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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：
DAVID E FISHER
金额：
$ 35.34万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10245261
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.

项目总结