Synergistically Acting Targeted Therapeutics for Melanoma

描述(申请人提供)：恶性黑色素瘤仍然是最致命的皮肤癌，没有有效的药物可供患者长期治疗。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或途径的治疗方法，以协同方式有效治疗这种疾病。虽然人们认为MAP和PI3激酶途径需要与其他关键途径一起被抑制，但目前黑色素瘤还不存在特定基因的同一性和实现这一目标的治疗方法。使用基于siRNA的药物靶向在播散性黑色素瘤中解除调控的关键激酶是一种方法，但使用siRNA协同作用抑制肿瘤的靶向激酶的特性尚不清楚，并且在动物中传递siRNA仍然是一个挑战。我们的长期目标是开发治疗药物，抑制转移性黑色素瘤中放松调控的蛋白质，以协同作用的方式缩小肿瘤。为了实现这一目标，中心假说提出，靶向AKT3、V600EB-Raf和黑色素瘤中解除调控的其他关键激酶的siRNA可以被装载到纳米脂质体中，并用于协同抑制转移疾病的发展。中心假设将通过以下方面进行评估：(1)确定当靶向V600EB-Raf和AKT3时，哪些关键激酶与V600EB-Raf和AKT3一起导致协同作用的肿瘤抑制。基于siRNA的筛选将用于识别黑色素瘤细胞系中放松调控的激酶，验证参与肿瘤和转移发展，并确定抑制与V600EB-Raf和AKT3一起是否导致协同抑制。(2)评价靶向V600EB-Raf、AKT3等黑色素瘤关键蛋白的siRNA纳米脂质体能否协同抑制黑色素瘤的转移。将开发含有针对黑色素瘤V600EB-Raf、AKT3和其他关键激酶的siRNA的纳米脂质体，并在动物身上评估协同抑制转移性黑色素瘤发展的有效性。开发针对促进黑色素瘤转移的关键激酶的协同作用的治疗药物将是一项重大的、新颖的和创新的科学进步。这些药物将为一种新的治疗药物奠定基础，以更有效地治疗播散性黑色素瘤患者。从长远来看，它将增加目前可用于治疗转移性疾病的有效疗法的少量武器库，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药物以抑制播散性转移性黑色素瘤将是一项重大的、新颖的和创新的科学进步。这项建议中概述的研究将证明包含针对AKT3、V600EB-Raf和黑色素瘤中放松调控的其他关键激酶的siRNA的治疗性纳米脂质体的可行性，以协同作用的方式抑制肿瘤的发展。此外，它们还将为一种新的治疗药物奠定基础，以便更有效地治疗这种疾病的患者。从长远来看，它将增加目前可用于治疗播散性转移性黑色素瘤的少量有效治疗药物，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.