Identification of Druggable Targets to Complement Melanoma Therapy

确定可补充黑色素瘤治疗的药物靶点

• 批准号: 10630160
• 负责人: Alan Tackett
• 金额: $ 34.1万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630160
• 关键词: Animal Model; Antitumor Response; Autoimmunity; Bioinformatics; Biology; Biometry; Biopsy; CTLA4 gene; Centers of Research Excellence; Combined Modality Therapy; Complement; Coupled; Cutaneous; Data Analyses; Dermatopathology; Disease; Drug Design; Epigenetic Process; Genetic Transcription; Goals; Histones; Homeostasis; Immune checkpoint inhibitor; Immune system; Immunotherapy; Intelligence; Investigation; Laboratories; Malignant Neoplasms; Mass Spectrum Analysis; Molecular; Monoclonal Antibodies; Nivolumab; Oncology; Operative Surgical Procedures; Pathway interactions; Patients; Positioning Attribute; Post-Translational Protein Processing; Proteins; Proteomics; Reporting; Resistance; Resolution; Resources; Survival Rate; Systems Biology; Tissues; United States National Institutes of Health; cell type; checkpoint therapy; computer cluster; druggable target; histone modification; ipilimumab; mass spectrometer; melanoma; neoplastic cell; patient response; patient subsets; pembrolizumab; pre-clinical; prevent; programmed cell death protein 1; relapse patients; responders and non-responders; response; standard of care; success; tumor immunology

Abstract Historically, treatment options for melanoma were limited, and 5-year survival rates were <10% for patients with advanced-stage disease. Recently, immune checkpoint inhibitors (ICIs) have shown encouraging success for treatment of melanoma. However, approximately 40% of patients with advanced melanoma have primary ICI resistance and sub-populations of initially responding patients develop secondary resistance. Can we identify druggable molecular pathways in these non-responders to increase their ICI responsiveness and potentially save lives? We have performed the only reported proteomics investigation of pre-ICI treatment melanoma biopsies from responders and non-responders (6). In this preliminary study, we were able to identify a panel of protein and histone epigenetic signatures that provided evidence for dysregulated molecular pathways correlated to ICI responsiveness – providing the scientific premise for the outlined studies. This preliminary study will be expanded to include 1) a larger number of patients, 2) patients with primary and secondary ICI therapy resistance, and 3) tumor cell-type analyses. The overall goal of this proposal is to combine state-of-the-art proteomics of patient tissues with pre-clinical animal models of ICI responsiveness to create a functional proteomics pipeline for uncovering cellular protein and histone epigenetic pathways functionally dysregulated in melanoma ICI non-responders. We will use a rigorous strategy to target gene transcription and histone modifying proteins as these are upstream pathway effectors that can be druggable. We hypothesize that certain proteins involved in gene transcription and posttranslational modification of histones will be dysregulated in ICI non-responders and functionally coupled to molecular mechanisms of ICI responsiveness, which will identify these proteins as high-priority, druggable candidates for complementing existing ICI therapy. The aims of this study are: 1) perform functional proteomics to identify dysregulated gene transcription protein pathways in melanoma ICI non-responders, 2) use high-resolution mass spectrometry to identify dysregulated histone modifying protein pathways in melanoma ICI non-responders, and 3) determine the functional significance in antitumor responses to ICI therapy for gene transcription and histone modifying proteins dysregulated in melanoma ICI non-responders.

摘要 从历史上看，黑色素瘤的治疗选择有限，5年存活率为10%。 患有晚期疾病的患者。最近，免疫检查点抑制剂(ICIS)显示出令人鼓舞的迹象 治疗黑色素瘤取得成功。然而，大约40%的晚期黑色素瘤患者 原发ICI耐药和初始应答患者的亚群发展为继发性耐药。能 我们在这些无反应者中识别可用药的分子通路，以增加他们的ICI反应性和 有可能拯救生命吗？我们进行了唯一报道的ICI前治疗的蛋白质组学研究。 黑色素瘤活检来自应答者和无应答者(6)。在这项初步研究中，我们能够 确定一组蛋白质和组蛋白表观遗传学特征，这些特征提供了失调的证据 与ICI反应性相关的分子途径--为概述 学习。这项初步研究将扩大到包括1)更多的患者，2)患有 原发和继发ICI治疗耐药性，以及3)肿瘤细胞类型分析。这个项目的总体目标是 建议将患者组织的最新蛋白质组学与ICI的临床前动物模型相结合 创建用于揭示细胞蛋白和组蛋白表观遗传学的功能蛋白质组学管道的响应性 黑色素瘤ICI无反应者的通路功能失调。我们将使用严格的战略来瞄准 基因转录和组蛋白修饰蛋白，因为它们是上游途径效应器，可以 可下药的。我们假设某些蛋白质参与了基因转录和翻译后修饰 在ICI无反应者中组蛋白的表达将失调，并在功能上与ICI的分子机制相偶联 响应性，这将确定这些蛋白质作为补充的高优先级、可用药的候选 现有的ICI疗法。本研究的目的是：1)进行功能蛋白质组学研究，以确定失调基因 黑色素瘤ICI无反应者的转录蛋白途径，2)使用高分辨率质谱仪 确定黑色素瘤ICI无反应者中失调的组蛋白修饰蛋白通路，以及3)确定 基因转录和组蛋白修饰在ICI抗肿瘤反应中的功能意义 黑色素瘤ICI无反应者的蛋白质调节失调。