Targeting Constitutively Active SUMO Modified Androgen Receptors in Endocrine Resistant Breast Cancer

靶向组成型活性 SUMO 修饰雄激素受体治疗内分泌耐药乳腺癌

基本信息

批准号：
10663317
负责人：
Tasneem Bawa-Khalfe
金额：
$ 34.88万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663317
关键词：
AR gene Androgen Antagonists Androgen Receptor Androgens Binding Breast Cancer Cell Breast Cancer Patient Cancer Model Cell physiology Chemosensitization Chromatin Clinical Trials Data Disease Endocrine Enzymes Exhibits Genetic Transcription Genomics Growth HSPB1 gene Laboratories Ligands Ligase Malignant Neoplasms Molecular Chaperones Mus Neoplasm Metastasis Nuclear Oncogenes Patients Phosphorylation Pilot Projects Post-Translational Protein Processing Process Proliferating Property Proteins Qualifying RNA Binding RNA Recognition Motif Reporting Research Personnel Resistance Role Small Ubiquitin-Related Modifier Proteins Sumoylation Pathway System Testing Therapeutic Tumor Escape Ubiquitin advanced breast cancer androgen sensitive antagonist breast cancer progression cancer subtypes clinically relevant design effective therapy enzalutamide genetic signature hormone receptor-positive hormone therapy improved inhibitor innovation knock-down malignant breast neoplasm migration mimetics novel novel marker novel therapeutics overexpression prevent receptor receptor binding receptor function recruit refractory cancer response targeted treatment therapeutic evaluation therapy resistant tool transcriptome translational study tumor growth tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Forty percent of patients with the most prevalent luminal hormone receptor positive (HR+) breast cancer (BCa) subtype are unresponsive to conventional endocrine therapy (ET) and readily present with incurable metastatic disease. Patients with ET resistant (ET-R) BCa exhibit an “endocrine-switch” to androgen receptor (AR)- dependent tumor growth and metastasis. Anti-androgens are emerging as promising therapy for other advanced BCa subtypes but surprisingly, AR overexpressing ET-R BCa cells are unresponsive to AR antagonists. Our new findings show constitutively active AR accumulate and evade the inhibitory actions of anti-androgen Enzalutamide (Enz). Hence, the objective of the current project is to design a therapeutic strategy to effectively target AR and prevent metastatic progression of ET-R BCa. We demonstrate that unlike other cancer models, persistent SUMO post-translational modification (PTM) of AR (SUMO-AR) occurs natively in acquired and intrinsic ET-R BCa cells. SUMO-PTM is a critical dynamic cellular process and an imbalance in SUMO-specific enzymes drive select types of BCa including basal and Myc- dependent BCa as reported by us and others. Independent of the established SUMO enzymatic system, we identify a dual SUMO-ubiquitin ligase that is druggable and destabilizes SUMO-AR in ET-R BCa. This proposal will delineate the regulatory control of this novel ligase in ET-R BCa and its role in Enz-response. Our new data suggests that constitutive SUMO-AR genomic activity requires interaction with a lncRNA. Hence, we will delineate how SUMO-AR/lncRNA interaction facilitates ligand-independent genomic activity in ET-R BCa cells. Finally, the proposed studies will test unique approaches to either 1) inhibit AR activity or 2) potentiate AR degradation versus the current standard Enz. In the process, we will generate novel therapeutics and evaluate clinically relevant compounds specifically for advanced ET-R BCa. Consistently, completion of the project will validate the need and establish the tools for more comprehensive translational studies on SUMO-AR in ET-R HR+ BCa.

项目摘要有40％的患有最普遍的Luminal Horseone受体阳性（HR+）乳腺癌（BCA）的患者亚型对常规内分泌疗法（ET）无反应，并且很容易出现无法治愈的转移性疾病。 ET耐药（ET-R）BCA患者暴露于雄激素受体（AR） - 依赖性肿瘤生长和转移。抗雄激素正在作为其他人的承诺治疗晚期BCA亚型，但令人惊讶的是，AR过表达的ET-R BCA细胞对AR没有反应对手。我们的新发现显示了组成性的AR丙烯酸，并逃避了抑制作用抗雄激素enzalutamide（ENZ）。因此，当前项目的目的是设计治疗性有效靶向AR并防止ET-R BCA转移进展的策略。我们证明，与其他癌症模型不同，AR的持续转移后转基修饰（PTM）（SUMO-AR）本地发生在获得的和内在的ET-R BCA细胞中。 SUMO-PTM是一个关键的动态细胞流程和EMO特异性酶的不平衡驱动选择类型的BCA类型，包括基本和MYC- 根据我们和其他人报告的依赖BCA。独立于已建立的Sumo酶系统，我们确定可药物可药物并在ET-R BCA中不稳定的双泛素连接酶。这个建议将描述ET-R BCA中这种新型连接酶的调节控制及其在ENZ反应中的作用。我们的新数据表明构型SUMO-AR基因组活性需要与LNCRNA相互作用。因此，我们会的描述SUMO-AR/LNCRNA相互作用如何促进ET-R BCA细胞中的配体非依赖性基因组活性。最后，拟议的研究将测试独特的方法1）抑制AR活性或2）潜在的AR 降解与当前标准ENZ。在此过程中，我们将生成新颖的疗法并评估专门针对晚期ET-R BCA的临床相关化合物。一致地，该项目的完成将验证需求并建立工具以更全面 ET-R HR+ BCA中的SUMO-AR的翻译研究。