Therapeutic strategies for treatment of giant congenital melanocytic nevi
巨大先天性黑素细胞痣的治疗策略
基本信息
- 批准号:10570507
- 负责人:
- 金额:$ 51.17万
- 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 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcidsAgonistAnguishAnimal ModelAnti-Inflammatory AgentsBindingBody SurfaceCD8-Positive T-LymphocytesCD8B1 geneChildChildhoodChildhood MelanomaClinicalClinical TrialsComplementCongenital melanocytic nevusCutaneousDeformityDermatologyDiseaseDoseEngineeringEstersExcisionExhibitsFundingGeneticGenetically Engineered MouseGoalsHaptensHistologyHumanHyperpigmentationImiquimodImmunityImmunodeficient MouseImmunologic Deficiency SyndromesIndividualInfantInflammationInflammatoryInstitutional Review BoardsKineticsLaser injuryLasersLesionLoxP-flanked alleleMEK inhibitionMEKsMacrophageMeasurableMedicalMelanocytic NeoplasmMelanocytic nevusMelanosomesMethodsModelingModificationMorbidity - disease rateMouse StrainsMusNational Institute of Arthritis, and Musculoskeletal, and Skin DiseasesNatural ImmunityNatural Killer CellsNeoplasmsNevusNevus CellOncogenesOperative Surgical ProceduresPIK3CG genePeptidesPharmacotherapyPhasePre-Clinical ModelPreventionProbabilityPublishingRegimenRegressing MelanomaReportingReproducibility of ResultsResectedRiskSILV geneScheduleSkinSymptomsT-LymphocyteTamoxifenTestingTherapeuticTissuesTitrationsTopical applicationToxic effectTransplantationTreatment-related toxicityVisualXenograft procedureadaptive immunityanti-PD-1constitutive expressioneffector T cellgiant congenital nevushuman diseaseinducible Creinducible gene expressioninhibitorkinase inhibitormelanocytemelanomamortalitymouse modelneoantigenspre-clinicalpreventpromoterrecruitsenescenceskin lesiontreatment strategytumor
项目摘要
Abstract
Congenital Melanocytic Nevi (CMN) can reach giant sizes, transform to childhood melanoma, and thus trigger
pre-emptive surgery inducing profound morbidity. In the prior funding period, we constructed four CMN models
to test regression-inducing treatments aimed at avoiding surgery. Three are genetically engineered mice driven
by the (floxed)NRASQ61R oncogene, responsible for most human CMN, with melanocyte-targeting via tamoxifen-
inducible or constitutive expression from Tyr or Dct promoters (varied strengths). The fourth model is xenografted
resected human CMNs on immunodeficient mice. Several models displayed melanoma transformation after long
latency. Inducible NRASQ61R clarified the kinetics of proliferative vs senescent nevus phases and verified
regressive treatments to succeed in either phase. Tyr-Cre;NRASQ61R exhibited severe human-like CNS and skin
lesions whereas the weaker Dct-Cre induced a more typical skin-restricted giant nevi for which inhibitors of MEK,
PI3K, or cKIT induced incomplete (~80%) regressions and combinations fully depleted visual nevocytes. Topical
treatment with the proinflammatory hapten Squaric Acid Dibutyl Ester (SADBE) induced complete visual CMN
regression after 3 doses. This regimen also fully prevented murine melanoma transformation, within all treated
nevus skin. We found that topical SADBE requires macrophages (not B, T, or NK cells), so it could be tested in
human CMN xenografted onto SHO mice (which lack adaptive immunity but retain macrophages). SADBE
recruited murine macrophages into the human xenografts and regressed ~90% of the human nevocytes. Since
SADBE is already used elsewhere in dermatology, and has been reported to induce “depigmentation,” we plan
to test it clinically. However, since clinical trials with efficacy endpoints are not supported in R01s from NIAMS,
we are seeking separate funding to support this clinical trial that already received FDA/IND and IRB approvals.
While we are excited by the models and strategies uncovered during this funding period, we believe it is crucial
to build on this progress to increase the likelihood of achieving real therapeutic breakthrough for this devastating
children’s disease. Accordingly Aims 1-3 use our models to boldly seek further enhanced efficacy and minimized
toxicity of treatments: Aim 1 deeply and systematically develops kinase inhibitor combinations. It also tests MEK
inhibitors (MEKi) with SADBE, as both exhibit individual efficacy and MEKi was recently shown to promote M1-
like (pro-inflammatory) over M2-like macrophage differentiation, a mechanistic feature that may enhance
SADBE’s efficacy. Aim 2 seeks localized T cell adaptive immunity recruitment, to complement SADBE’s
macrophage induction. We have shown anti-PD1 triggers recruitment of melanocyte (gp100) targeted T-cells
when combined with topical SADBE. We will also combine fractional laser treatment plus anti-PD1 which, as we
recently published, also triggers local recruitment of melanocyte-targeted T-cells. Aim 3 systematically uses our
models to test varied dose/schedules of anti-inflammatory approaches that are commonly used in infants, to
optimize SADBE’s nevus regression efficacy while minimizing cutaneous toxicity and inflammatory symptoms.
抽象的
先天性黑色素细胞痣 (CMN) 可以达到巨大尺寸,转变为儿童黑色素瘤,从而引发
先发制人的手术会导致严重的发病率。在前期资助期间,我们构建了四个CMN模型
测试旨在避免手术的回归诱导治疗。其中三种是基因工程小鼠驱动的
由(floxed)NRASQ61R癌基因负责,负责大多数人类CMN,通过他莫昔芬靶向黑素细胞-
Tyr 或 Dct 启动子的诱导型或组成型表达(不同强度)。第四种模型是异种移植的
在免疫缺陷小鼠身上切除人类 CMN。几个模型在长时间后显示出黑色素瘤转化
延迟。诱导型 NRASQ61R 阐明了增殖痣与衰老痣阶段的动力学并得到验证
回归治疗在任一阶段都取得成功。 Tyr-Cre;NRASQ61R 表现出严重的类人中枢神经系统和皮肤
病变,而较弱的 DCT-Cre 诱发更典型的皮肤限制性巨大痣,MEK 抑制剂,
PI3K 或 cKIT 诱导不完全 (~80%) 消退,并且组合完全耗尽视觉神经细胞。专题
使用促炎半抗原方酸二丁酯 (SADBE) 治疗可诱导完全视觉 CMN
3剂后消退。该方案还完全阻止了所有接受治疗的小鼠黑色素瘤转化
痣皮肤。我们发现局部 SADBE 需要巨噬细胞(不是 B、T 或 NK 细胞),因此可以在
将人类 CMN 异种移植到 SHO 小鼠(缺乏适应性免疫但保留巨噬细胞)上。萨德贝
将小鼠巨噬细胞招募到人类异种移植物中,并使约 90% 的人类神经细胞退化。自从
SADBE 已在皮肤科的其他地方使用,据报道会引起“色素脱失”,我们计划
进行临床测试。然而,由于 NIAMS 的 R01 不支持具有疗效终点的临床试验,
我们正在寻求单独的资金来支持这项已获得 FDA/IND 和 IRB 批准的临床试验。
虽然我们对本次融资期间发现的模型和策略感到兴奋,但我们认为这是至关重要的
在此基础上再接再厉,增加针对这种毁灭性的疾病取得真正治疗突破的可能性
儿童疾病。因此,目标 1-3 使用我们的模型大胆寻求进一步增强功效并最小化
治疗的毒性:目标1深入、系统地开发激酶抑制剂组合。它还测试 MEK
抑制剂 (MEKi) 与 SADBE,因为两者都表现出各自的功效,并且 MEKi 最近被证明可以促进 M1-
与 M2 样巨噬细胞分化类似(促炎症),这一机制特征可能会增强
SADBE的功效。目标 2 寻求局部 T 细胞适应性免疫招募,以补充 SADBE
巨噬细胞诱导。我们已经证明抗 PD1 会触发黑色素细胞 (gp100) 靶向 T 细胞的募集
与局部 SADBE 联合使用时。我们还将结合点阵激光治疗和抗 PD1 治疗,因为我们
最近发表的研究还触发了针对黑色素细胞的 T 细胞的局部募集。目标 3 系统地使用我们的
模型来测试婴儿常用的不同剂量/时间表的抗炎方法,
优化 SADBE 的痣消退功效,同时最大限度地减少皮肤毒性和炎症症状。
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:
$ 51.17万 - 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:
$ 51.17万 - 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:
$ 51.17万 - 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:
$ 51.17万 - 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:
$ 51.17万 - 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
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