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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：
10580032
负责人：
TODD W RIDKY
金额：
$ 41.94万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580032
关键词：
Acceleration Agonist Cessation of life Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA Damage DNA Repair DNA Sequence Alteration Data Development Diagnosis Disease Drug Targeting EP300 gene 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 Gravin 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 Phosphorylation Physiological Pregnancy Prevention strategy Proliferating Proteins Receptor Activation Receptor Signaling Risk Signal Induction 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 estrophilin exome sequencing experimental study high risk high risk population histone acetyltransferase improved in vivo male melanocyte melanoma men novel therapeutics pharmacologic 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.

项目总结：尽管黑色素瘤治疗取得了进展，但只有33%的晚期黑色素瘤患者对最有效的治疗有反应，平均生存期只有23个月。数百万人红头发或浅色皮肤的人患黑色素瘤的风险特别高。虽然战略，我们最近的发现表明，黑色素瘤的发病率可能是雌激素受体（GPER）是一种蛋白质，活性完全不同于经典雌激素受体（ERα/β）的黑素细胞。虽然目前还没有批准的靶向GPER的药物，GPER在黑素细胞中被一种选择性合成的化合物（G-1）不具有任何经典的雌激素活性。我们最近确定，体内药理学GPER激活主要通过诱导终末癌细胞的分化。我们的初步研究表明，G-1介导的GPER激活在黑素细胞中诱导长期的表观遗传变化，防止未来的黑色素瘤，同时允许皮肤黑色素细胞继续正常运作。在目的I中，我们将使用原代人类黑素细胞来确定特定的组蛋白修饰酶所需的诱导表观遗传转录记忆，保持高度状态的细胞在瞬时GPER激活后，HDAC抑制是否增强了细胞的分化， GPER激动剂的分化作用。在目标II中，我们将验证初步结果，表明GPER信号转导诱导的途径，促进DNA修复，从而最大限度地减少紫外线（UV）照射后DNA突变的积累 exposure.我们将确定GPER下游介导改善DNA的机制，损伤反应，这可能有助于突出其他治疗靶点。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是否 GPER的激活促进体内UV暴露后的DNA修复，并抑制黑素瘤发展