Epiproteomics of Sezary Syndrome

塞扎里综合征的表观蛋白质组学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 SEZARY 综合征的表蛋白组人们对外周 T 细胞淋巴瘤（包括皮肤 T 细胞淋巴瘤 (CTCL)）知之甚少，并且许多亚型表现出侵袭性临床病程和高死亡率，且预期寿命短（2 年）对 CTCL 发病机制的了解不足会导致诊断。次优的诊断亚分类和缺乏靶向治疗。综合征 (SS) 是 CTCL 的两种主要形式，并且 MF 和 SS 的结果取决于临床分期。血液中肿瘤细胞的数量，而 SS 是一种侵袭性疾病，总体生存率较差。（5 年时为 42.3%，根据定义，诊断时已处于疾病晚期，有许多患者患有低血压肿瘤负荷（早期 CTCL）由于主观性而导致诊断延迟的患者诊断标准。平均诊断延迟（以从出现皮肤病变到出现症状的时间来衡量）。 SS 诊断时间较长（4.2 年；中位 2.8 年），且差异显着（1 个月至 32 年）。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。被引入作为抗癌剂，其部分通过抑制脱乙酰化来实现其治疗效果然而，尽管包括 SS 在内的 CTCL 是第一个获得 FDA 批准的疾病。批准 HDACi 治疗后，每位患者对药物的反应明显不同。临床需求是缺乏可靠的生物标志物直接询问可以预测的组蛋白 PTM 我们最近开发了一种基于质谱 (MS) 的新策略，以实现无偏见。鉴定组蛋白 PTM 并证明其适用于分析 SS 的原始样品。重要的是，这些表蛋白质组分析研究揭示了区分 SS 的独特组蛋白 PTM 标记我们的中心假设是，表观蛋白质组修饰来自健康个体的 CD4+ T 细胞。 SS（组蛋白密码）可用于早期诊断并作为反应的预测因子因此，我们建议研究基于 MS 的表观蛋白质组学分析在早期诊断中的实用性。 SS 的诊断和 HDACi 反应的预测该提案的总体影响是建立新的表蛋白质组生物标志物，这将改善结果，特别是在侵袭性 CTCL。