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:
    9977915
  • 负责人:
  • 金额:
    $ 36.43万
  • 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 2022-07-31
  • 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.
项目摘要 巨大的先天性黑素细胞痣实际上总是NRAS驱动的黑素细胞克隆增殖, 在子宫内发育,不受紫外线的影响,可覆盖身体的80%。最危险的 巨大痣的后果是发展为黑色素瘤的风险。这提示完全手术切除 病变,产生深刻的和永久的发病率。能够使这些病变消退的药物治疗 最大限度地减少黑色素瘤的终生风险对这些儿童非常有益。我们已经生成 使用组成型Cre或局部他莫昔芬诱导的Cre表达的几种小鼠巨痣模型 (both黑素细胞限制的)以从其内源性启动子激活致癌NRASQ 61 R表达。在 除了类似于人类巨痣的清晰的组织学和生物标志物特征外,这些模型还表现出 增殖期,然后是衰老期,并以相似的频率转化为侵袭性黑色素瘤 和人类一样目标1将描述这些特征,确定衰老的过渡时间,因为治疗 可以在早期/增殖性病变与晚期/衰老性病变中产生不同的功效。我们还将检查 毛发生长在我们的模型(也类似于人类巨大痣),以及明显增加的侵略性, 这些病变在Mc 1 re/e红头发的遗传背景,最近建议为人类。我们已经开始 对这些模型应用手术保留,主要是局部给药的药物治疗(目标2),包括: 1)NRAS下游信号传导的小分子拮抗剂(MEK、ERK、PI 3激酶和AKT抑制剂); 2)黑素细胞谱系特异性毒性剂(靶向cKIT、MITF和酪氨酸酶的拮抗剂);和 引发局部炎症和表位扩散并产生白癜风样结果的方法(咪喹莫特, 化学半抗原[接触致敏剂],亲脂性STING(干扰素基因刺激剂)激动剂,和BCG, 单独和与抗PD 1组合)。我们的初步结果表明,显着清除痣 使用多个单一和组合方法的群体,尽管需要进一步优化。我们 假设巨大先天性黑色素细胞痣的有效、安全的治疗方法可以从应用中获得, 利用局部药物递送的关键益处的上述方法。治疗的重点是根除 活跃增殖细胞(如新生儿病变)和衰老细胞(如年龄较大的儿童),两者均建模 这里.我们已经验证了一套严格的信号活动生物标志物以及关键细胞群, 用于病变和治疗的灵敏监测。预防黑色素瘤的形成也可以测试 使用我们的模型。为了进一步验证有前途的方法在实际生活的人类巨大痣,我们现在例行 并将手术切除的儿童巨痣组织稳定地移植到免疫缺陷小鼠上(目的3)。 这些病变将接受在研究中发现的最佳单一或组合(非免疫)方案治疗。 目的2,从而允许严格的临床前治疗评估在生活人类巨大痣。

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(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

DAVID E FISHER其他文献

DAVID E FISHER的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    $ 36.43万
  • 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:
    $ 36.43万
  • 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:
    $ 36.43万
  • 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:
    $ 36.43万
  • 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:
    10245261
  • 财政年份:
    2017
  • 资助金额:
    $ 36.43万
  • 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:
    $ 36.43万
  • 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:
    $ 36.43万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8415143
  • 财政年份:
    2013
  • 资助金额:
    $ 36.43万
  • 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:
    $ 36.43万
  • 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:
    $ 36.43万
  • 项目类别:

相似国自然基金

Agonist-GPR119-Gs复合物的结构生物学研究
  • 批准号:
    32000851
  • 批准年份:
    2020
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
  • 批准号:
    24K12256
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
  • 批准号:
    24K19176
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
  • 批准号:
    10578068
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
  • 批准号:
    10933287
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
  • 批准号:
    10650593
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
  • 批准号:
    10649275
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
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
  • 批准号:
    10784209
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
  • 批准号:
    10734158
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
  • 批准号:
    10580259
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
Fentanyl Addiction: Individual Differences, Neural Circuitry, and Treatment with a GLP-1 Receptor Agonist
芬太尼成瘾:个体差异、神经回路和 GLP-1 受体激动剂治疗
  • 批准号:
    10534864
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了