Identification of Druggable Targets to Complement Melanoma Therapy

摘要 从历史上看，黑色素瘤的治疗选择是有限的，5年生存率<10%， 晚期疾病患者。最近，免疫检查点抑制剂（ICI）显示出令人鼓舞的 成功治疗黑色素瘤。然而，大约40%的晚期黑素瘤患者 原发性ICI耐药和最初应答患者的亚群发展为继发性耐药。可以 我们在这些无应答者中鉴定了可药物化的分子途径，以增加他们的ICI反应性， 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 应答者和非应答者的黑素瘤活检（6）。在这项初步研究中，我们能够 鉴定了一组蛋白质和组蛋白表观遗传特征，这些特征为调节异常提供了证据。 与ICI反应相关的分子途径-为概述的 问题研究这项初步研究将扩大到包括1）更多数量的患者，2） 原发性和继发性ICI治疗抗性，和3）肿瘤细胞类型分析。这个项目的总体目标是 建议将联合收割机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 响应创建功能蛋白质组学管道，以揭示细胞蛋白质和组蛋白表观遗传 黑色素瘤ICI无应答者中功能失调的通路。我们将采取严格的战略， 基因转录和组蛋白修饰蛋白，因为这些是上游途径效应物， 可下药的我们假设某些参与基因转录和翻译后修饰的蛋白质 组蛋白的表达将在ICI无应答者中失调，并在功能上与ICI的分子机制相关联。 反应，这将确定这些蛋白质作为高优先级，可药用的候选人，以补充 现有ICI疗法。本研究的主要目的是：1）利用功能蛋白质组学技术，筛选出表达异常的基因 黑色素瘤ICI无应答者中的转录蛋白途径，2）使用高分辨率质谱， 鉴定黑色素瘤ICI无应答者中失调的组蛋白修饰蛋白途径，和3）确定 基因转录和组蛋白修饰在ICI抗肿瘤治疗中的作用 黑色素瘤ICI无应答者中失调的蛋白质。

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.