BIOCHEMOPREVENTION THERAPY IN ADVANCED LARYNGEAL DYSPLAS

描述：(申请人描述) 这是一项前瞻性随机临床试验，旨在研究 生物化学联合预防治疗逆转的生物学效应 喉发育不良的临床特点及非维甲酸维持治疗的疗效 维持或获得进一步的反应。在上呼吸道中 带有实质性基因变化的晚期癌前病变不是 仅用维甲酸有效地逆转了这一现象。13-顺的组合 维甲酸(13cRA)、α生育酚和α-干扰素已经产生 大多数喉发育不良病变的戏剧性逆转 目前正在进行的一项研究中进行了治疗，但某些基因变化仍然存在 尽管有完全的反应。这一提议背后的假设是：a) 慢性喉癌致喉上皮中重度不典型增生 致癌物暴露，并可作为开发化学预防的模型 战略。B)生物标记物可以用来定义分子和细胞 与野致癌和多步骤致癌以及癌症相关的变化 风险评估。C)生物化学预防疗法将在#年有效 逆转中重度喉发育不良并将改变生物标志物 表情。D)Fenretinde将有效地维持反应和 维持生物标记物的调节，毒性低于诱导 治疗，将比安慰剂更有效。E)芬雷替尼将 逆转持续性损伤，并将进一步调节并可能逆转 尚未被调节或逆转的基因和表型改变 诱导疗法。提出了以下目标：a)确认 联合生物化学预防12个月的疗效和毒性 中至重度喉发育不良患者。B)比较 非维甲酸维持或实现进一步反应的疗效 安慰剂对照并测定其毒性。C)评价以下方面的效果 遗传生物标记物(染色体)表达的生物化学预防 染色体9p、3p和17p、p53、p16的多倍体和杂合性丢失 和细胞周期蛋白D1基因状态和蛋白表达)，表型变化 生物标记物(增殖：Ki-67)与维甲酸核受体 表情。D)评价维持治疗在维持治疗中的效果 逆转和/或逆转持续性的基因和表型异常。 所有患者(目标样本量为100)将接受联合治疗 生物化学预防治疗12个月，有反应或 稳定期疾病将随机分为非维甲酸维持组和安慰剂组 已经24个月了。对于生物标记物研究，石蜡包埋活检 他将使用基线、12个月和36个月的标本。我们会 染色体原位杂交分析遗传不稳定性：9P、 3p和17p的微卫星分析；p53的改变 免疫组织化学和直接测序分析；以及 免疫组织化学方法检测Ki-67、p16和细胞周期蛋白D1的表达。的研究。 生物标志物将加强我们对癌症发生和疾病的理解 干预的作用机制；它将提高我们的能力 用于风险评估。拟议中的研究最终将指导未来 癌症前的干预试验，不仅在喉部，而且在喉部 一般在上皮性癌变中起作用。

DESCRIPTION: (Applicant's Description) This is a prospective randomized clinical trial designed to study the biologic effects of combination biochemopreventive therapy in the reversal of laryngeal dysplasia and the effects of fenretinide maintenance therapy in maintaining or obtaining further response. In the upper aerodigestive tract advanced premalignant lesions harboring substantial genetic changes are not effectively reversed with retinoids alone. The combination of 13-cis retinoic acid (13cRA), alpha tocopherol, and alpha-interferon has produced dramatic reversal of the majority of the laryngeal dysplastic lesions treated in a currently ongoing study, but certain genetic changes persisted despite complete response. The hypotheses underlying this proposal are: a) Moderate to severe dysplasia in laryngeal epithelium results from chronic carcinogen exposure and may serve as a model for developing chemoprevention strategies. b) Biomarkers may be used to define the molecular and cellular changes associated with field and multistep carcinogenesis and for cancer risk assessment. c) Biochemopreventive therapy will be effective in reversing moderate to severe laryngeal dysplasia and will alter biomarker expression. d) Fenretinde will be effective in response maintenance and in maintenance of biomarker modulation with less toxicity than induction therapy and will be more effective than placebo. e) Fenretinide will reverse persistent lesions and will further modulate and possibly reverse genotypic and phenotypic alterations not already modulated or reversed by induction therapy. The following objectives are proposed: a) To confirm the efficacy and toxicity of combination biochemoprevention for 12 months in patients with moderate to severe laryngeal dysplasia. b) To compare the efficacy of fenretinide in maintaining or achieving further response with a placebo control and determine its toxicity. c) Evaluate the effects of biochemoprevention on the expression of genetic biomarkers (chromosome polysomy, loss of heterotozygosity at chromosomes 9p, 3p and 17p, p53, p16 and cyclin Dl gene status and protein expression), phenotypic change biomarkers (proliferation: Ki-67), and nuclear retinoic acid receptor expression. d) Evaluate the efficacy of maintenance therapy in maintaining reversal and or reversing persistent genotypic and phenotypic abnormalities. All patients (a target sample size of 100) will receive combination biochemopreventive therapy for 12 months, and those showing response or stable disease will be randomized to fenretinide maintenance versus placebo for 24 months. For the biomarker studies, paraffin-embedded biopsy specimens at baseline, 12 months, and 36 months will he used. We will analyze genetic instability by chromosome in situ hybridization; LOH of 9p, 3p, and 17p by microsatellite analysis; p53 alterations by immunohistochemistry and direct sequencing analysis; and alterations in ki-67, p16, and cyclin Dl expression by immunohistochemistry. The study of biomarkers will enhance our understanding of carcinogenesis and of mechanisms of action of the intervention; and, it will improve our ability for risk assessment. The proposed research will eventually direct future intervention trials in premalignancy, not only in the laryngeal setting but in epithelial carcinogenesis in general.