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: 10163815
• 负责人: Alan Tackett
• 金额: $ 34.79万
• 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/10163815
• 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; Immunological Models; Immunotherapy; Intelligence; Investigation; Laboratories; 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.

抽象的 从历史上看，黑色素瘤的治疗选择有限，5 年生存率 <10% 患有晚期疾病的患者。最近，免疫检查点抑制剂（ICIs）显示出令人鼓舞的效果 黑色素瘤治疗取得成功。然而，大约 40% 的晚期黑色素瘤患者患有 原发性 ICI 耐药性和最初有反应的患者亚群出现继发性耐药性。能 我们在这些无反应者中确定了可药物分子途径，以提高他们的 ICI 反应性 有可能挽救生命吗？我们对 ICI 前治疗进行了唯一报道的蛋白质组学研究 来自有反应者和无反应者的黑色素瘤活检 (6)。在这项初步研究中，我们能够 鉴定一组蛋白质和组蛋白表观遗传特征，为失调提供证据 与 ICI 反应相关的分子途径——为概述提供科学前提 研究。这项初步研究将扩大到包括 1) 更多的患者，2) 患有以下疾病的患者 主要和继发性 ICI 治疗耐药性，以及 3) 肿瘤细胞类型分析。本次活动的总体目标 提议是将最先进的患者组织蛋白质组学与 ICI 临床前动物模型相结合 创建功能性蛋白质组学管道以揭示细胞蛋白质和组蛋白表观遗传的响应能力 黑色素瘤 ICI 无反应者的通路功能失调。我们将用严格的策略来瞄准 基因转录和组蛋白修饰蛋白，因为这些是上游途径效应子，可以 可下药的。我们假设某些蛋白质参与基因转录和翻译后修饰 组蛋白在 ICI 无反应者中失调，并在功能上与 ICI 的分子机制耦合 反应性，这将把这些蛋白质识别为高优先级、可药物候选的补充 现有的 ICI 疗法。本研究的目的是：1）进行功能蛋白质组学来识别失调基因 黑色素瘤 ICI 无反应者中的转录蛋白途径，2) 使用高分辨率质谱法 识别黑色素瘤 ICI 无反应者中失调的组蛋白修饰蛋白通路，以及 3) 确定 ICI 疗法对基因转录和组蛋白修饰的抗肿瘤反应的功能意义 黑色素瘤 ICI 无反应者中蛋白质失调。