Epiproteomics of Sezary Syndrome

塞扎里综合征的表观蛋白质组学

• 批准号: 10703845
• 负责人: KOJO S. J. ELENITOBA-JOHNSON
• 金额: $ 52.87万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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/10703845
• 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.

项目总结 Sezary综合征的表型 外周T细胞淋巴瘤，包括皮肤T细胞淋巴瘤(CTCL)，人们对其了解很少， 许多亚型表现出侵袭性的临床病程和高死亡率，术后预期寿命短(2年) 诊断。对CTCL发病机制的认识不足是导致CTCL发病的原因之一 次优的诊断亚类和缺乏针对性的治疗。真菌病(MF)与S 综合征(SS)是CTCL的两种主要形式。MF和SS的临床分期和预后取决于 血液中肿瘤细胞的数量。而SS是一种侵袭性疾病，总体存活率很低 (42.3%在5年，根据定义被诊断为晚期疾病，有许多患者低 肿瘤负担(早期CTCL)由于肿瘤的主观性质而延误诊断 诊断标准。平均诊断延迟(衡量的是从皮损出现到 SS的诊断)时间长(4.2年；中位数2.8年)，差异显著(1个月至32年)。这个 疾病检测的次优诊断准确率和不精确度是发展的必然 SS的定性和客观生物标志物。组蛋白脱乙酰酶抑制剂(HDACi)已被 作为抗癌剂被引入，其部分治疗效果是通过抑制 组蛋白。然而，尽管包括SS在内的CTCL是第一批接受FDA治疗的疾病 对于HDACi治疗的批准，每个患者对药物的反应明显不同。一个未被满足的人 临床需要是缺乏可靠的生物标记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的基于质谱学(MS)的无偏策略 鉴定了组蛋白PTMS，并证明了其在SS初级样品分析中的适用性。 重要的是，这些表观蛋白质组学研究揭示了区分SS的独特的组蛋白PTM标记 来自健康个体的CD4+T细胞。我们的中心假设是表观蛋白质组修饰 SS的(组蛋白密码)可用于早期诊断和作为反应的预测指标 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的应用 SS的诊断和对HDACi反应的预测。这项建议的总体影响是 建立新的表观蛋白质组生物标记物将改善预后，特别是侵袭性疾病 CTCL。