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长期治疗患者。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，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，但目前尚不存在针对黑色素瘤的特定基因和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靶向激酶的身份仍然未知，并且siRNA在动物中的传递仍然是一个挑战。我们的长期目标是开发治疗药物，抑制转移性黑色素瘤中失调的蛋白质，以协同作用的方式缩小肿瘤。为了实现这一目标，中心假设提出，sirna靶向的Akt3、V600EB-Raf和其他在黑色素瘤中失调的关键激酶可以被装载到纳米脂体中，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Akt3一起协同作用肿瘤抑制。基于sirna的筛选将用于识别黑色素瘤细胞系中失调的激酶，验证其与肿瘤和转移发展的关系，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sirna靶向V600EB-Raf、Akt3等黑素瘤脱调控关键激酶的纳米脂体是否能协同作用抑制转移性疾病。将开发含有siRNA的纳米脂体，用于靶向黑色素瘤中的V600EB-Raf、Akt3和其他关键激酶，并在动物实验中评估其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药物将是一项重大的、新颖的和创新的科学进展。这些药物将为一种新的治疗药物类别奠定基础，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用于治疗转移性疾病的有效治疗方法，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.