Pilot Clinical & Molecular Analysis of Atypical Nevus Response to Sulforaphane

描述(申请人提供)：对疯牛病-L-萝卜硫素反应的非典型痣的试点临床-病理和分子分析摘要黑色素瘤是一种流行的实体肿瘤，在晚期疾病的背景下未能进行系统治疗。在佐剂环境中，只有高剂量的干扰素α-2b在无复发生存方面显示出可重复的益处，两项试验显示总体生存益处。尽管全球监管机构批准了干扰素，但其毒性限制了其用于辅助治疗，并排除了其用于预防的考虑。非典型痣是黑色素瘤的非专一性前体和危险标记，其中存在BRAF基因突变等进展标记和STAT3的结构性表达。我们已经证明了STAT3在有黑色素瘤个人病史的患者的非典型痣中的表达及其与非典型性程度的相关性。富含萝卜硫素的天然西兰花芽提取物(BSE-SFN)已显示出在几种实体肿瘤中作为化学预防药物的前景；临床前研究表明，它抑制STAT3，以及诱导促凋亡和抑制黑色素瘤的生长活性。我们建议对口服BSE-SFN的三种剂量(每天50、100和200？摩尔，每剂量6名患者随机分配)进行初步评估。这项试点试验的候选人将有多个非典型痣和既往黑色素瘤病史，并接受评估 对于口服BSE-SFN的耐受性和临床病理影响的特定目标1，在每天口服28剂BSE-SFN之前和之后，将通过照片和活检记录非典型痣。BSE-SFN在皮肤上的定位和STAT3信号在非典型痣中的调制也将在特定的目标2中进行评估。UPCI的多学科黑色素瘤计划的试点试验将允许我们在合作小组的环境下，在ECOG或黑色素瘤预防工作组中，选择一个剂量用于在更多的黑色素瘤和非典型痣受试者中进行II期评估。

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.