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: 10412077
• 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/10412077
• 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，免疫切除点抑制剂（ICI）表现出令人鼓舞的 黑色素瘤治疗的成功。但是，大约40％的晚期黑色素瘤患者患有 最初反应患者的原发性ICI耐药性和亚群会发展出次要抵抗。能 我们在这些非反应者中确定可吸毒的分子途径，以提高其ICI响应性和 有可能挽救生命？我们已经进行了唯一报道的ICI治疗的蛋白质组学投资 来自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 识别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 分子途径与ICI响应性相关 - 为概述提供了科学前提 研究。这项初步研究将扩展到包括1）大量患者，2）患者 初级和继发ICI治疗耐药性，以及3）肿瘤细胞类型分析。总体目标 建议是将患者组织的最先进蛋白质组学与ICI前临床动物模型相结合 为创建功能性蛋白质组学管道的响应能力，以发现细胞蛋白和Hisstone表观遗传学 ICI非反应者黑色素瘤中功能失调的途径。我们将使用严格的策略来针对 基因转录和组蛋白修饰蛋白质，因为这些是上游途径效应子，可以是 可吸毒。我们假设某些参与基因转录和翻译后修饰的蛋白质 ICI非反应器中的组蛋白的失调，并在功能上与ICI的分子机制耦合 响应能力，这将确定这些蛋白质是高优先级，可吸毒的候选者 现有的ICI疗法。这项研究的目的是：1）执行功能蛋白质组学以识别失调的基因 黑色素瘤ICI非反应器中的转录蛋白途径，2）使用高分辨率质谱法 鉴定非反应剂中黑色素瘤中蛋白质途径的组蛋白失调，并确定3）确定 抗肿瘤对ICI治疗的抗肿瘤反应的功能意义，用于修饰基因转录和Hisstone 蛋白质中的蛋白质非反应性黑色素瘤失调。