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：
DAVID E FISHER
金额：
$ 36.43万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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

来源：
https://reporter.nih.gov/project-details/9977915
关键词：
1-Phosphatidylinositol 3-Kinase Agonist Alleles Automobile Driving BCG Live Behavior Biological Markers Birth Body Surface Area Categories Cells Cessation of life Chemicals Child Dangerousness Data Dermatopathology Development Diagnosis Disadvantaged Drug Delivery Systems Epitope spreading Excision Exhibits FRAP1 gene Face Frequencies Genetic Genetic Engineering Genetically Engineered Mouse Growth Hair Hair Removal Hair follicle structure Haptens Histologic Histone Deacetylase Histone Deacetylase Inhibitor Human Imatinib Imiquimod Immune Immunodeficient Mouse Individual Infant Inflammation Injections Lesion MEKs Measures Medical Melanocortin 1 Receptor Modeling Mole the mammal Monitor Monobenzone Monophenol Monooxygenase Morbidity - disease rate Mus Mutation Neonatal Nevus Nevus Cell Oncogenes Oncogenic Operative Surgical Procedures PI3K/AKT Pathway interactions Patients Pharmacology Pharmacotherapy Phase Pigments Population Pre-Clinical Model Prevention Proliferating Property Proto-Oncogene Proteins c-akt Publishing Regimen Reporting Resected Risk Signal Transduction Skin Stimulator of Interferon Genes System Tamoxifen Testing Therapeutic Time Tissue Grafts Tissues Topical application Transgenic Organisms Variant Vitiligo Xenograft procedure anti-PD-1 base drug candidate giant congenital nevus healing high risk immune checkpoint blockade in utero inhibitor/antagonist lifetime risk lipophilicity melanocyte melanoma model building mouse model mutant novel therapeutic intervention pre-clinical preclinical evaluation prevent promoter psychosocial senescence small molecule social success therapeutic evaluation treatment strategy tumorigenic virtual

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.

项目摘要巨型先天性黑素细胞NEVI实际上是NRAS驱动的黑色素细胞的克隆增殖独立于紫外线的子宫内发育，可能覆盖多达80％的身体。最危险的巨型NEVI的结果是进展到黑色素瘤的风险。这提示了完整的手术切除病变产生深远而永久的发病率。能够回归这些病变的药物治疗最大程度地降低黑色素瘤的终身风险可能对这些儿童非常有益。我们已经生成了使用本构型CRE或局部他莫昔芬诱导的CRE表达（两种黑素细胞都受到限制）激活其内源性启动子中的致癌NRASQ61R表达。在除了清晰的组织学和生物标志物具有类似于人类巨人Nevi的特征，这些模型表现出一种增生阶段，然后是衰老期，并以相似频率转化为浸润性黑色素瘤就像在人类中一样。 AIM 1将表征这些特征，确定过渡时间到衰老，因为疗法可能在早期/增殖与后期/衰老病变中产生不同的效率。我们还将检查变更我们的模型中的头发生长（也类似于人类巨人Nevi），并且显然提高了侵略性如最近建议的人类，这些病变在MC1RE/E红头发的遗传背景中。我们已经开始要对这些模型进行主要管理药物疗法的治疗（AIM 2），包括： 1）NRAS下游信号传导的小分子拮抗剂（MEK，ERK，PI3激酶和AKT抑制剂）； 2）黑素细胞特异性有毒剂（靶向CKIT，MITF和酪氨酸酶的拮抗剂）； 3）免疫接近触发局部炎症和表位散布的方法（imiquimod，imiquimod，化学触觉[接触敏化剂]，一种亲脂性刺激（干扰素基因的刺激剂）激动剂，BCG，BCG，单独和与抗PD1的组合）。我们的初步结果表明了奈夫的显着清除率种群使用多种单一和组合方法，尽管需要进一步优化。我们假设可以从应用中得出有效的巨型先天性黑素细胞NEVI的安全疗法在上述方法中利用局部药物输送的主要好处。治疗将集中于根除既活跃地增殖细胞（如新生儿病变）和衰老细胞（如在大儿童中），均为建模这里。我们已经验证了一组严格的信号活动的生物标志物以及关键细胞种群用于对病变和治疗的敏感监测。预防黑色素瘤形成也可以测试使用我们的模型。为了进一步验证实际活着的人类巨人尼维的有希望的方法，我们现在常规并稳定地植入了从儿童的手术切除的巨型柳组织到免疫缺陷的小鼠（AIM 3）。在 AIM 2，从而可以在人类巨人Nevi中进行严格的临床前治疗评估。