Small molecule GPR10 antagonists for the treatment of uterine fibroids

小分子 GPR10 拮抗剂治疗子宫肌瘤

基本信息

批准号：
9759969
负责人：
Vargheese Mani Chennathukuzhi
金额：
$ 30.2万
依托单位：
UNIVERSITY OF KANSAS 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：
2018-08-08 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759969
关键词：
Affect Age Benign Brain Cell Proliferation Cells Chromosomal translocation Clinical Data Development Environmental Risk Factor Epigenetic Process Event FRAP1 gene Fertility Fibroid Tumor G-Protein-Coupled Receptors Gene Expression Genes Genetic Genetic Models Genome Stability Goals Growth Heterogeneity Hormones Human Hypothalamic structure Hysterectomy In Vitro Knowledge Laboratories Lead Leiomyoma Ligands Link Medical Genetics Methods Molecular Molecular Target Morbidity - disease rate Mutate Mutation Nature Neurons PI3K/AKT Pathogenesis Pathway interactions Pelvic Neoplasms Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phenotype Pituitary Gland Play Pre-Clinical Model Preclinical Testing Proteins Proto-Oncogene Proteins c-akt Quality of life Repressor Proteins Research Rest Role Safety Signal Pathway Signal Transduction Smooth Muscle Myocytes Stress Structure-Activity Relationship Testing Tissues Transgenic Organisms Transplantation Tumor Burden Tumor Suppressor Proteins United States Uterine Fibroids Uterus Validation Woman Xenograft procedure burden of illness cell growth cost drug discovery efficacy testing experience functional loss in vivo malignant breast neoplasm mouse model mutant mutational status myometrium neoplastic cell novel overexpression peptidomimetics premature preservation prolactin-releasing peptide reproductive small molecule therapeutic target therapy development transcription factor tumor tumor growth tumor heterogeneity

项目摘要

PROJECT SUMMARY/ABSTRACT Uterine fibroids (UL, uterine leiomyomas) are benign smooth muscle cell (SMC) tumors of the myometrium. Leiomyomas represent the most frequent clinical indication for hysterectomy that often prematurely ends a woman's fertility. In the year 2010, the estimated annual cost of uterine fibroid tumors in the United States was up to $34.4 billion. Yet in spite of this, there are currently no approved drugs that can provide effective, long-term treatment for UL. There is an unmet need to identify molecular targets and to develop therapies to treat uterine fibroids. The goal of our research is to understand the molecular pathogenesis of uterine UL so that effective pharmacotherapies could be developed. Dysregulated PI3K/AKT pathway leading to the activation of mTOR play an essential role in the pathogenesis of leiomyomas. Our preliminary data suggest that GPR10, a GPCR normally silenced in the periphery by the tumor suppressor REST/ NRSF, is near ubiquitously over-expressed human leiomyomas, which harbor a very high degree of heterogeneity in other markers. Further, REST protein is dramatically reduced in leiomyomas. Crucial to the current project, the activation of GPR10, or the loss of REST triggers PI3K/AKT signaling and tumor cell proliferation. We hypothesize that the loss of REST leads to GPR10 expression in leiomyomas and this aberrant gene expression functionally promotes cell proliferation contributing to the pathogenesis of uterine fibroids. The current project will establish the functional role that REST-GPR10-AKT-mTOR pathway has on the pathogenesis of uterine fibroids using in vitro methods and novel in vivo genetic models. Additionally, the project will identify, conduct structure activity relationship (SAR) studies, and pre-clinically test, small molecule GPR10 antagonists as potential treatments for UL.

项目概要/摘要子宫肌瘤（UL，子宫肌瘤）是良性平滑肌细胞 (SMC) 肿瘤子宫肌层。平滑肌瘤是子宫切除术最常见的临床指征，通常过早终止女性的生育能力。 2010 年，子宫肌瘤每年的费用估计为美国高达344亿美元。尽管如此，目前还没有批准的药物可以为 UL 提供有效、长期的治疗。识别分子靶点和开发治疗子宫肌瘤的疗法。我们研究的目标是了解分子子宫肌瘤的发病机制，以便开发有效的药物疗法。 PI3K/AKT 失调导致 mTOR 激活的途径在平滑肌瘤的发病机制中发挥着重要作用。我们的初步数据表明 GPR10，一种通常在外周被肿瘤抑制因子沉默的 GPCR REST/NRSF，是几乎无处不在的过度表达的人类平滑肌瘤，其具有非常高的水平其他标记的异质性。此外，平滑肌瘤中的 REST 蛋白显着减少。对目前的项目中，GPR10的激活或REST的缺失会触发PI3K/AKT信号传导和肿瘤细胞增殖。我们假设 REST 的缺失导致平滑肌瘤中 GPR10 的表达，这异常的基因表达功能性地促进细胞增殖，从而导致子宫肌瘤的发病机制肌瘤。当前的项目将确定 REST-GPR10-AKT-mTOR 通路的功能作用使用体外方法和新颖的体内遗传模型研究子宫肌瘤的发病机制。此外，项目将识别、进行结构活性关系（SAR）研究并进行临床前测试，小分子 GPR10 拮抗剂作为 UL 的潜在治疗方法。