HDAC Inhibitors and CTCL

HDAC 抑制剂和 CTCL

• 批准号: 8069162
• 负责人: LOUISE C. SHOWE
• 金额: $ 39.63万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069162
• 关键词: ABCB1 gene; Allogenic; Archives; Asses; Benign; Biological Markers; Biopsy; Blood specimen; Cell Culture System; Cell Culture Techniques; Cell Line; Characteristics; Clinical; Clinical Trials; Cutaneous; Cutaneous Involvement; Dendritic Cells; Depsipeptides; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Early treatment; Formalin; Gene Expression; Gene Expression Profile; Histone Deacetylase Inhibitor; Homing; Hour; Immunohistochemistry; In Vitro; Individual; Lead; Lymphoid; Malignant Neoplasms; Microarray Analysis; Mixed Lymphocyte Culture Test; Modeling; Molecular Profiling; Monitor; Mycosis Fungoides; Non-Hodgkin' s Lymphoma; Outcome; Paraffin Embedding; Patients; Pattern; Pennsylvania; Peripheral Blood Mononuclear Cell; Phase; Population; RNA; Refractory; Relapse; Resistance; Sampling; Sezary Syndrome; Skin; Small Interfering RNA; Staging; System; T-Cell Lymphoma; T-Lymphocyte; Testing; Time; Treatment Protocols; University Hospitals; Validation; Variant; Vorinostat; Work; base; cancer cell; chemotherapy; cytokine; effective therapy; in vivo; outcome forecast; peripheral blood; public health relevance; response; skin disorder; success; treatment effect; tumor

DESCRIPTION (provided by applicant): Cutaneous T cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas of "skin-homing" T- lymphocytes. The most common forms are skin associated mycosis fungoides (MF) and Sezary syndrome (SS), an aggressive leukemic variant. Early detection and treatment are directly correlated with favorable outcome for both MF and SS. Our previous studies identified markers for diagnosis and prognosis of SS by microarray analysis of RNA from PBMC of patients and healthy controls. We have now extended these studies on a small number of patient samples to the more common MF/CTCL to obtain a disease signature in the peripheral blood to assist clinicians in distinguishing MF from benign skin diseases with which it is frequently confused with good success. We expect the PBMC profiles will provide a non-invasive approach to monitoring disease progression and response to therapy. This preliminary PBMC signature must be confirmed using a greater number of patient samples. We will use the PBMC signatures for MF and SS to examine the mechanism of action of the HDAC inhibitor (HDCAIs), depsipeptide (DP), which has shown remarkably efficacy in CTCL treatment, in particular the treatment of highly refractory patients with limited options. We will use four parallel approaches based mainly on gene-expression microarrays. 1) We will develop biomarkers for MF patients, as we have done for SS, that will be used for diagnosis, prognosis, and responsiveness to therapy. We will profile heavily infiltrated plaque and tumor samples from formalin fixed paraffin embedded (FFPE) CTCL samples using the Illumina DASL system and in a complimentary study we will asses profiles in PBMC. 2) Gene expression profiles in PBMCs from patients in DP Phase II/III clinical trials will be assessed pre and post therapy and gene expression profiles used to determine whether markers for responsiveness are present pre-therapy and/or post-therapy and evaluate changes that occur during progressive treatments over a period of 4-6 months. 3) We will augment the in vivo studies with in vitro treatments of patient and control PBMC to study the effects of treatment on the malignant cells and the normal lymphoid populations, in particular the dendritic cells. Finally, 4) HDACI resistant CTCL cell lines will be used to develop models to study HDACI resistance. We present promisin preliminary results from DP clinical trials and in vitro studies. PUBLIC HEALTH RELEVANCE: CTCL is a cancer with many treatments but no cures. The proposed studies examine how a new and effective treatment for CTCL works in samples from patients in clinical trials and in studies in cell culture systems. Based on our preliminary studies we propose to develop tests that will identify those patients that will respond to therapy (approximately 35%) and those that will not before therapy is initiated. Understanding the characteristics that define why one patient responds and another patient does not, can lead to the identification of ways to convert the non-responsive patients to responsive ones.

描述(申请人提供)：皮肤T细胞淋巴瘤(CTCL)是一组异质性的非霍奇金淋巴瘤的“皮肤归巢”T淋巴细胞。最常见的形式是皮肤相关性真菌样肉芽肿(MF)和Sezary综合征(SS)，这是一种侵袭性白血病变体。早期发现和治疗直接关系到MF和SS的良好预后。我们以前的研究通过对患者和健康对照的PBMC中的RNA进行微阵列分析，确定了SS的诊断和预后标志物。我们现在已经将这些研究扩展到更常见的MF/CTCL患者样本，以获得外周血中的疾病特征，以帮助临床医生区分MF和良性皮肤病，后者经常被混淆为良好的成功。我们期望PBMC图谱将提供一种非侵入性的方法来监测疾病进展和治疗反应。这一初步的PBMC签名必须使用更多的患者样本进行确认。我们将使用MF和SS的PBMC信号来研究HDAC抑制剂(HDCAIs)的作用机制，DP在CTCL治疗中显示出显著的疗效，特别是在治疗选择有限的高度难治性患者方面。我们将使用四种主要基于基因表达微阵列的并行方法。1)我们将为MF患者开发生物标志物，就像我们为SS所做的那样，这些生物标志物将用于诊断、预后和治疗反应。我们将使用Illumina DASL系统分析来自福尔马林固定石蜡包埋(FFPE)CTCL样本的重度浸润性斑块和肿瘤样本，并在一项免费研究中评估PBMC中的样本。2)DP II/III期临床试验患者的PBMC的基因表达谱将在治疗前和治疗后进行评估，基因表达谱将用于确定治疗前和/或治疗后是否存在反应性标记，并评估在4-6个月的渐进治疗期间发生的变化。3)我们将通过体外处理患者和对照PBMC来加强体内研究，以研究处理对恶性细胞和正常淋巴组织，特别是树突状细胞的影响。最后，将利用耐HDACi的CTCL细胞株来建立研究HDACi抗性的模型。我们介绍了来自DP临床试验和体外研究的初步结果。与公共卫生相关：CTCL是一种癌症，有许多治疗方法，但没有治愈方法。拟议的研究检验了一种新的有效治疗CTCL的方法在临床试验和细胞培养系统研究中的患者样本中是如何起作用的。根据我们的初步研究，我们建议开发测试，以确定那些在治疗开始前对治疗有反应的患者(约35%)和那些不会有反应的患者。了解定义为什么一个患者有反应而另一个患者没有反应的特征，可以导致确定将无反应的患者转变为有反应的患者的方法。