinct, our x-ray co-crystal structures showed that the most effective molecules engaged the same S537-E380 hydrogen bond to reinforce the therapeutic antagonist conformation. Therefore, we hypothesize that novel ligand-dependent structural interactions will improve therapeutic antagonistic activities in the Y537S ESR1 setting. In this study, we will leverage our library of over 100 diverse SERMs and SERDs to reveal the structural-transcriptional relationships that underlie improved anti- cancer activities Y537S ESR1 breast cancer cells. We will start by studying how our library binds to and affects Y537S ERα structure and anti-cancer activities (Aim 1). This approach will reveal the ligand binding modes and structural interactions that enable potency. Next, we will study how the most effective molecules impact Y537S ERα genomic activities including protein-protein interactions, genome binding, and transcriptional programing (Aim 2). This approach will show whether the efficacies of SERMs and SERDs arise from alterations to Y537S ERα genomic activities. Finally, we will reveal the anti-tumor and tissue-specific activities of the most effective SERMs and SERDs in hormone-resistant ER+ breast cancer in vivo (Aim 3). This approach will reveal whether our in vitro observations correspond to improved anti-cancer activities in patient-relevant tumor models. Overall, these studies will provide detailed structural-transcriptional relationships to improve therapeutic targeting of Y537S ERα in hormone-resistant breast cancer.

总结该提案研究了药物诱导的Y 537 S雌激素受体α（ERα）的结构变化如何影响抗肿瘤作用。抗肿瘤乳腺癌细胞中的肿瘤活性。乳腺癌是导致癌症的第二大原因死亡在美国。对激素治疗的获得性耐药性是死亡率的主要原因。在大约40%的进展性ER+患者，抗雌激素治疗的长期选择性压力，引起携带激活体细胞ESR 1（ERα基因）突变的肿瘤。这些突变抵抗抑制通过临床批准的激素疗法，并参与新的转录程序，潜力Y 537 S错义突变是最常见的，并且能够使最大的无错义突变发生。转录活性和抗雌激素抗性。下一代选择性雌激素受体降解剂（SERD）已在临床上部署，以解决这种耐药性机制。然而，它们显示 Y 537 S ESR 1乳腺癌中的可变活性，并具有常见的副作用，这将限制其长期使用.我们最近研究了一组17种选择性雌激素受体调节剂（SERM）和SERD如何结合并影响乳腺癌细胞Y 537 S ERα活性。我们确定了结构上不同的SERM和SERD 在这种环境下进行改进的活动。虽然在结构上不同，但我们的X射线共晶结构表明，最有效的分子接合相同的S537-E380氢键以增强治疗性拮抗剂构象因此，我们假设新的配体依赖性结构相互作用将改善在Y 537 S ESR 1环境中的治疗拮抗活性。在这项研究中，我们将利用我们的图书馆， 100种不同的SERMs和SERD，以揭示结构-转录关系，这些关系是改善抗- Y 537 S ESR 1乳腺癌细胞。我们将从研究我们的库如何绑定并影响 Y 537 S ERα结构与抗癌活性（目的1）。这种方法将揭示配体结合模式，结构上的相互作用，使潜力。接下来，我们将研究最有效的分子如何影响Y 537 S ERα基因组活动，包括蛋白质-蛋白质相互作用、基因组结合和转录编程 (Aim 2）。这种方法将显示SERM和SERD的功效是否源于Y 537 S的改变 ERα基因组活性。最后，我们将揭示最有效的抗肿瘤和组织特异性活性 SERM和SERD在体内抗肿瘤ER+乳腺癌中的作用（目的3）。这种方法将揭示，我们的体外观察结果对应于患者相关肿瘤模型中抗癌活性的改善。总的来说，这些研究将提供详细的结构-转录关系，以改善治疗靶向， Y 537 S ERα在乳腺癌耐药中的作用