Synergistically Acting Targeted Therapeutics for Melanoma

描述（由申请人提供）：恶性黑色素瘤仍然是最致命的皮肤癌，没有有效的药物可用于患者的长期治疗。黑色素瘤社区认为，需要靶向促进转移性黑色素瘤发展的关键蛋白质或途径的疗法，这些疗法以协同方式有效治疗这种疾病。虽然认为MAP和PI 3激酶途径需要与其他关键途径一起被沿着抑制，但是目前对于黑色素瘤不存在要靶向的特定基因的身份和实现该目标的治疗剂。使用基于siRNA的试剂靶向播散性黑素瘤中失调的关键激酶是一种方法，但是使用siRNA靶向的激酶的身份用于协同作用的肿瘤抑制仍然是未知的，并且siRNA在动物中的递送仍然是一个挑战。我们的长期目标是开发抑制转移性黑色素瘤中失调蛋白的治疗剂，以协同作用的方式缩小肿瘤。为了实现这一目标，中心假设提出，siRNA靶向的Akt 3，V600 EB-Raf和其他在黑色素瘤中失调的关键激酶可以加载到纳米脂质体中，并用于协同抑制转移性疾病的发展。将通过以下方式评估中心假设：（1）鉴定当与V600 EB-Raf和Akt 3一起沿着靶向时哪些关键激酶导致协同作用的肿瘤抑制。基于siRNA的筛选将用于鉴定黑素瘤细胞系中失调的激酶，验证肿瘤以及转移发展中的参与，并确定与V600 EB-Raf和Akt 3一起沿着的抑制是否导致协同抑制。(2)评估含有siRNA靶向V600 EB-Raf、Akt 3和其他在黑色素瘤中失调的关键激酶的纳米脂质体是否可以以协同作用的方式抑制转移性疾病。将开发含有设计用于靶向V600 EB-Raf、Akt 3和黑色素瘤中其他关键激酶的siRNA的纳米脂质体，并在动物中评价协同抑制转移性黑色素瘤发展的功效。开发靶向促进黑色素瘤转移发展的关键激酶的协同作用治疗剂将是重要的、新颖的和创新的科学进步。这些药物将为一类新的治疗药物奠定基础，以更有效地治疗患有播散性黑色素瘤的患者。从长远来看，它将增加目前可用的有效治疗转移性疾病的小武器库，从而直接降低死亡率。 公共卫生相关性：开发协同作用的治疗剂来抑制播散性转移性黑色素瘤将是一个重要的、新颖的和创新的科学进步。本提案中概述的研究将证明含有siRNA靶向Akt 3、V600 EB-Raf和其他在黑色素瘤中失调的关键激酶的治疗性纳米脂质体以协同作用方式抑制肿瘤发展的可行性。此外，它们将为一类新的治疗药物奠定基础，以更有效地治疗患有这种疾病的患者。长期而言，它将增加目前可用的用于治疗播散性转移性黑色素瘤的有效疗法的小武库，从而直接降低死亡率。

DESCRIPTION (provided by applicant): Malignant melanoma remains the most deadly skin cancer with no effective drugs available for the long-term treatment of patients. The melanoma community believes that therapies targeting key proteins or pathways promoting metastatic melanoma development is needed that act in a synergistic manner to effectively treat this disease. While it's thought that the MAP and PI3 kinase pathways need to be inhibited along with other key pathways, the identity of particular genes to target and therapeutics to accomplish this objective do not currently exist for melanoma. Targeting key kinases deregulated in disseminated melanoma using siRNA-based agents is one approach but the identity of kinases to target using siRNA for synergistically acting tumor inhibition remains unknown and delivery of siRNA in animals remains a challenge. Our long-term goal is to develop therapeutic agents inhibiting proteins deregulated in metastatic melanoma to shrink tumors in a synergistically acting manner. To accomplish this objective, the central hypothesis proposes that siRNA-targeting Akt3, V600EB-Raf and other key kinases deregulated in melanoma can be loaded into nanoliposomes and used to synergistically inhibit metastatic disease development. The central hypothesis will be evaluated by: (1) Identifying which key kinases when targeted along with V600EB-Raf and Akt3 lead to synergistically acting tumor inhibition. An siRNA-based screen will be used to identify kinases deregulated in melanoma cell lines, validate involvement in tumor as well as metastasis development and determine whether inhibition along with V600EB-Raf and Akt3 leads to synergistic inhibition. (2) Evaluating whether nanoliposomes containing siRNA-targeting V600EB-Raf, Akt3 and other key kinases deregulated in melanoma can inhibit metastatic disease in a synergistically acting manner. Nanoliposomes containing siRNA designed to target V600EB-Raf, Akt3 and other key kinases in melanoma will be developed and efficacy for synergistically inhibiting metastatic melanoma development evaluated in animals. Development of synergistically acting therapeutic agents targeting key kinases promoting melanoma metastasis development would be a significant, novel and innovative scientific advancement. These agents would lay the foundation for a new category of therapeutic drug to more effectively treat patients suffering from disseminated melanoma. Long- term it would increase the currently available small arsenal of effective therapeutics for treating metastatic disease, thereby directly decreasing mortality rates. PUBLIC HEALTH RELEVANCE: Development of synergistically acting therapeutic agents to inhibit disseminated metastatic melanoma would be a significant, novel and innovative scientific advancement. Studies outlined in this proposal would demonstrate the feasibility of therapeutic nanoliposomes containing siRNA-targeting Akt3, V600EB-Raf and other key kinases deregulated in melanoma to inhibit tumor development in a synergistically acting manner. Furthermore, they would lay the foundation for a new category of therapeutic drugs to more effectively treat patients suffering from this disease. Long-term it would increase the currently available small arsenal of effective therapeutics for treating disseminated metastatic melanoma, thereby directly decreasing mortality rates.