Preclinical models and therapeutic strategies for treatment of giant congenital melanocytic nevi

先天性巨大黑素细胞痣的临床前模型及治疗策略

基本信息

  • 批准号:
    10245261
  • 负责人:
  • 金额:
    $ 35.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-01 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary Giant congenital melanocytic nevi are virtually always NRAS-driven clonal proliferations of melanocytes that develop in utero independently of UV and may cover up to 80% of the body. The most dangerous consequence of giant nevi is the risk of progression to melanoma. This prompts complete surgical excision of the lesions, producing profound and permanent morbidity. Drug treatments capable of regressing these lesions and minimizing lifetime risk of melanoma could be extremely beneficial to these children. We have generated several murine giant nevus models using either constitutive Cre or topical tamoxifen-inducible Cre expression (both melanocyte restricted) to activate oncogenic NRASQ61R expression from its endogenous promoter. In addition to clear histologic and biomarker features resembling human giant nevi, these models exhibit a proliferative phase followed by a senescent phase, and transform to invasive melanoma at similar frequencies as in humans. Aim 1 will characterize these features, identifying transition time to senescence, since therapies may produce distinct efficacies in early/proliferative vs. later/senescent lesions. We will also examine altered hair growth in our model (also similar to human giant nevi), as well as apparently increased aggressiveness of these lesions in the Mc1re/e red-haired genetic background, as recently suggested for humans. We have begun to apply surgery-sparing, primarily locally administered drug therapies to these models (Aim 2), including: 1) small molecule antagonists of NRAS downstream signaling (MEK, ERK, PI3 kinase, and AKT inhibitors); 2) melanocyte lineage-specific toxic agents (antagonists targeting cKIT, MITF, and tyrosinase); and 3) immune approaches triggering localized inflammation and epitope spreading with vitiligo-like results (imiquimod, chemical haptens [contact sensitizers], a lipophilic STING (Stimulator of Interferon Genes) agonist, and BCG, alone and in combinations with anti-PD1). Our preliminary results demonstrate significant clearance of nevus populations using multiple single and combination approaches, albeit requiring further optimization. We hypothesize that effective, safe therapies for giant congenital melanocytic nevi can be derived from application of the above approaches exploiting key benefits of localized drug delivery. Treatments will focus on eradicating both actively proliferating cells (as in neonatal lesions) and senescent cells (as in older children), both modeled here. We have validated a set of rigorous biomarkers of signaling activities as well as key cell populations, for use in sensitive monitoring of lesions and treatments. Prevention of melanoma formation can also be tested using our models. To further validate promising approaches in actual living human giant nevi, we now routinely and stably engraft surgically resected giant nevus tissue from children onto immunodeficient mice (Aim 3). These lesions will be subjected to the best single or combination (non-immunologic) regimens discovered in Aim 2, thereby permitting rigorous preclinical therapeutic assessments in living human giant nevi.
项目总结

项目成果

期刊论文数量(0)
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DAVID E FISHER其他文献

DAVID E FISHER的其他文献

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{{ truncateString('DAVID E FISHER', 18)}}的其他基金

MITF from control of pigmentation to melanoma risk
MITF 从控制色素沉着到黑色素瘤风险
  • 批准号:
    10828041
  • 财政年份:
    2023
  • 资助金额:
    $ 35.34万
  • 项目类别:
A druggable dependency in low-MITF/high-AXL melanoma: preclinical efficacy and mechanism of action in a key treatment-resistant subclass.
低 MITF/高 AXL 黑色素瘤的药物依赖性:关键耐药亚类的临床前疗效和作用机制。
  • 批准号:
    10331800
  • 财政年份:
    2018
  • 资助金额:
    $ 35.34万
  • 项目类别:
Preclinical models and therapeutic strategies for treatment of giant congenital melanocytic nevi
先天性巨大黑素细胞痣的临床前模型及治疗策略
  • 批准号:
    9753925
  • 财政年份:
    2017
  • 资助金额:
    $ 35.34万
  • 项目类别:
Preclinical models and therapeutic strategies for treatment of giant congenital melanocytic nevi
先天性巨大黑素细胞痣的临床前模型及治疗策略
  • 批准号:
    9376481
  • 财政年份:
    2017
  • 资助金额:
    $ 35.34万
  • 项目类别:
Therapeutic strategies for treatment of giant congenital melanocytic nevi
巨大先天性黑素细胞痣的治疗策略
  • 批准号:
    10570507
  • 财政年份:
    2017
  • 资助金额:
    $ 35.34万
  • 项目类别:
Preclinical models and therapeutic strategies for treatment of giant congenital melanocytic nevi
先天性巨大黑素细胞痣的临床前模型及治疗策略
  • 批准号:
    9977915
  • 财政年份:
    2017
  • 资助金额:
    $ 35.34万
  • 项目类别:
Development of next-generation cancer functional diagnostics
下一代癌症功能诊断的开发
  • 批准号:
    8492572
  • 财政年份:
    2013
  • 资助金额:
    $ 35.34万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8415143
  • 财政年份:
    2013
  • 资助金额:
    $ 35.34万
  • 项目类别:
Project 1: Remodeling Chromatin and the Tumor Microenvironment: Direct Oncogenesis and Therapeutic Targeting
项目 1:重塑染色质和肿瘤微环境:直接肿瘤发生和治疗靶向
  • 批准号:
    10443720
  • 财政年份:
    2013
  • 资助金额:
    $ 35.34万
  • 项目类别:
Targetable epigenetic and transcriptional mechanisms in melanoma that shape the microenvironment
黑色素瘤中塑造微环境的靶向表观遗传和转录机制
  • 批准号:
    9792731
  • 财政年份:
    2013
  • 资助金额:
    $ 35.34万
  • 项目类别:

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研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
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    2023
  • 资助金额:
    $ 35.34万
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