RSK2 in Estrogen Receptor Positive (ER+) Breast Cancer

雌激素受体阳性 (ER) 乳腺癌中的 RSK2

基本信息

批准号：
10207532
负责人：
Deborah Lannigan
金额：
$ 36万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207532
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/antagonist 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

项目摘要

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.

基于内分泌的治疗在降低死亡率方面非常有效，但约 25% 的患者会出现病情进展并且只有 30% 的转移性疾病患者会做出反应，因此，非常需要进行识别。驱动雌激素受体α阳性（ER+）乳腺癌并促进侵袭的机制。发现 ERα 将激活的 RSK2（一种 Ser/Thr 蛋白激酶）隔离到细胞核中，促进肿瘤形成转化和侵袭性肿瘤生长。抗雌激素破坏了 RSK2/ERα 复合物，驱动了 RSK2。我们捕捉到了破坏细胞质的失败。 RSK2 和 ERα 与内分泌治疗之间的相互作用导致转移。假设 RSK2 基因特征根据阳性率对浸润性乳腺癌患者进行分层 ERα。RSK2 促进 ER+ 乳腺癌进展的机制将被确定并在患者来源的异种移植物中进行评估（目标 1），我们将测试 RSK2 是否与他莫昔芬复合。耐药 ERα 突变体使用工程 ER+ 乳腺系驱动转移（基于 RSK 抑制剂）。将生成母体化合物 SL0101，以鉴定具有改善的体内抑制功效的化合物 ER+ 肿瘤生长和转移（目标 3）将使用以下方法进行分析。终点和纵向分析的适当统计 RSK 抑制剂的成功开发。可以显着改善 ER+ 转移性乳腺癌患者的预后。