MARKERS OF RESPONSE IN CUTANEOUS T-CELL LYMPHOMA

描述：（申请人摘要）皮肤T细胞淋巴瘤（CTCL）是一种 发病率增加，但其原因尚不清楚。 蕈样肉芽肿 CTCL的最常见形式与良性皮肤病有相似之处。 实验性维甲酸正在开发用于治疗CTCL，但 它们的作用机制尚未完全了解。 类维生素A影响 通过与核受体结合进行基因转录， 与DNA序列和转录因子相互作用。 的配体 RXR-α β γ受体“类Rexinoids”具有广泛的潜力 二聚体伴侣，因此可能影响许多系统中的基因表达 包括甲状腺（TR）、肝脏胆固醇代谢（LXR）和 过氧化物酶体增殖物激活剂（PPARs）。 Targretin（LGD 1069）是 第一个进入癌症实验性试验的RXR选择性维甲酸，是 正在MF患者中进行局部和口服研究。 塔格列廷群岛 假设通过1）逆转类维生素A的减少来缓解MF病变 受体（和其他RXR配体），2）调节γ IFN和关键细胞因子 3）引起T细胞凋亡。 了解Targretin如何在早期改善 CTCL病变申请人拟研究30例CTCL的皮肤标本 正在进行的1期和2/3期临床试验中的患者。 具体目标1： Targretin增加其自身受体及其二聚化的假说 将通过基于地高辛的原位研究伴侣（RAR、TR、LXR） 杂交方法 基线时的病变将与正常皮肤进行比较， 在治疗8周后也是如此。 免疫组织化学和QRT-PCR 将用于确认。 具体目标2解决了Targretin是否 作用包括调节关键细胞因子：IFN-γ、诱导蛋白 10、TNF和IL-8。 在具体目标3中，Targretin对T细胞的作用是通过免疫抑制剂来实现的。 浸润和角质细胞凋亡将在较小的 通过tunel方法对10名患者的活检研究的子集进行DNA切口。 RARs、RXR、LXR、TR RNA和RXRs的表达模式和强度与对照组相比无显著性差异（P> 0.05）。 蛋白质（特异性目标1）;细胞因子（γ-IFN、TNF-α和IL-8）和 趋化因子IP-10（特异性Aim 2）和FasL和tunel阳性（特异性 目标3）将采用半定量量表进行评估， 用Kruskal-Wallis单因素方差分析和相关性分析。 观察到的效应 如果局部和口服给药很重要， 用于治疗疾病。 研究其作用机制， 新的RXR类维生素A治疗CTCL应该增加我们对该疾病的理解 发病机制，并导致改善，更安全的生物疗法， 恶性淋巴瘤

DESCRIPTION: (Applicant's Abstract) Cutaneous T cell lymphoma (CTCL) are increasing in incidence, but their cause is unknown. Mycosis fungoides, the most common form of CTCL, has similarities to benign skin diseases. Experimental retinoids are being developed for the therapy of CTCL, but their mechanisms of action are not fully understood. Retinoids influence gene transcription by binding to nuclear receptors that dimerize and interact with DNA sequences and transcription factors. Ligands for the RXR-alpha beta gamma receptors "rexinoids" have a wide range of potential dimer partners and thus may influence gene expression in many systems including thyroid (TR), liver cholesterol metabolism (LXR) and peroxisome-proliferator activators (PPARs). Targretin (LGD1069) is the first RXR selective retinoid to enter experimental trials for cancer and is being studied in MF patients topically and orally. Targretin is hypothesized to remit MF lesions by 1) reversing the decrease in retinoid receptors (and other RXR ligands), 2) modulating gamma IFN and key cytokines and 3) causing T cell apoptosis. To understand how Targretin improves early CTCL lesions the applicant proposes to study skin specimens from 30 CTCL patients in ongoing Phase 1 and 2/3 clinical trials. In Specific Aim 1, the hypothesis that Targretin increases its own receptors and its dimerization partners (RARs, TRs, LXRs) will be studied by digoxigenin based in situ hybridization. The lesions at baseline will be compared to normal skin and to the same following 8 weeks of therapy. Immunohistochemistry and QRT-PCR will be used for confirmation. Specific Aim 2 addresses whether Targretin's effect includes modulation of key cytokines: IFN-gamma, inducible protein 10, TNF and IL-8. In Specific Aim 3, the effect of Targretin on T cell infiltrates and keratinocyte apoptosis will be determined in a smaller subset of 10 patients' biopsies studies for DNA nicking by the tunel method. The pattern and intensity of expression of RARs, RXRs, LXRs, TR RNAs and protein (Specific Aim 1); cytokines (gamma-IFN, TNF-alpha and IL-8) and chemokine IP-10 (Specific Aim 2); and FasL and tunel positivity (Specific Aim 3) will be evaluated with semi-quantitative scales and groups will be analyzed by Kruskal-Wallis one way ANOVA and correlations. Effects seen with topical and oral administration should be similar if they are important for treatment of the disease. Studying the mechanism of action of this novel RXR retinoid in CTCL should increase our understanding of the disease pathogenesis and result in improved, safer biological therapies for this devastating lymphoma.