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
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAgonistAllelesAutomobile DrivingBCG LiveBehaviorBiological MarkersBirthBody Surface AreaCategoriesCellsCessation of lifeChemicalsChildDangerousnessDataDermatopathologyDevelopmentDiagnosisDisadvantagedDrug Delivery SystemsEpitope spreadingExcisionExhibitsFRAP1 geneFaceFrequenciesGeneticGenetic EngineeringGenetically Engineered MouseGrowthHairHair RemovalHair follicle structureHaptensHistologicHistone DeacetylaseHistone Deacetylase InhibitorHumanImatinibImiquimodImmuneImmunodeficient MouseIndividualInfantInflammationInjectionsLesionMEKsMeasuresMedicalMelanocortin 1 ReceptorModelingMole the mammalMonitorMonobenzoneMonophenol MonooxygenaseMorbidity - disease rateMusMutationNeonatalNevusNevus CellOncogenesOncogenicOperative Surgical ProceduresPI3K/AKTPathway interactionsPatientsPharmacologyPharmacotherapyPhasePigmentsPopulationPre-Clinical ModelPreventionProliferatingPropertyProto-Oncogene Proteins c-aktPublishingRegimenReportingResectedRiskSignal TransductionSkinStimulator of Interferon GenesSystemTamoxifenTestingTherapeuticTimeTissue GraftsTissuesTopical applicationTransgenic OrganismsVariantVitiligoXenograft procedureanti-PD-1basedrug candidategiant congenital nevushealinghigh riskimmune checkpoint blockadein uteroinhibitor/antagonistlifetime risklipophilicitymelanocytemelanomamodel buildingmouse modelmutantnovel therapeutic interventionpre-clinicalpreclinical evaluationpreventpromoterpsychosocialsenescencesmall moleculesocialsuccesstherapeutic evaluationtreatment strategytumorigenicvirtual
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
巨大的先天性黑色素细胞痣实际上总是由NRAS驱动的黑素细胞的克隆性增殖
在子宫内发育,独立于紫外线,可能覆盖高达80%的身体。最危险的
巨大痣的后果是有发展为黑色素瘤的风险。这促使手术完全切除了
损害,产生深刻和永久性的发病率。能够使这些损伤消退的药物治疗
将患黑色素瘤的风险降至最低对这些儿童来说可能是非常有益的。我们已经产生了
用结构性Cre和局部他莫昔芬诱导Cre表达的几种小鼠巨型痣模型
(两种黑素细胞都受到限制)从其内源性启动子激活致癌的NRASQ61R表达。在……里面
除了清晰的组织学和生物标志物特征类似于人类巨型痣外,这些模型还表现出
增殖期之后是衰老期,并以类似的频率转化为侵袭性黑色素瘤
就像人类一样。目标1将描述这些特征,确定向衰老的过渡时间,因为治疗
对早期/增生性皮损与晚期/衰老性皮损可能产生明显的疗效。我们还将检查更改后的
我们的模型中的毛发生长(也类似于人类巨型痣),以及明显增加的攻击性
这些损害发生在Mc1Re/e红发遗传背景中,最近对人类提出了建议。我们已经开始了
对这些模型(目标2)应用节省手术、主要在当地实施的药物疗法,包括:
1)NRAS下游信号传导的小分子拮抗剂(MEK、ERK、PI3和AKT抑制剂);
2)黑素细胞系特异性毒物(针对cKit、MITF和酪氨酸酶的拮抗剂);以及3)免疫
触发局部炎症和白癜风样结果的表位扩散的方法(咪喹莫特,
化学半抗原[接触敏感剂],一种亲脂性刺痛(干扰素基因刺激物)激动剂,以及卡介苗,
单独或与抗PD1抗体联合应用)。我们的初步结果显示有显著的雀斑清除。
使用多种单一和组合方法的人口,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衍生出来
利用本地化给药的主要好处的上述方法。治疗的重点将是根除
活跃的增殖细胞(如新生儿皮损)和衰老细胞(如年龄较大的儿童)都建立了模型
这里。我们已经验证了一套严格的信号活动生物标记物以及关键细胞群,用于
用于对病变和治疗进行敏感监测。预防黑色素瘤的形成也可以测试
使用我们的模型。为了进一步在现实生活中验证有希望的方法,我们现在例行地
并稳定地将从儿童身上切除的巨大痣组织移植到免疫缺陷小鼠身上(目标3)。
这些损害将受到最好的单一或联合(非免疫学)方案的影响
目的2,从而允许对活体人类巨大痣进行严格的临床前治疗评估。
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)
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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:
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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:
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
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10443720 - 财政年份:2013
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$ 35.34万 - 项目类别:
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9792731 - 财政年份:2013
- 资助金额:
$ 35.34万 - 项目类别:
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