Synergistically Acting Targeted Therapeutics for Melanoma

黑色素瘤的协同作用靶向治疗

• 批准号: 8011210
• 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/8011210
• 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; 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，目前尚无有效药物可用于患者的长期治疗。黑色素瘤界认为，需要针对促进转移性黑色素瘤发展的关键蛋白质或途径的疗法，以协同方式发挥作用，以有效治疗这种疾病。虽然人们认为 MAP 和 PI3 激酶途径需要与其他关键途径一起受到抑制，但目前黑色素瘤尚不存在针对特定目标基因的身份以及实现这一目标的治疗方法。使用基于 siRNA 的药物靶向播散性黑色素瘤中失调的关键激酶是一种方法，但使用 siRNA 协同作用肿瘤抑制的激酶的身份仍然未知，并且在动物中递送 siRNA 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蛋白质失调的治疗药物，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，可以将靶向 Akt3、V600EB-Raf 和黑色素瘤中失调的其他关键激酶的 siRNA 装载到纳米脂质体中，并用于协同抑制转移性疾病的发展。中心假设将通过以下方式进行评估：(1) 确定哪些关键激酶与 V600EB-Raf 和 A​​kt3 一起靶向时会产生协同作用的肿瘤抑制作用。基于 siRNA 的筛选将用于识别黑色素瘤细胞系中失调的激酶，验证对肿瘤和转移发展的参与，并确定与 V600EB-Raf 和 A​​kt3 一起抑制是否会产生协同抑制。 (2) 评估含有针对黑色素瘤中失调的 siRNA 的 V600EB-Raf、Akt3 和其他关键激酶的纳米脂质体是否能够以协同作用的方式抑制转移性疾病。将开发含有 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，并在动物身上评估协同抑制转移性黑色素瘤发展的功效。开发针对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一项重大、新颖和创新的科学进步。这些药物将为新型治疗药物奠定基础，以更有效地治疗患有播散性黑色素瘤的患者。从长远来看，它将增加目前治疗转移性疾病的有效疗法的小规模库，从而直接降低死亡率。 公共健康相关性：开发具有协同作用的治疗药物来抑制播散性转移性黑色素瘤将是一项重大、新颖和创新的科学进步。该提案中概述的研究将证明含有 siRNA 靶向 Akt3、V600EB-Raf 和黑色素瘤中失调的其他关键激酶的治疗性纳米脂质体以协同作用的方式抑制肿瘤发展的可行性。此外，它们还将为新型治疗药物奠定基础，以更有效地治疗患有这种疾病的患者。从长远来看，它将增加目前治疗播散性转移性黑色素瘤的有效疗法的小规模库，从而直接降低死亡率。