Synergistically Acting Targeted Therapeutics for Melanoma

黑色素瘤的协同作用靶向治疗

• 批准号: 8207282
• 负责人: Gavin P. Robertson
• 金额: $ 31.22万
• 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: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207282
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animal Model; Animals; Categories; Cell Line; Cell Survival; Communities; Cultured Cells; Data; Development; Disease; Drug Formulations; Foundations; Generations; Genes; Goals; Human; Individual; Lead; Mediating; Melanoma Cell; Metastatic Melanoma; Mitogen-Activated Protein Kinases; Modeling; Nature; Neoplasm Metastasis; Normal Cell; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Proteins; Research; Skin Cancer; Small Interfering RNA; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Work; animal model development; base; cancer cell; design; innovation; killings; melanoma; mortality; mouse model; mutant; nanoliposome; novel; public health relevance; success; therapeutic target; tumor; uptake

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.

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，需要以协同方式起作用的促进转移性黑色素瘤发育的关键蛋白质或促进转移性黑色素瘤发育的疗法以有效治疗这种疾病。虽然认为需要抑制地图和PI3激酶途径与其他关键途径一起抑制，但特定基因对靶向和治疗剂的身份目前不存在黑色素瘤。靶向使用基于siRNA的剂在传播黑色素瘤中失控的关键激酶是一种方法，但是激酶使用siRNA进行协同作用作用抑制siRNA仍然未知，动物中siRNA的递送仍然是一个挑战。我们的长期目标是开发抑制在转移性黑色素瘤中失调的蛋白质以协同作用方式缩小肿瘤的治疗剂。为了实现这一目标，中央假设提出，靶向siRNA靶向AKT3，V600EB-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育。中央假设将通过：（1）确定与V600EB-RAF和AKT3一起靶向哪些关键激酶，导致协同作用起作用肿瘤。基于siRNA的筛查将用于鉴定在黑色素瘤细胞系中失调的激酶，验证参与肿瘤以及转移的发育，并确定与V600EB-RAF和AKT3一起抑制是否会导致协同抑制。 （2）评估含有含siRNA的V600EB-RAF，AKT3和其他关键激酶的纳米型体是否可以以协同的作用方式抑制转移性疾病。将开发含有含有siRNA的纳米脂质体，旨在靶向黑色素瘤中的V600EB-RAF，AKT3和其他关键激酶，并有效地抑制动物中评估的转移性黑色素瘤发育。针对促进黑色素瘤转移发展的关键激酶的协同作用的治疗剂的开发将是一个重大，新颖和创新的科学进步。这些药物将为一种新的治疗药物奠定基础，以更有效地治疗患有传播黑色素瘤的患者。长期，它将增加当前可用的有效治疗疗法的小武器库来治疗转移性疾病，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以抑制传播的转移性黑色素瘤将是一个重大，新颖和创新的科学进步。该提案中概述的研究将证明含有含SiRNA靶向AKT3，V600EB-RAF的治疗性纳米脂质体的可行性，而其他在黑色素瘤中失调的其他关键激酶可抑制肿瘤在协同行动方式中抑制肿瘤的发展。此外，他们将为一种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，它将增加当前可用的有效疗法的小武器库来治疗传播转移性黑色素瘤，从而直接降低死亡率。