MARKERS OF RESPONSE IN CUTANEOUS T-CELL LYMPHOMA

描述：(申请者摘要)皮肤T细胞淋巴瘤 发病率在增加，但其原因尚不清楚。真菌样肉芽肿， 最常见的CTCL与良性皮肤病有相似之处。 用于治疗CTCL的实验性维甲酸正在开发中，但 它们的作用机制还没有完全被理解。维甲酸类物质的影响 通过与核受体结合进行基因转录，核受体二聚化 与DNA序列和转录因子相互作用。蛋白质的配基 RXR-α-β-伽马受体“rexinoid”具有广泛的潜力 二聚体配对，因此可能会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物(PPAR)。Targretin(LGD1069)是 第一个RXR选择性维甲酸进入癌症实验试验 在MF患者中进行局部和口服研究。塔格列汀是 假设通过1)逆转维甲酸的减少来缓解MF病变 受体(和其他RXR配体)，2)调节γ-干扰素和关键细胞因子 (3)引起T细胞凋亡。要了解Targretin是如何早期改进的 CTCL病变申请人建议研究来自30个CTCL的皮肤样本 正在进行的1期和2/3期临床试验中的患者。在具体目标1中， 塔格列汀增加自身受体的假说及其二聚化 合作伙伴(RAR、TRS、LXR)将通过基于地高辛的原位研究 杂交。基线上的损伤将与正常皮肤和 在治疗8周后恢复到相同的水平。免疫组织化学和QRT-PCR 将用于确认。《特定目标2》探讨了塔格列汀的 作用包括对关键细胞因子的调节：干扰素-γ，诱导蛋白 10、肿瘤坏死因子和白介素8。在特定目标3中，塔格列汀对T细胞的影响 浸润液和角质形成细胞的凋亡率将在较小的 10例患者的DNA缺口DNA末端标记法活检研究的子集。 RARs、RXRs、LXRs、TRRNAs和 蛋白质(特异性靶标1)；细胞因子(γ-干扰素、肿瘤坏死因子-α和白介素8)和 趋化因子IP-10(特异性靶点2)；FasL和TUNEL阳性(特异性 目标3)将使用半定量量表进行评估，并将分组 经Kruskal-Wallis单因素方差分析和相关分析。看到的效果 如果局部用药和口服用药重要的话，应该是相似的 用于治疗这种疾病。研究其作用机理。 CTCL中新的RXR维甲酸应该会增加我们对这种疾病的了解 发病机制，并导致改进的，更安全的生物疗法 毁灭性的淋巴瘤。

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.