Pilot Clinical & Molecular Analysis of Atypical Nevus Response to Sulforaphane

摘要：黑色素瘤是一种流行的实体肿瘤，在疾病晚期无法进行全身治疗。在辅助治疗中，只有高剂量IFN α -2b在无复发生存期中显示出可重复的益处，两项试验显示了总生存期的益处。尽管世界各地的监管机构都批准了IFN，但其毒性限制了其作为辅助治疗的采用，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危险标志物，其中存在进展标志物，如BRAF基因突变和STAT3的组成性表达。我们已经证明STAT3的表达及其与非典型黑色素瘤患者的非典型痣的非典型程度的相关性。富含萝卜硫素的天然西兰花芽提取物（BSE-SFN）有望成为几种实体肿瘤的化学预防剂；临床前研究表明其抑制STAT3，以及诱导促凋亡和抑制黑色素瘤生长活性。我们建议对三种剂量的口服BSE-SFN（每天50、100和200 mol，随机分配到每剂量6名患者的组中）进行试点评估。该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，并进行评估

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.