The GNAQ pathway as a therapeutic target in uveal melanoma

GNAQ 通路作为葡萄膜黑色素瘤的治疗靶点

• 批准号: 9105099
• 负责人: Boris C. Bastian
• 金额: $ 30.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105099
• 关键词: Adult; Affect; Affinity Chromatography; Aggressive behavior; Area; BRAF gene; CRISPR/Cas technology; Cell Line; Clinical; Codon Nucleotides; Combined Modality Therapy; Complement; Cutaneous; Cutaneous Melanoma; Data; Disease; Frequencies; Funding; GNAQ gene; Genes; Genetic; Genetic Engineering; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Heterotrimeric GTP-Binding Proteins; Human; Immune; In Vitro; Individual; Literature; MEK inhibition; MEKs; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Mitogen-Activated Protein Kinases; Mutation; Nature; Oncogenes; Oncogenic; Output; Pathway interactions; Patients; Pattern; Phenotype; Pre-Clinical Model; Proteins; Reporting; Resistance; Signal Transduction; Somatic Mutation; Staging; Survival Rate; Therapeutic; Tissues; Treatment Efficacy; United States; Uveal Melanoma; base; beta catenin; combinatorial; effective therapy; improved; in vivo; inhibitor/antagonist; loss of function; melanocyte; melanoma; mortality; mouse model; mutant; new therapeutic target; notch protein; phosphoproteomics; pre-clinical; public health relevance; research study; small molecule; synergism; targeted treatment; therapeutic target; treatment strategy; tumor; tumor initiation; tumorigenesis

 DESCRIPTION (provided by applicant): Uveal melanoma (UM) is the most common intraocular malignancy in the United States and has a 10-year disease specific survival rate of 50%. No effective treatment options exist. Mutations in known melanoma oncogenes such as BRAF, NRAS, or KIT that prevail in cutaneous and mucosal melanoma are absent in UM. We recently identified somatic mutations in the heterotrimeric G protein alpha q subunits, GNAQ and GNA11, in over 80% of uveal melanomas. The constitutively activating mutations occur in a mutually exclusive pattern. The proportion of GNA11 mutant tumors increases with progression stage, suggesting that mutant GNA11 is a more potent oncogene. The mutations activate GNAQ and GNA11, but inactivating their GTPase activity similar to ras activation making it difficult to target them directly with small molecules. Therefore, it is paramount to characterize their respective downstream effector pathways to identify opportunities for targeted therapy. Both PKC/MAP-kinase and YAP pathways contribute to oncogenic GNAQ mediated tumorigenesis. However, the details of their activation are incompletely understood, and therapeutic targeting of those pathway shows limited therapeutic efficacy indicating that other oncogenic effector pathways might be involved. Therefore, there is a strong need to better delineate the signaling cascades triggered by oncogenic GNAQ and GNA11, explore the mechanism of adaptive resistance to pathway inhibition, and to identify additional therapeutic targets to develop a refined therapeutic strategy. In this project, we will fill this gap and investigate the three overlapping areas by using both candidate and unbiased approaches: in Aim 1, we will fill in the emerging signal network downstream of oncogenic GNAQ proteins to identify therapeutic targets. In Aim 2, we will investigate the factors that render GNA11 a more potent uveal melanoma oncogene compared to GNAQ. In Aim 3, we will validate therapeutic targets identified in Aims 1 and 2 using pre-clinical models, identify the mechanism of adaptive resistance to targeted therapy and identify synergisms between therapeutic approaches with the goal to develop improved therapeutic combination strategies for patients.

 描述(由申请人提供)：葡萄膜黑色素瘤(UM)是美国最常见的眼内恶性肿瘤，其10年特定疾病存活率为50%。没有有效的治疗选择。在皮肤和粘膜黑色素瘤中普遍存在的已知黑色素瘤癌基因突变，如BRAF、NRAS或KIT，在UM中是不存在的。我们最近在超过80%的葡萄膜黑色素瘤中发现了异源三聚体G蛋白αQ亚基GNAQ和GNA11的体细胞突变。结构性激活突变以一种相互排斥的模式发生。GNA11突变型肿瘤的比例随病程进展而增加，提示突变型GNA11是一种更有效的癌基因。这些突变激活了GNAQ和GNA11，但使它们的GTPase活性失活，这类似于ras的激活，使得它们很难直接与小分子靶向。因此，最重要的是确定它们各自的下游效应通路，以确定靶向治疗的机会。PKC/MAP-K和YAP通路均参与GNAQ介导的肿瘤发生。然而，它们的激活细节还不完全清楚，针对这些通路的治疗靶向显示出有限的治疗效果，表明其他致癌效应通路可能参与其中。因此，迫切需要更好地描述致癌基因GNAQ和GNA11触发的信号级联反应，探索适应性抵抗途径抑制的机制，并寻找更多的治疗靶点来制定完善的治疗策略。在这个项目中，我们将填补这一空白，并通过候选和无偏见的方法研究三个重叠的区域：在目标1中，我们将填充致癌GNAQ蛋白下游的新出现的信号网络，以确定治疗靶点。在目标2中，我们将调查使GNA11成为比GNAQ更有效的葡萄膜黑色素瘤癌基因的因素。在目标3中，我们将使用临床前模型验证目标1和目标2中确定的治疗目标，确定靶向治疗适应性抵抗的机制，并确定治疗方法之间的协同作用，目标是为患者开发改进的联合治疗策略。