HDAC Inhibitors and CTCL

描述（由申请人提供）：皮肤T细胞淋巴瘤（CTCL）是一种异质性的非霍奇金淋巴瘤，“皮肤归巢”T淋巴细胞。最常见的形式是皮肤相关真菌病（MF）和Sezary综合征（SS），一种侵袭性白血病变体。早期发现和治疗与MF和SS的良好预后直接相关。我们之前的研究通过对患者和健康对照者PBMC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少数患者样本中，以获得更常见的MF/CTCL外周血中的疾病特征，以帮助临床医生区分MF与良性皮肤病，后者经常被混淆，但取得了良好的成功。我们期望PBMC概况将提供一种非侵入性的方法来监测疾病进展和对治疗的反应。这个初步的PBMC特征必须用更多的患者样本来证实。我们将使用MF和SS的PBMC特征来检查HDAC抑制剂（HDCAIs），抑郁肽（DP）的作用机制，该抑制剂在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时。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，用于诊断、预后和对治疗的反应性。我们将使用Illumina DASL系统分析福尔马林固定石蜡包埋（FFPE） CTCL样本中严重浸润的斑块和肿瘤样本，并在一项补充研究中评估PBMC的剖面。2) DP II/III期临床试验患者的pbmc基因表达谱将在治疗前和治疗后进行评估，基因表达谱用于确定治疗前和/或治疗后是否存在反应性标志物，并评估在4-6个月的进行性治疗期间发生的变化。3)我们将在体内研究的基础上，结合患者和对照PBMC的体外治疗，研究治疗对恶性细胞和正常淋巴细胞群，特别是树突状细胞的影响。最后，利用HDACI耐药CTCL细胞系建立HDACI耐药模型。我们从DP临床试验和体外研究中提出了令人满意的初步结果。公共卫生相关性：CTCL是一种有多种治疗方法但无法治愈的癌症。拟议的研究考察了CTCL的一种新的有效治疗方法如何在临床试验和细胞培养系统研究中从患者样本中起作用。根据我们的初步研究，我们建议开发一种测试方法，在开始治疗之前识别出那些对治疗有反应的患者（约35%）和那些没有反应的患者。了解决定为什么一个病人有反应而另一个病人没有反应的特征，可以使我们找到将无反应的病人转变为有反应的病人的方法。

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.