Epiproteomics of Sezary Syndrome

塞扎里综合征的表观蛋白质组学

• 批准号: 10406932
• 负责人: KOJO S. J. ELENITOBA-JOHNSON
• 金额: $ 13.46万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406932
• 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; biomarker signature; cohort; diagnostic accuracy; diagnostic biomarker; diagnostic criteria; diagnostic tool; improved; improved outcome; indexing; innovation; mortality; neoplastic cell; novel; patient response; predict responsiveness; predicting response; predictive marker; response; skin lesion; targeted treatment; 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 SEZARY综合征的肾上腺素 外周T细胞淋巴瘤，包括皮肤T细胞淋巴瘤（CTCL）了解甚少， 许多亚型表现出侵略性的临床过程和高死亡率， 诊断.对CTCL发病机制的认识不足有助于 次优诊断亚分类和缺乏靶向治疗。蕈样肉芽肿（MF）和Sézary 综合征（SS）是CTCL两种主要形式。MF和SS的临床分期和结局取决于 血液中肿瘤细胞的数量虽然SS是一种侵袭性疾病， (42.3%，并且根据定义在晚期疾病时被诊断，有许多患者具有低 肿瘤负荷（早期CTCL），由于主观性质而导致诊断延迟。 诊断标准平均诊断延迟（测量为从皮肤病变出现到 诊断为SS）的时间较长（4.2年;中位数2.8年），具有显著变化（1个月至32年）。的 次优的诊断准确性和疾病检测的不精确性需要开发 SS的定性和客观生物标志物。组蛋白去乙酰化酶抑制剂（HDACi）已被广泛应用于临床。 作为抗癌剂引入，其部分地通过抑制 组蛋白然而，尽管包括SS在内的CTCL是第一批获得FDA批准的疾病， 在批准HDACi治疗后，每个患者对药物的反应是显著可变的。未满足的 临床需要的是缺乏可靠的生物标志物直接询问组蛋白PTM， 对药物的反应。我们最近开发了一种新的基于质谱（MS）的无偏策略， 鉴定组蛋白PTM，并证明其适用于SS的主要样品的分析。 重要的是，这些表观蛋白质组学分析研究揭示了区别SS的独特组蛋白PTM标记， 来自健康个体的CD 4 + T细胞。我们的中心假设是，表观蛋白质组修饰 (the组蛋白编码）可用于SS的早期诊断，并作为对 HDACi。因此，我们建议研究基于MS的表观蛋白质组学分析在早期癌症中的应用。 诊断SS和预测对HDACi的反应。这一提议的总体影响是， 建立新的表观蛋白质组学生物标志物，将改善预后，特别是在侵袭性 CTCL。