Using Nonclassical Estrogen Signaling to Prevent Melanoma

使用非经典雌激素信号传导预防黑色素瘤

基本信息

批准号：
10381619
负责人：
TODD W RIDKY
金额：
$ 42.42万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381619
关键词：
AKAP12 gene Agonist Cessation of life Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA Damage DNA Repair DNA Sequence Alteration Data Development Diagnosis Disease Drug Targeting Enzymes Epigenetic Process Estradiol Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptors Estrogens Exposure to Family history of Female Future G-Protein-Coupled Receptors GTP-Binding Proteins Gender Genetic Genetic Transcription Genetically Engineered Mouse Genome Stability Growth Hair Health Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Immunofluorescence Immunologic Immunotherapy In Vitro Incidence Ligands Light Malignant - descriptor Mass Spectrum Analysis Mediating Medical Memory Metastatic Melanoma Modeling Mus Mutagenesis Mutation Nucleotide Excision Repair Oncogenic Outcome Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Phosphorylation Physiological Pregnancy Prevention strategy Proteins Receptor Activation Receptor Signaling Risk Signal Transduction Site Skin Skin Cancer Skin Pigmentation Somatic Mutation Southwestern Blotting Sun Exposure Surgical incisions Testing Transferase UV Radiation Exposure UV induced DNA damage Withdrawal Work XPA gene advanced disease antagonist cancer cell effective therapy epigenetic memory estrogen receptor gamma estrophilin exome sequencing experimental study high risk histone acetyltransferase improved in vivo male melanocyte melanoma men novel therapeutics prevent protective effect recruit response sex skin xenograft targeted treatment therapeutic target tumor tumor progression ultraviolet

项目摘要

Project summary: Despite advances in melanoma treatment, only 33% of patients with advanced disease respond to the most effective therapy and mean survival is only 23 months. Millions of people with red hair, or light skin pigmentation have an especially high melanoma risk. Although strategies to decrease this risk are lacking, our recent discoveries suggest that melanoma incidence may be diminished by pharmacologically activating the G-Protein Estrogen Receptor (GPER), a protein on melanocytes with activity completely distinct from the classic estrogen receptor (ERα/β). Although there are no approved drugs that target GPER, GPER is activated in melanocytes by a selective synthetic compound (G-1) that does not have any classic estrogen activity. We recently determined that pharmacologic GPER activation in vivo inhibits established melanomas, largely by inducing terminal differentiation in cancer cells. Our preliminary studies now suggest that G-1 mediated GPER activation in melanocytes induces long-term epigenetic changes that prevent future melanoma, while allowing skin melanocytes to continue to function normally. In Aim I we will use primary human melanocytes to determine the specific histone modifying enzymes required for inducing epigenetic transcriptional memory that maintains a heightened state of cellular differentiation after transient GPER activation, and test whether HDAC inhibition potentiates the differentiation effects of the GPER agonist. In Aim II we will validate preliminary results suggesting that GPER signaling induces pathways that promote DNA repair, and thereby minimizes the accumulation of DNA mutations after ultraviolet (UV) exposure. We will determine the mechanism(s) downstream of GPER that mediate the improved DNA damage response, which may help highlight additional therapeutic targets. In Aim III we will use both human and mouse melanoma models to directly test whether G-1 activation of GPER promotes DNA repair after UV exposure in vivo, and inhibits melanoma development.

项目摘要：尽管黑色素瘤治疗进展，但只有33％的晚期患者疾病对最有效的疗法有反应，平均生存率仅为23个月。数百万人红头发或浅色皮肤色素沉着具有特别高的黑色素瘤风险。虽然策略降低这种风险是缺乏的，我们最近的发现表明黑色素瘤事件可能是通过药物激活G蛋白雌激素受体（GPER）的药物减少，蛋白质上的蛋白具有活性的黑素细胞与经典的雌激素受体（ERα/β）完全不同。虽然那里没有批准的药物可以通过选择性合成在黑素细胞中激活GPER的药物没有任何经典雌激素活性的化合物（G-1）。我们最近确定药物GPER在体内的激活抑制建立的黑色素瘤，主要由诱导的末端癌细胞的分化。我们的初步研究现在表明G-1介导的GPER激活在黑素细胞中，诱导长期表观遗传学变化，以防止未来黑色素瘤，同时允许皮肤黑素细胞继续正常起作用。在目的中，我将使用原代人黑色素细胞来确定特定的组蛋白修饰酶诱导表观遗传转录记忆所必需的，该记忆保持细胞状态增强瞬态GPER激活后分化，并测试HDAC抑制是否势 GPER激动剂的分化效应。在AIM II中，我们将验证初步结果，表明GPER信号会影响途径促进DNA修复，从而最大程度地减少紫外线（UV）后DNA突变的积累接触。我们将确定GPER下游的机制，该机制介导了改善的DNA 损伤反应可能有助于突出其他治疗靶标。在AIM III中，我们将使用人类和小鼠黑色素瘤模型直接测试G-1 GPER的激活可促进体内紫外线暴露后的DNA修复，并抑制黑色素瘤发展。