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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 40%的最常见的管腔激素受体阳性（HR+）乳腺癌（BCa）患者亚型对常规内分泌治疗（ET）无反应，疾病ET抵抗（ET-R）BCa患者表现出雄激素受体（AR）的“内分泌转换”- 依赖性肿瘤生长和转移。抗雄激素正在成为其他有希望的治疗方法。但令人惊讶的是，AR过表达ET-R的BCa细胞对AR无反应，对手。我们的新发现表明，组成性活跃的AR积累和逃避抑制作用，抗雄激素恩杂鲁胺（Enzamide）。因此，本项目的目标是设计一种治疗方法，有效靶向AR和预防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SUMO翻译后修饰（PTM） SUMO-AR天然存在于获得性和内在ET-R BCa细胞中。SUMO-PTM是一个关键的动态细胞过程和SUMO特异性酶的不平衡驱动选择类型的BCa，包括基础和Myc- 我们和其他人报告的依赖性BCa。独立于已建立的SUMO酶系统，我们鉴定可药物化并使ET-R BCa中SUMO-AR不稳定的双重SUMO-泛素连接酶。这项建议将描述这种新型连接酶在ET-R BCa中的调节控制及其在Enz-response中的作用。我们的新数据表明组成型SUMO-AR基因组活性需要与lncRNA相互作用。因此，我们将描述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1）抑制AR活性或2）增强AR的独特方法与当前标准品Enz相比的降解。在这个过程中，我们将开发新的疗法，临床相关化合物，专门用于晚期ET-R BCa。同样，项目的完成将验证需要，并建立更全面的工具， SUMO-AR在ET-R HR+ BCa中的翻译研究。