Targeted Chemoprevention for Melanoma

黑色素瘤的靶向化学预防

• 批准号: 8596798
• 负责人: Gavin P. Robertson
• 金额: $ 39.41万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-12 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596798
• 关键词: Achievement; Animal Disease Models; Animal Model; Animals; Antibodies; Attention; Cell Survival; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Cutaneous Melanoma; Development; Disease; Disease Progression; Drug Formulations; Excision; Gene Combinations; Gene Targeting; Goals; Health; Home environment; Human; Incidence; Interdisciplinary Study; Lead; Lesion; Liposomes; Luciferases; Lymphatic; Lymphatic System; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Monitor; Movement; Mus; Mutate; Operative Surgical Procedures; PTEN gene; Pathway interactions; Patients; Penetration; Phosphotransferases; Physiological; Premalignant; Primary Lesion; Primary Neoplasm; Proteins; Research; Sentinel Lymph Node Biopsy; Signal Transduction; Skin; Skin Cancer; Small Interfering RNA; Staging; Techniques; Technology; Testing; Time; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; Translations; Ultrasonography; Work; base; cancer cell; clinical application; clinically significant; design; innovation; interest; killings; lymph nodes; melanoma; migration; mortality; mutant; nanoliposome; nanoscale; novel; novel strategies; prevent; public health relevance; reconstruction; tumor

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（由申请人提供）：恶性黑色素瘤是所有皮肤癌中最致命的。尽管具有致命性，但尚无靶向局部化学预防剂可以在其早期形式或当细胞存在于早期原发性病变附近的淋巴系统中时抑制这种癌症。 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，从而促进黑色素瘤的发展。使用基于 siRNA 的药物抑制 Akt3 和其他关键激酶来靶向早期黑素细胞病变细胞对于靶向黑色素瘤化学预防可能很重要，但 siRNA 的递送仍然是一个挑战。目前，还没有技术或方法利用 siRNA 作为化学预防剂来抑制早期黑色素瘤的发展。该申请重点关注黑色素瘤化学预防，通过使用基于 siRNA 的药物抑制 Akt3 和突变型 V600EB-Raf、GSK31 或 Wee1 激酶来靶向早期黑色素细胞病变，这些药物被证明可以协同抑制黑色素细胞病变细胞。因此，本研究的中心假设是，针对 Akt3 和突变体 V600EB-Raf、GSK31 或 Wee1 激酶的 siRNA 可以通过新型超声纳米脂质体技术递送到含有早期黑色素细胞病变的皮肤中，以防止黑色素瘤发展以及这些细胞侵入或通过淋巴系统。其基本原理是，针对这些基因的 siRNA 将作为途径特异性靶向化学预防剂来预防黑色素瘤的发展。我们基于原理证明的初步发现制定了这一假设，该发现确定了可以与 Akt3 抑制协同作用的靶标激酶。此外，我们还发现，针对 Akt3 和 V600EB-Raf 的 siRNA 可以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，有效抑制黑素瘤细胞的存活，如果一起递送，可以协同预防疾病的发展。因此，本申请的目的是首先评估含有 siRNA 靶向 Akt3 和突变体 V600EB-Raf、GSK31 或 Wee1 激酶的新型纳米脂质体在疾病转基因动物模型中的化学预防功效，在该模型中 Akt3 和 V600EB-Raf 均失调以促进自发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 加载到针对抗体的纳米脂质体中，并在超声处理后，有效地将药物递送到动物皮肤中自发形成的早期黑素细胞病变中来实现。其次，我们将确定这些药物是否可以预防或减少早期黑素细胞对淋巴结的侵袭，从而减少疾病的发展并有助于生存。这将通过在黑素细胞病变细胞侵入淋巴结盆地之前或之后用纳米脂质体 siRNA 治疗小鼠来实现，以确定它是否会阻止疾病进展。在超声介导的皮肤透化后，使用抗体靶向纳米脂质体制剂递送针对关键激酶的 siRNA 是一种新方法，对于更有效地化学预防黑色素瘤并抑制其扩散到淋巴系统并通过淋巴系统扩散至关重要。