HDAC Inhibitors and CTCL

项目说明 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S综合征(SS)， 一种侵袭性白血病变种。早期发现和治疗与预后良好直接相关。 MF和SS都是。我们以前的研究通过基因芯片确定了SS的诊断和预后的标志物 患者和健康人外周血单个核细胞RNA分析。我们现在已经将这些研究扩展到一个小的 患者样本的数量要到更常见的MF/CTCL才能在外周血中获得疾病征兆 协助临床医生区分恶性皮肤病和良性皮肤病，而良性皮肤病常常与良性皮肤病混淆 成功。我们希望PBMC图谱将提供一种非侵入性的方法来监测疾病的进展 对治疗的反应。这种初步的PBMC签名必须使用更多的患者进行确认 样本。我们将使用MF和SS的PBMC签名来检查HDAC的作用机制 抑制剂(HDCAIs)，去脂肽(DP)，在CTCL治疗中显示出显著的疗效，特别是 治疗选择有限的高顽固性患者。我们将使用四种并行方法，主要基于 基因表达微阵列。1)我们将为MF患者开发生物标记物，就像我们为SS所做的那样，这将 用于诊断、预后和治疗反应。我们将分析严重渗入的斑块和 使用Illumina DASL系统的福尔马林固定石蜡包埋(FFPE)CTCL样本中的肿瘤样本 在一项免费研究中，我们将评估PBMC中的个人资料。2)患者外周血单核细胞基因表达谱 在DP期II/III临床试验中，将评估治疗前和治疗后以及用于 确定治疗前和/或治疗后是否存在反应性标志物，并评估 在4-6个月的渐进性治疗期间发生的变化。3)我们将增强体内的 用患者和对照外周血单核细胞体外处理研究治疗对恶性肿瘤的影响 细胞和正常淋巴组织，特别是树突状细胞。4)抗HDACi CTCL 细胞系将被用来开发研究HDACi抗性的模型。我们提出了有希望的初步结果 来自DP临床试验和体外研究。

Project Description 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 S¿zary 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 promising preliminary results from DP clinical trials and in vitro studies.