Targeted Chemoprevention for Melanoma

黑色素瘤的靶向化学预防

基本信息

批准号：
8044192
负责人：
Gavin P. Robertson
金额：
$ 43.21万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
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：
https://reporter.nih.gov/project-details/8044192
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 nanoscale novel novel strategies prevent public health relevance reconstruction tumor

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. PUBLIC HEALTH RELEVANCE: Over the long-term, discovery of targeted chemopreventive agents that inhibit kinases involved in melanocytic lesion development are predicted to significantly decrease melanoma incidence rates. Specifically, development of this nanoscale antibody-targeted chemopreventive agent would have significant potential to impact human health by decreasing the number of people developing this disease, thereby directly decreasing mortality rates from melanoma. Therefore, the positive impact of this study for preventing melanoma would be significant.

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。尽管具有致死性，但尚无靶向局部化学预防剂以最早的形式抑制该癌症，或者在早期原发性病变附近淋巴系统中存在细胞时。在可能的化学预防靶标中，AKT3的活性在约70％的肿瘤中增加以促进黑色素瘤发育。使用基于siRNA的剂靶向早期黑素细胞病变细胞来抑制AKT3和其他关键激酶对于靶向黑色素瘤化学预防可能很重要，但是siRNA的递送仍然是一个挑战。目前，尚无技术或方法利用siRNA作为化学预防剂来抑制早期黑色素瘤的发育。该应用的重点是通过使用基于siRNA的剂抑制AKT3和突变体V600EB-RAF，GSK31或WEE1激酶的早期黑素细胞病变来靶向黑色素瘤化学预防，这些病变被证明可协同抑制黑素细胞细胞。因此，提出的研究的中心假设是，靶向Akt3和突变体V600EB-RAF，GSK31或WEE1激酶可以通过新型的超声纳米型技术传递到含有早期黑素细胞病变的皮肤中，以防止这些细胞发育和入侵这些细胞，以防止这些细胞进入或侵袭这些细胞通过淋巴系统。理由是，针对这些基因的siRNA将作为特定靶向化学预防剂的途径，以防止黑色素瘤发育。我们基于鉴定可以与Akt3抑制协同作用的激酶的主要初步发现提出了这一假设。此外，我们表明，针对AKT3和V600EB-RAF的siRNA可以加载到纳米注合体中，并放在超声治疗后含有黑色素细胞病变的皮肤上，有效地抑制黑色素瘤细胞的存活，并且如果递送在一起，可以合作防止疾病的发展。因此，本应用的目标是首先，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的化学预防疗效，在AKT3和V600EB-RAF的转基因动物模型中受管制以促进自发的黑素细胞病变的发育。这将通过将靶向AKT3和V600EB-RAF，GSK31或WEE1的siRNA加载到抗体靶向抗体靶向的纳米型纳米脂质体并进行超声处理后来实现，从而有效地将剂传递到动物皮肤皮肤皮肤皮肤中的早期早期黑素细胞病变中。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细胞的淋巴结侵袭，从而减少疾病发育并有助于生存。这将通过在黑素细胞病变细胞侵袭淋巴结盆地之前或之后用纳米脂质体siRNA治疗小鼠来实现这一点，以确定它是否会预防疾病进展。超声介导的皮肤通信后使用抗体靶向的纳米脂质体配方对关键激酶进行siRNA是一种新颖的方法，这是一种非常有效的化学预防化学性化学性化学方法，并通过淋巴系统抑制其扩散。公共卫生相关性：在长期的，发现抑制黑色素细胞病变发育涉及的激酶的靶向化学预防剂可显着降低黑色素瘤发病率。具体而言，这种纳米级抗体靶向化学预防剂的开发将通过减少患上这种疾病的人数来影响人类健康的巨大潜力，从而直接降低了黑色素瘤的死亡率。因此，这项研究对预防黑色素瘤的积极影响将是显着的。