Pilot Clinical & Molecular Analysis of Atypical Nevus Response to Sulforaphane

试点临床

• 批准号: 8302813
• 负责人: John Munn Kirkwood
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-12 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302813
• 关键词: Adjuvant; Adjuvant Therapy; Adoption; Apoptotic; Atypia; BRAF Gene Mutation; Biopsy; Broccoli - dietary; Cancer and Leukemia Group B; Chemopreventive Agent; Clinical; Cutaneous Melanoma; Dose; Dysplastic Nevus; Eastern Cooperative Oncology Group; Epidemic; Evaluation; Growth; Interferon Alfa-2b; Interferons; Methods; Molecular; Molecular Analysis; North Central Cancer Treatment Group; Oral; Patients; Phase; Pilot Projects; Prevention; Preventive; Recording of previous events; Relapse; Risk Marker; STAT3 gene; Signal Transduction; Skin; Skin Cancer; Solid Neoplasm; Southwest Oncology Group; Sulforaphane; Systemic Therapy; Technology; Toxic effect; University of Pittsburgh Cancer Institute; abstracting; advanced disease; dosage; improved; melanoma; multidisciplinary; pilot trial; preclinical study; programs; progression marker; response; working group

DESCRIPTION (provided by applicant): Pilot Clinical-pathological and Molecular Analysis of Atypical Nevi in Response to BSE-L-Sulforaphane Abstract Melanoma is an epidemic solid tumor that has eluded systemic therapy in the setting of advanced disease. In the adjuvant setting, only high-dose IFN alfa-2b has shown reproducible benefit in relapse-free survival, and two trials demonstrating overall survival benefit. Despite regulatory approval worldwide, the toxicity of IFN has limited its adoption for adjuvant therapy, and precludes its consideration for prevention. Atypical nevi are non- obligate precursors and risk markers of melanoma, in which the presence of progression markers such as mutation of the BRAF gene, and the constitutive expression of STAT3 have been documented. We have demonstrated STAT3 expression and its correlation with the degree of atypia in atypical nevi of patients with a personal history of melanoma. The natural broccoli sprout extract enriched in sulforaphane (BSE-SFN) has shown promise as a chemopreventive agent in several solid tumors; preclinical studies demonstrate its inhibition of STAT3, as well as the induction of pro-apoptotic and growth-inhibitory activity against melanoma. We propose a pilot evaluation of three dosages of oral BSE-SFN (50, 100, and 200 ¿mol per day, assigned at random in groups of 6 patients per dosage). Candidates for this pilot trial will have multiple atypical nevi and a history of prior melanoma, and be evaluated in Specific Aim 1 for tolerance and clinical-pathological effects of oral BSE-SFN Atypical nevi will be documented by photograph and biopsy, prior to and following 28 daily oral doses of BSE-SFN. BSE-SFN localization to the skin and modulation of STAT3 signaling in atypical nevi will also be evaluated in Specific Aim 2. The pilot trial of the multidisciplinary Melanoma Program of the UPCI will allow us to select a dosage for Phase II evaluation in larger numbers of subjects with melanoma and atypical nevi, in the cooperative group setting, either in ECOG or in the Melanoma Prevention Working Group. PUBLIC HEALTH RELEVANCE: This pilot project will develop the broccoli sprout extract enriched in sulforaphane (BSE-SFN) as a non-toxic natural chemopreventive agent for melanoma for patients who have multiple atypical nevi and a prior history of cutaneous melanoma. The pilot studies proposed in this application will assess the effects of 28 days of oral BSE-SFN at one of three dosages upon the clinical and pathological features, as well as STAT3 signaling which is constitutively activated in atypical nevi, which are established risk markers and non-obligate precursors of melanoma, and improve our scientific understanding of the clinical and molecular effects of BSE- SFN in relation to atypical nevi as surrogates for melanoma. The methods and technologies we develop in the context of this study will drive further studies of BSE-SFN in the context of the Melanoma and Skin Cancer Program of the University of Pittsburgh Cancer Institute, as well as the Melanoma Prevention Working Group we have formed amongst ECOG, SWOG, NCCTG and CALGB.

描述（由申请人提供）：对 BSE-L-萝卜硫素反应的非典型痣的初步临床病理学和分子分析 摘要黑色素瘤是一种流行性实体瘤，在晚期疾病的辅助治疗中无法进行全身治疗。 ，只有高剂量 IFN alfa-2b 在无复发生存方面表现出可重复的益处，并且两项试验证明了总体生存益处，尽管全球监管机构已批准，但 IFN 的毒性限制了其使用。非典型痣是黑色素瘤的非必然前体和风险标志物，其中存在进展标志物，例如 BRAF 基因突变和 STAT3 的组成型表达。我们已经证明了 STAT3 表达及其与有黑色素瘤个人病史的非典型痣患者的非典型程度的相关性。萝卜硫素 (BSE-SFN) 在多项实体瘤中显示出作为化学预防剂的前景；临床前研究表明其可抑制 STAT3，并可诱导针对黑色素瘤的促凋亡和生长抑制活性。口服 BSE-SFN 剂量（50、100 和 200 ¿ mol/天，每个剂量随机分配为 6 名患者）。该试点试验的候选者将患有多个非典型痣和既往黑色素瘤病史，并接受评估。 在具体目标 1 中，口服 BSE-SFN 的耐受性和临床病理影响将在 28 日口服 BSE-SFN 定位到皮肤和调节 STAT3 之前和之后通过照片和活检记录非典型痣。非典型痣中的信号传导也将在特定目标 2 中进行评估。 UPCI 多学科黑色素瘤计划的试点试验将使我们能够选择一种剂量，在大量受试者中进行 II 期评估黑色素瘤和非典型痣，在合作小组环境中，无论是在 ECOG 中还是在黑色素瘤预防工作组中。 公共健康相关性：该试点项目将开发富含萝卜硫素的西兰花芽提取物（BSE-SFN），作为一种无毒的天然黑色素瘤化学预防剂，用于患有多发性非典型痣和既往皮肤黑色素瘤病史的患者。本申请将评估口服 BSE-SFN 三种剂量之一 28 天对临床和病理特征以及 STAT3 的影响信号在非典型痣中被组成性激活，非典型痣是黑色素瘤的既定风险标记和非专性前体，并提高了我们对 BSE-SFN 作为黑色素瘤替代物与非典型痣相关的临床和分子效应的科学理解。我们在本研究中开发的技术将进一步推动匹兹堡大学癌症研究所黑色素瘤和皮肤癌项目以及黑色素瘤预防工作背景下的 BSE-SFN 研究我们由 ECOG、SWOG、NCCTG 和 CALGB 组成。