Targeted Chemoprevention for Melanoma
黑色素瘤的靶向化学预防
基本信息
- 批准号:8403919
- 负责人:
- 金额:$ 38.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-12 至 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:AchievementAnimal Disease ModelsAnimal ModelAnimalsAntibodiesAttentionCell SurvivalCellsChemopreventionChemopreventive AgentClinicalCutaneous MelanomaDevelopmentDiseaseDisease ProgressionDrug FormulationsExcisionGene CombinationsGene TargetingGoalsHealthHome environmentHumanIncidenceInterdisciplinary StudyLeadLesionLiposomesLuciferasesLymphaticLymphatic SystemMalignant NeoplasmsMediatingMelanoma CellMetastatic MelanomaModelingMonitorMovementMusMutateOperative Surgical ProceduresPTEN genePathway interactionsPatientsPenetrationPhosphotransferasesPhysiologicalPremalignantPrimary LesionPrimary NeoplasmProteinsResearchSentinel Lymph Node BiopsySignal TransductionSkinSkin CancerSmall Interfering RNAStagingTechniquesTechnologyTestingTimeTransgenic AnimalsTransgenic MiceTransgenic ModelTransgenic OrganismsTranslationsUltrasonographyWorkbasecancer cellclinical applicationclinically significantdesigninnovationinterestkillingslymph nodesmelanomamigrationmortalitymutantnanoliposomenanoscalenovelnovel strategiespreventpublic health relevancereconstructiontumor
项目摘要
DESCRIPTION (provided by applicant): Malignant melanoma is the most deadly of all skin cancers. Despite its lethality, no targeted topical chemopreventive agents exist to inhibit this cancer in its earliest forms or when cells are present in the lymphatic system in the proximity of the early primary lesion. Among possible chemopreventive targets is Akt3 whose activity increases in ~70% of tumors to promote melanoma development. Targeting early melanocytic lesion cells using siRNA-based agents to inhibit Akt3 and other key kinases could be important for targeted melanoma chemoprevention, but delivery of siRNA remains a challenge. Currently, no technology or approach utilizes siRNA as a chemopreventive agent to inhibit early melanoma development. This application focuses on melanoma chemoprevention by targeting early melanocytic lesions using siRNA-based agents to inhibit Akt3 and mutant V600EB-Raf, GSK31 or Wee1 kinases, which are shown to synergistically inhibit melanocytic lesion cells. Thus, the central hypothesis for the proposed research is that siRNA targeting Akt3 and mutant V600EB-Raf, GSK31 or Wee1 kinases can be delivered via novel ultrasound-nanoliposomal technology into skin containing early melanocytic lesions to prevent melanoma development and invasion of these cells into or through the lymphatic system. The rationale is that siRNA targeting these genes would serve as pathway specific targeted chemopreventive agents to prevent melanoma development. We formulated this hypothesis based on proof-of-principal preliminary discoveries identifying kinases to target that can synergise with Akt3 inhibition. Furthermore, we show that siRNA against Akt3 and V600EB-Raf can be loaded into nanoliposomes and placed on skin containing melanocytic lesions following ultrasound treatment, effectively inhibiting melanoma cell survival, and if delivered together it can cooperatively prevent disease development. Thus, the objectives of this application are to first, evaluate the chemopreventive efficacy of novel nanoliposomes containing siRNA-targeting Akt3 and mutant V600EB-Raf, GSK31 or Wee1 kinases in a transgenic animal model of the disease in which both Akt3 and V600EB-Raf are deregulated to promote spontaneous melanocytic lesion development. This will be accomplished by loading siRNA targeting Akt3 and V600EB-Raf, GSK31 or Wee1 into antibody-targeted nanoliposomes and following ultrasound treatment, effectively deliver agents into spontaneously developing early melanocytic lesions in skin of animals. Second, we will determine whether these agents can prevent or decrease lymph node invasion by early melanocytic cells to decreased disease development and aid survival. This will be accomplished by treating mice with nanoliposomal siRNA prior to or following invasion of the lymph node basin by melanocytic lesion cells to establish whether it will prevent disease progression. Delivery of siRNA against key kinases using an antibody-targeted nanoliposomal formulation following ultrasound-mediated skin permeabalization is a novel approach critically needed for more effective chemoprevention of melanoma and inhibition of its spread into and through the lymphatic system.
描述(申请人提供):恶性黑色素瘤是所有皮肤癌中最致命的。尽管它是致命的,但没有靶向的局部化学预防药物可以抑制这种癌症的早期形式,或者当细胞出现在早期原发病变附近的淋巴系统时。AKT3是可能的化学预防靶点之一,其活性在约70%的肿瘤中增加,以促进黑色素瘤的发展。靶向早期黑素细胞病变细胞使用基于siRNA的药物来抑制AKT3和其他关键激酶对于靶向黑色素瘤的化学预防可能是重要的,但siRNA的传递仍然是一个挑战。目前,还没有技术或方法利用siRNA作为化学预防药物来抑制早期黑色素瘤的发展。这一应用侧重于通过靶向早期黑素细胞病变的化学预防,使用基于siRNA的药物来抑制AKT3和突变的V600EB-Raf、GSK31或Wee1激酶,这些酶被证明可以协同抑制黑素细胞病变细胞。因此,这项研究的中心假设是,针对AKT3和突变的V600EB-Raf、GSK31或Wee1激酶的siRNA可以通过新型超声-纳米脂质体技术传递到包含早期黑素细胞病变的皮肤中,以防止黑色素瘤的发展和这些细胞入侵淋巴系统。其基本原理是,针对这些基因的siRNA将作为路径特异性靶向化学预防药物,以防止黑色素瘤的发展。我们提出这一假设是基于初步发现的主要证据,确定了可以与AKT3抑制协同作用的靶向激酶。此外,我们发现针对AKT3和V600EB-Raf的siRNA可以被装载到纳米脂质体中,并在超声治疗后放置在含有黑素细胞病变的皮肤上,有效地抑制黑色素瘤细胞的存活,如果一起传递,它可以协同预防疾病的发展。因此,本应用的目的是首先评估新型纳米脂质体在转基因动物模型中的化学预防效果,在转基因动物模型中,AKT3和V600EB-Raf都被解除调控,以促进自发性黑素细胞病变的发展。这将通过将针对AKT3和V600EB-Raf、GSK31或Wee1的siRNA装载到抗体靶向纳米脂质体中,并在超声波治疗后,有效地将药物输送到动物皮肤自发形成的早期黑素细胞损伤中。其次,我们将确定这些药物是否可以防止或减少早期黑素细胞对淋巴结的侵袭,以减少疾病的发展和帮助生存。这将通过在黑素细胞病变细胞侵入淋巴结盆之前或之后用纳米脂质体siRNA治疗小鼠来实现,以确定它是否可以防止疾病的进展。在超声介导的皮肤渗透后,使用抗体靶向纳米脂质体配方针对关键激酶传递siRNA是一种新的方法,对于更有效地化学预防黑色素瘤和抑制其扩散到淋巴系统和通过淋巴系统是至关重要的。
项目成果
期刊论文数量(0)
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Gavin P. Robertson其他文献
Compositions et procédés comprenant de la léélamine et de l'arachidonyl trifluorométhyl cétone concernant le traitement du cancer
涉及癌症特性的亚麻胺和花生四烯基三氟甲基丙酮的组合物和程序
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Gavin P. Robertson;Omer F. Kuzu - 通讯作者:
Omer F. Kuzu
Functional and therapeutic significance of Akt deregulation in malignant melanoma
- DOI:
10.1007/s10555-005-1577-9 - 发表时间:
2005-06-01 - 期刊:
- 影响因子:8.700
- 作者:
Gavin P. Robertson - 通讯作者:
Gavin P. Robertson
Managing telomerase and telomere dysfunction in acral melanoma
肢端黑色素瘤中端粒酶和端粒功能障碍的处理
- DOI:
10.1016/j.phrs.2025.107700 - 发表时间:
2025-05-01 - 期刊:
- 影响因子:10.500
- 作者:
Vishnu Sravan Bollu;Yu-Chi Chen;Fan Zhang;Krishne Gowda;Shantu Amin;Arun K. Sharma;Todd D. Schell;Jiyue Zhu;Gavin P. Robertson - 通讯作者:
Gavin P. Robertson
Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length
用人类调控序列修饰端粒酶基因可将小鼠端粒重置为人类长度
- DOI:
10.1038/s41467-025-56559-6 - 发表时间:
2025-02-04 - 期刊:
- 影响因子:15.700
- 作者:
Fan Zhang;De Cheng;Kenneth I. Porter;Emily A. Heck;Shuwen Wang;Hui Zhang;Christopher J. Davis;Gavin P. Robertson;Jiyue Zhu - 通讯作者:
Jiyue Zhu
Gavin P. Robertson的其他文献
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{{ truncateString('Gavin P. Robertson', 18)}}的其他基金
Targeting Aldehyde Dehydrogenase for Cancer Prevention
以醛脱氢酶为靶点预防癌症
- 批准号:
10589837 - 财政年份:2020
- 资助金额:
$ 38.26万 - 项目类别:
Synergistically Acting Targeted Therapeutics for Melanoma
黑色素瘤的协同作用靶向治疗
- 批准号:
8011210 - 财政年份:2010
- 资助金额:
$ 38.26万 - 项目类别:
Synergistically Acting Targeted Therapeutics for Melanoma
黑色素瘤的协同作用靶向治疗
- 批准号:
7782587 - 财政年份:2010
- 资助金额:
$ 38.26万 - 项目类别:
Synergistically Acting Targeted Therapeutics for Melanoma
黑色素瘤的协同作用靶向治疗
- 批准号:
8207282 - 财政年份:2010
- 资助金额:
$ 38.26万 - 项目类别:
Synergistically Acting Targeted Therapeutics for Melanoma
黑色素瘤的协同作用靶向治疗
- 批准号:
8403542 - 财政年份:2010
- 资助金额:
$ 38.26万 - 项目类别:
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