Pilot Clinical & Molecular Analysis of Atypical Nevus Response to Sulforaphane

试点临床

• 批准号: 8509629
• 负责人: John Munn Kirkwood
• 金额: $ 18.71万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509629
• 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.

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，在晚期疾病中无法进行全身治疗。在辅助治疗中，只有高剂量 IFN alfa-2b 在无复发生存方面显示出可重复的益处，并且两项试验证明了总体生存益处。尽管获得了全球监管部门的批准，但干扰素的毒性限制了其辅助治疗的采用，并排除了其用于预防的考虑。非典型痣是黑色素瘤的非专性前体和风险标记，其中已记录了进展标记的存在，例如 BRAF 基因突变和 STAT3 的组成型表达。我们已经证明了有黑色素瘤个人病史的患者的非典型痣中 STAT3 的表达及其与异型程度的相关性。富含萝卜硫素的天然西兰花芽提取物 (BSE-SFN) 已显示出作为多种实体瘤化学预防剂的前景；临床前研究证明其可抑制 STAT3，并诱导针对黑色素瘤的促凋亡和生长抑制活性。我们建议对三种口服 BSE-SFN 剂量（每天 50、100 和 200 µmol，每个剂量随机分配为 6 名患者）进行初步评估。该试点试验的候选人将具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效应将在每日 28 次口服 BSE-SFN 之前和之后通过照片和活检记录非典型痣。 BSE-SFN 的皮肤定位和非典型痣中 STAT3 信号的调节也将在特定目标 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在合作小组环境中（ECOG 或黑色素瘤预防工作组）选择用于对大量黑色素瘤和非典型痣受试者进行 II 期评估的剂量。