RSK2 in Estrogen Receptor Positive (ER+) Breast Cancer

雌激素受体阳性 (ER) 乳腺癌中的 RSK2

• 批准号: 10430176
• 负责人: Deborah Lannigan
• 金额: $ 35.28万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430176
• 关键词: Antiestrogen Therapy; Automobile Driving; Biochemical; Biological; Breast; Bypass; Cell Nucleus; Cells; Complex; Crystallography; Cytoplasm; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Drug Design; Drug Kinetics; Ductal Epithelium; Endocrine; Engineering; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen receptor positive; Evaluation; Failure; Generations; Genetic; Genetic Transcription; Growth; In Vitro; Induced Mutation; Intraductal Hyperplasia; Knockout Mice; Lead; Legal patent; Malignant Neoplasms; Mammary gland; Mediating; Metastatic breast cancer; Modeling; Molecular Conformation; Neoplasm Metastasis; Neoplastic Cell Transformation; Nuclear; Parents; Patient-Focused Outcomes; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Population; Process; Proliferating; Property; Protein Kinase; Resistance; Series; Specificity; Structure; Structure-Activity Relationship; Tamoxifen; Testing; Toxic effect; Transgenic Mice; analog; base; breast cancer progression; cardiovascular infection; clinical translation; estrogen disruption; experimental study; genetic signature; hormone therapy; improved; improved outcome; in vitro activity; in vitro testing; in vivo; in vivo Model; inhibitor; insight; longitudinal analysis; malignant breast neoplasm; mortality; mouse model; mutant; novel; novel therapeutics; overexpression; patient derived xenograft model; patient response; patient stratification; programs; side effect; statistics; therapy resistant; tumor; tumor growth; tumorigenesis

Endocrine-based therapies have been very effective at reducing mortality but ~ 25% of patients will progress and only 30% of those with metastatic disease will respond. Therefore, there is a tremendous need to identify the mechanisms that drive estrogen receptor alpha positive (ER+) breast cancer and promote invasion. We found that ERα sequesters activated RSK2, a Ser/Thr protein kinase, into the nucleus to promote neoplastic transformation and invasive tumor growth. Anti-estrogens disrupted the RSK2/ERα complex, driving RSK2 into the cytoplasm with corresponding reduced tumor growth. We hypothesize that failure to disrupt the interaction between RSK2 and ERα with endocrine-based therapy leads to metastasis. In support of this hypothesis the RSK2 gene signature stratifies patients with invasive breast cancer based on positivity for ERα. The mechanism by which RSK2 promotes ER+ breast cancer progression will be identified and evaluated in patient-derived xenografts (aim 1). We will test whether RSK2 in complex with a tamoxifen- resistant ERα mutant drives metastasis using engineered ER+ breast lines (aim 2). RSK inhibitors based on the parent compound, SL0101, will be generated to identify compounds with improved in vivo efficacy to inhibit ER+ tumor growth and metastasis (aim 3). Data generated in this proposal will be analyzed using the appropriate statistics for end point and longitudinal analysis. The successful development of a RSK inhibitor could dramatically improve outcomes for patients with ER+ metastatic breast cancer.

以内分泌为基础的治疗在降低死亡率方面非常有效，但约25%的患者会出现进展

项目成果

Synthesis and Biological Evaluation of 4'-Substituted Kaempfer-3-ols.

4-取代的山奈-3-醇的合成和生物学评价。

• DOI: 10.1021/acs.joc.9b03461
• 发表时间: 2020
• 期刊: The Journal of organic chemistry
• 作者: Kim,Sugyeom;Li,Yu;Lin,Lin;Sayasith,PeytonR;Tarr,ArielT;Wright,EricB;Yasmin,Sharia;Lannigan,DeborahA;O'Doherty,GeorgeA
• 通讯作者: O'Doherty,GeorgeA

The affinity of RSK for cylitol analogues of SL0101 is critically dependent on the B-ring C-4'-hydroxy.

RSK 对 SL0101 的 cylitol 类似物的亲和力主要取决于 B 环 C-4-羟基。

• DOI: 10.1039/d0cc00128g
• 发表时间: 2020
• 期刊: Chemical communications (Cambridge, England)
• 作者: Li,Yu;Seber,Pedro;Wright,EricB;Yasmin,Sharia;Lannigan,DeborahA;O'Doherty,GeorgeA
• 通讯作者: O'Doherty,GeorgeA