Partial Agonists at Estrogen Receptor alpha for Breast Cancer Therapy

用于乳腺癌治疗的雌激素受体α部分激动剂

基本信息

批准号：
9251781
负责人：
Gregory R. J Thatcher
金额：
$ 47.43万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-06 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251781
关键词：
Adverse effects Affinity Agonist Androgen Receptor Animal Model Animals Apoptosis Benchmarking Binding Biological Assay Biological Availability Breast Breast Cancer Cell Breast Cancer Treatment Breast Cancer therapy Breast Epithelial Cells Cell Line Cell Survival Cells Chemicals Chemistry Chemoprevention Clinical Collection Computer-Aided Design Computing Methodologies Data Data Correlations Development Diethylstilbestrol Drug Targeting Endometrial Endometrial Carcinoma Endometrium Estradiol Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptor Status Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Europe Exposure to Female Fluorescence Resonance Energy Transfer Future Generations Genes Growth Gynecology Human In Vitro Indoles Lead Libraries Ligand Binding Domain Ligands Link Liver Microsomes MCF7 cell MDA MB 231 Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Measurement Measures Messenger RNA Metabolism NCOA3 gene Oral PRKCA gene Parents Patients Pharmaceutical Preparations Pharmacology Phenotype Plasma Postmenopausal Osteoporosis Progesterone Receptors Proteins Proteomics Pyrazoles Raloxifene Reporter Resistance Resistance development Risk Safety Selective Estrogen Receptor Modulators Structure T47D TFF1 gene Tamoxifen Testing Therapeutic Therapeutic Agents Therapeutic Index Tissues Transcription Factor AP-1 Uterus Validation Woman Women&apos s Health Xenograft Model Xenograft procedure base benzothiophene bone cancer risk chemotherapy counterscreen design drug development drug metabolism effective therapy epidemiology study estrogenic exhaustion experience improved in vivo in vivo Model iterative design lead series malignant breast neoplasm mortality neglect novel novel therapeutics oncology outcome forecast overexpression personalized medicine prototype public health relevance radioligand receptor receptor function response scaffold screening small molecule standard of care success survivin three dimensional cell culture tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The estrogen receptor (ER) is a drug target that has been exploited clinically by selective estrogen receptor modulators (SERMs) that antagonize estrogenic effects in breast tissue and act as agonists in bone. The proto- type of the SERM drug class, tamoxifen (TAM) has for 3 decades been the standard of care in breast cancer therapy, although agonist activity in the uterus increases risk of endometrial cancer. Conversely, the therapeutic potential of ERa agonists has not been explored or exploited. Up to 80% of breast cancers are ER+, in which estradiol (E2) fuels tumor growth. Of these, 30-50% are unresponsive to TAM or develop resistance, leaving few treatment options. Paradoxically, prior to the introduction of TAM, both E2 and the ER agonist diethylstilbestrol achieved success in the treatment of breast cancer, but with unacceptable side effects, including agonist activity in breast and uterus. A partial agonist at ERa without estrogenic actions in normal gynecological tissues, but with the ability to regress TAM-resistant cancers is a compelling concept, validated by us in 2 animal models with 2 small molecules. The assembled team at UI, Greg Thatcher, John Katzenellenbogen, Terry Moore, and Deb Tonetti has all assays and chemistry in place to achieve the proposed aims: Aim 1. A library of ~350 com- pounds consisting of 4 lead series will be completed and screened using a FRET assay for SRC3 co-activator binding to ERa and ERß. The ER interaction with co-activator is seen as the minimal predictor of phenotype. Radioligand displacement for ER represents a secondary, confirmatory assay. Partial agonists at ERa with agonist/inactive responses at ERß will be obtained and iteratively optimized using data from Aim 2 to provide SAR development for computer-aided design. Aim 2. Selected ERa agonists from FRET screening will be studied using reporter assays in endogenous ERa (MCF-7; T47D) and in ERß (ß43) mammary epithelial cells and endometrial cells to reveal potency, and agonist/antagonist pharmacology. Partial agonists will be further studied using PCR measurement of ERE, AP-1, and Sp1-sensitive genes. The primary phenotypic assay is apoptosis of TAM-resistant MCF7-5C cells. Counterscreens are proliferation of parent MCF7-5C and T47D cell lines. Aim 3. Drug metabolism in liver microsomes, multiplex CYP-inhibition, and oral plasma bioavailability will be used to refine ERa partial agonists as chemical probes. Our extensive experience with SERM metabolism and use of oral delivery in all preliminary data gives confidence in this approach. DMPK studies will provide final selection for animal studies. Three different TAM-resistant xenograft models will be used to test chemical probes and to determine therapeutic index for tumor regression. Safety will be predicted by uterine growth and parallel study of growth of estrogen-dependent T47D xenografts. Supportive mechanism of action studies are limited to ERa localization and target selectivity proteomics. Completion of these Aims will provide chemical probes to study the potential of novel partial agonists and allosteric modulators of ER function, and provide lead compounds for future testing in patient-derived xenografts of PKCa-overexpressing tumors as a prelude to drug development.

描述（由申请人提供）：雌激素受体（ER）是一种药物靶标，已在临床上通过选择性雌激素受体调节剂（SERM）进行开发，该调节剂可拮抗乳腺组织中的雌激素作用并充当骨中 SERM 药物类别的激动剂（他莫昔芬）。 3 年来，TAM 一直是乳腺癌治疗的标准，尽管子宫内的激动剂活性会增加子宫内膜癌的风险。 ERa 激动剂的治疗潜力尚未得到探索或开发，高达 80% 的乳腺癌属于 ER+，其中雌二醇 (E2) 会促进肿瘤生长，其中 30-50% 对 TAM 无反应或产生耐药性，因此治疗方法很少。矛盾的是，在引入 TAM 之前，E2 和 ER 激动剂己烯雌酚在治疗乳腺癌方面都取得了成功，但也有令人无法接受的副作用。 ERa 的部分激动剂在正常妇科组织中没有雌激素作用，但具有消退 TAM 耐药性癌症的能力，这是一个引人注目的概念，我们在 2 个动物模型中使用 2 个小分子进行了验证。 UI 的 Greg Thatcher、John Katzenellenbogen、Terry Moore 和 Deb Tonetti 组成的团队已准备好所有分析和化学方法来实现拟议的目标：目标 1. 一个包含以下内容的库：将完成由 4 个先导系列组成的约 350 种化合物，并使用 FRET 测定来筛选与 ERa 和 ERß 结合的 SRC3 共激活剂。 ER 与共激活剂的相互作用被视为 ER 表型的最小预测因子。表示将获得 ERa 的部分激动剂和 ERß 的激动剂/非活性反应，并使用 Aim 2 的数据进行迭代优化，以提供 SAR。目标 2. 将从 FRET 筛选中选择的 ERa 激动剂在内源性 ERa (MCF-7; T47D) 和 ERß (ß43) 乳腺上皮细胞和子宫内膜细胞中使用报告基因检测进行研究，以揭示其效力和激动剂。 /拮抗剂药理学将使用ERE、AP-1和Sp1敏感基因的PCR测量来进一步研究。表型测定是 TAM 抗性 MCF7-5C 细胞的凋亡。反筛选是母代 MCF7-5C 和 T47D 细胞系的增殖。目标 3。肝微粒体中的药物代谢、多重 CYP 抑制和口服血浆生物利用度将用于改进 ERa。我们在 SERM 代谢和所有初步数据中使用口服给药方面的丰富经验使我们对这种方法充满信心，将为动物提供最终选择。三种不同的 TAM 抗性异种移植模型将用于测试化学探针并通过子宫生长和雌激素依赖性 T47D 异种移植的支持机制研究来预测安全性。仅限于 ERa 定位和靶点选择性蛋白质组学。完成这些目标将为研究 ER 功能的新型部分激动剂和变构调节剂的潜力提供化学探针，并提供先导。化合物用于未来在患者来源的 PKCa 过表达肿瘤异种移植物中进行测试，作为药物开发的前奏。