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(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。 公共卫生相关性：这一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药物，适用于有多种非典型痣和既往皮肤黑色素瘤病史的患者。本申请中提出的试点研究将评估28天口服三种剂量之一的BSE-SFN对临床和病理特征以及在非典型痣中被结构性激活的STAT3信号的影响，这些信号是黑色素瘤的既定风险标记和非专有前体，并提高我们对BSE-SFN作为黑色素瘤替代品的临床和分子效应的科学理解。我们在这项研究中开发的方法和技术将推动匹兹堡大学癌症研究所黑色素瘤和皮肤癌计划以及我们由ECOG、SWOG、NCCTG和CALGB组成的黑色素瘤预防工作组对BSE-SFN的进一步研究。