Pilot Clinical & Molecular Analysis of Atypical Nevus Response to Sulforaphane

试点临床

基本信息

项目摘要

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):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,在晚期疾病的背景下无法进行全身治疗。在辅助治疗中,只有高剂量IFN α-2b显示出可重复的无复发生存获益,两项试验显示了总体生存获益。尽管在世界范围内获得了监管机构的批准,但IFN的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性前体和风险标志物,其中已经记录了进展标志物如BRAF基因突变和STAT 3的组成型表达的存在。我们已经证明了STAT 3的表达及其与黑色素瘤患者的非典型痣中色素沉着程度的相关性。富含萝卜硫素的天然西兰花芽提取物(BSE-SFN)已显示出作为几种实体瘤的化学预防剂的前景;临床前研究表明其抑制STAT 3,以及诱导促凋亡和生长抑制活性对抗黑色素瘤。我们建议对三种剂量的口服BSE-SFN(每天50、100和200 μ mol,随机分配,每组6名患者)进行初步评估。本试验的候选人将有多个非典型痣和先前的黑色素瘤病史, 在口服BSE-SFN的耐受性和临床-病理学效应的具体目标1中,在28次每日口服剂量的BSE-SFN之前和之后,通过拍照和活检记录非典型痣。BSE-SFN在皮肤中的定位和非典型痣中STAT 3信号传导的调节也将在特定目标2中进行评价。UPCI的多学科黑色素瘤项目的试点试验将允许我们在ECOG或黑色素瘤预防工作组的合作组环境中,在大量黑色素瘤和非典型痣受试者中选择用于II期评价的剂量。 公共卫生关系:该试点项目将开发富含萝卜硫素的西兰花芽提取物(BSE-SFN)作为黑色素瘤的无毒天然化学预防剂,用于患有多发性非典型痣和皮肤黑色素瘤既往史的患者。本申请中提出的初步研究将评估以三种剂量之一口服BSE-SFN 28天对临床和病理学特征以及在非典型痣中组成性激活的STAT 3信号传导的影响,所述非典型痣是黑色素瘤的既定风险标志物和非专性前体,并提高我们对BSE- SFN与非典型痣作为黑色素瘤替代物的临床和分子效应的科学理解。我们在本研究背景下开发的方法和技术将在匹兹堡大学癌症研究所的黑色素瘤和皮肤癌项目以及我们在ECOG,SWOG,NCCTG和CALGB中形成的黑色素瘤预防工作组的背景下推动BSE-SFN的进一步研究。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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John Munn Kirkwood其他文献

John Munn Kirkwood的其他文献

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{{ truncateString('John Munn Kirkwood', 18)}}的其他基金

Melanoma and Skin Cancer Program SPORE
黑色素瘤和皮肤癌计划 SPORE
  • 批准号:
    10270227
  • 财政年份:
    2021
  • 资助金额:
    $ 16.58万
  • 项目类别:
Melanoma and Skin Cancer Program SPORE
黑色素瘤和皮肤癌计划 SPORE
  • 批准号:
    10469631
  • 财政年份:
    2021
  • 资助金额:
    $ 16.58万
  • 项目类别:
Melanoma and Skin Cancer Program SPORE
黑色素瘤和皮肤癌计划 SPORE
  • 批准号:
    10683750
  • 财政年份:
    2021
  • 资助金额:
    $ 16.58万
  • 项目类别:
Training Program in Skin Biology and Cancer
皮肤生物学和癌症培训计划
  • 批准号:
    9272850
  • 财政年份:
    2014
  • 资助金额:
    $ 16.58万
  • 项目类别:
Training Program in Skin Biology and Cancer
皮肤生物学和癌症培训计划
  • 批准号:
    8607635
  • 财政年份:
    2014
  • 资助金额:
    $ 16.58万
  • 项目类别:
Training Program in Skin Biology and Cancer
皮肤生物学和癌症培训计划
  • 批准号:
    8857377
  • 财政年份:
    2014
  • 资助金额:
    $ 16.58万
  • 项目类别:
Pilot Clinical & Molecular Analysis of Atypical Nevus Response to Sulforaphane
试点临床
  • 批准号:
    8509629
  • 财政年份:
    2012
  • 资助金额:
    $ 16.58万
  • 项目类别:
SPORE in Skin Cancer
皮肤癌中的孢子
  • 批准号:
    8548580
  • 财政年份:
    2008
  • 资助金额:
    $ 16.58万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    9091460
  • 财政年份:
    2008
  • 资助金额:
    $ 16.58万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8933150
  • 财政年份:
    2008
  • 资助金额:
    $ 16.58万
  • 项目类别:

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