Epiproteomics of Sezary Syndrome

塞扎里综合征的表观蛋白质组学

• 批准号: 10031052
• 负责人: KOJO S. J. ELENITOBA-JOHNSON
• 金额: $ 61.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10031052
• 关键词: Address; Aggressive Clinical Course; Antineoplastic Agents; Behavior; Biological Assay; Biological Markers; Biological Process; Blood; CD4 Positive T Lymphocytes; CLIA certified; Chemicals; Clinical; Cutaneous T-cell lymphoma; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Exhibits; Flow Cytometry; Gene Expression; Goals; Histone Code; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Individual; Indolent; Laboratories; Learning; Life Expectancy; Lymphoid; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Modeling; Modification; Mycosis Fungoides; Nature; Neoplasm Circulating Cells; Outcome; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Prospective cohort; Resources; Retrospective cohort; Sampling; Sezary Syndrome; Skin; Skin Cancer; Staging; T-Cell Lymphoma; Testing; Therapeutic Effect; Time; Tumor Burden; Validation; Variant; accurate diagnosis; base; cohort; diagnostic accuracy; diagnostic biomarker; improved; improved outcome; indexing; innovation; mortality; neoplastic cell; novel; patient response; predicting response; predictive marker; response; skin lesion; targeted treatment; tool; treatment response

PROJECT SUMMARY EPIPROTEOME OF SEZARY SYNDROME Peripheral T-cell lymphomas including cutaneous T-cell lymphomas (CTCL) are poorly understood and many subtypes exhibit aggressive clinical course and high mortality with short (2-year) life expectancy after diagnosis. Poor understanding of mechanisms underlying the pathogenesis of CTCLs contributes to suboptimal diagnostic subcategorization and lack of targeted therapies. Mycosis fungoides (MF) and Sézary syndrome (SS) are two major forms of CTCL. Clinical staging and outcome of MF and SS is dependent on the quantity of neoplastic cells in the blood. While SS is an aggressive disease with poor overall survival (42.3% at 5 years and is by definition diagnosed at late stage disease, there are many patients with low tumor burden (Early-stage CTCL) who suffer from delay in diagnosis due to the subjective nature of the diagnostic criteria. The mean diagnostic delay (measured as the time from emergence of skin lesions to the diagnosis of SS) is long (4.2 year; median 2.8 years) with a significant variation (1 month to 32 years). The suboptimal diagnostic accuracy and imprecision of disease detection necessitates the development of qualitative and objective biomarkers of SS. Histone deacetylase inhibitors (HDACi) have been introduced as anti- cancer agents which achieve their therapeutic effect in part by inhibiting deacetylation of histones. However, despite the fact that CTCLs including SS were the first diseases which received FDA approval for treatment with HDACi, responses to the drugs in each patient are markedly variable. An unmet clinical need is the absence of reliable biomarkers directly interrogating the histone PTMs that can predict response to the drugs. We recently developed a novel mass spectrometry (MS)-based strategy for unbiased identification of histone PTMs and demonstrated its applicability for the analysis of primary samples of SS. Importantly, these epiproteomic profiling studies reveal distinctive histone PTM marks that distinguish SS from CD4+ T-cells from healthy individuals. It is our central hypothesis that epiproteomic modifications (the histone code) of SS can be utilized for the early diagnosis and as predictors of response to HDACi. Accordingly, we propose to investigate the utility of MS-based epiproteomic profiling for the early diagnosis of SS and for the prediction of response to HDACi. The overall impact of this proposal is the establishment of novel epiproteomic biomarkers that will improve outcomes particularly in aggressive CTCLs.

项目摘要 发作综合征的附生组 包括皮肤T细胞淋巴瘤（CTCL）的外周T细胞淋巴瘤知之甚少，并且 许多亚型暴露了积极进取的临床课程和高死亡率，较短（2年）的预期寿命 诊断。对CTCL发病机理的基础机制的不良理解有助于 次级诊断亚分类和缺乏靶向疗法。真菌病真菌（MF）和Sézary 综合征（SS）是CTCL的两种主要形式。 MF和SS的临床分期和结果取决于 血液中肿瘤细胞的数量。虽然SS是一种侵略性疾病，总生存率较差 （在5年时为42.3％，根据定义在晚期疾病处被诊断出，许多患者有很多 肿瘤负担（早期CTCL）因主题性质而受到诊断延迟 诊断标准。平均诊断延迟（以皮肤病变的出现到 SS的诊断为长（4。2年；中位2。8年），其差异很大（1个月至32年）。这 必要 SS的定性和客观生物标志物。组蛋白脱乙酰基酶抑制剂（HDACI）已经 作为抗癌剂引入，通过抑制脱乙酰化的部分来达到其治疗作用 希腊。但是，尽管包括包括SS在内的CTCL是接受FDA的第一批疾病 用HDACI治疗的批准，每位患者中对药物的反应是明显变化的。一个未满足的 临床需求是没有可靠的生物标志物直接询问可以预测的组蛋白PTM 对药物的反应。我们最近开发了一种新型的质谱法（MS）的公正策略 鉴定组蛋白PTM，并证明了其适用于分析SS的主要样品的适用性。 重要的是，这些附生蛋白质组织研究揭示了区分SS的独特组蛋白PTM标记 来自健康个体的CD4+ T细胞。我们的核心假设是增生蛋白质组学修饰 （组蛋白代码）SS可以用于早期诊断，并作为对 hdaci。根据，我们建议研究早期基于MS基于MS的表现型分析的实用性 SS的诊断和预测对HDACI的反应。该提议的总体影响是 建立新型的表现蛋白质组学生物标志物，这些标志物将改善结果，特别是在侵略性方面 CTCL。