HDAC Inhibitors and CTCL

描述（由申请人提供）：皮肤T细胞淋巴瘤（CTCL）是一组异质性的“皮肤归巢”T淋巴细胞非霍奇金淋巴瘤。最常见的形式是皮肤相关蕈样肉芽肿（MF）和塞扎里综合征（SS），一种侵袭性白血病变体。早期发现和治疗与MF和SS的良好结局直接相关。我们以前的研究通过对患者和健康对照者PBMC的RNA进行微阵列分析来确定SS诊断和预后的标志物。我们现在已经将这些研究从少量患者样本扩展到更常见的MF/CTCL，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，后者经常与MF混淆，并取得了很好的成功。我们希望PBMC谱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。必须使用更多数量的患者样本来确认该初步PBMC特征。我们将使用MF和SS的PBMC特征来检查HDAC抑制剂（HDCAIs）缩酚肽（DP）的作用机制，其在CTCL治疗中显示出显著的功效，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。我们将使用Illumina DASL系统对福尔马林固定石蜡包埋（FFPE）CTCL样本中的重度浸润斑块和肿瘤样本进行分析，并在一项补充研究中评估PBMC中的特征。2)将在治疗前和治疗后评估DP II/III期临床试验中患者PBMC的基因表达谱，并将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，并评价4-6个月期间进行性治疗期间发生的变化。3)我们将通过对患者和对照PBMC进行体外治疗来增强体内研究，以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，4）HDACI抗性CTCL细胞系将用于开发研究HDACI抗性的模型。我们目前的promisin的初步结果DP的临床试验和体外研究。公共卫生相关性：CTCL是一种有许多治疗方法但无法治愈的癌症。拟议的研究将检查一种新的有效的CTCL治疗方法如何在临床试验和细胞培养系统研究中的患者样本中发挥作用。根据我们的初步研究，我们建议开发测试，将确定那些患者将响应治疗（约35%）和那些不会在治疗开始之前。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，可以识别将无反应患者转化为有反应患者的方法。

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.