Targeted Therapies in Melanoma

黑色素瘤的靶向治疗

• 批准号: 8270012
• 负责人: Meenhard F Herlyn
• 金额: $ 239.56万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-16 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270012
• 关键词: 1-Phosphatidylinositol 3-Kinase; Apoptosis; BRAF gene; Biochemistry; Biological; Cell Survival; Cellular Immunity; Chemicals; Chemistry; Collaborations; Complex; Development; Disease; Generations; Goals; In Vitro; Induction of Apoptosis; MDM2 gene; MEKs; Melanoma Cell; Modeling; Molecular; Molecular Target; Mus; Mutate; Oncogenic; Pathway interactions; Phosphotransferases; Protein Isoforms; Proteins; Proto-Oncogene Proteins B-raf; Reagent; Ruthenium; Specificity; Structure; Tumor Biology; base; in vivo; in vivo Model; inhibitor/antagonist; melanoma; member; mutant; novel; overexpression; programs; scaffold; small molecule; structural biology; treatment strategy; tumor growth; tumor immunology

DESCRIPTION (provided by applicant): The long-term objective of this program project is to develop new strategies for the treatment of melanoma, based on a mechanistic understanding of key proteins that are associated with the disease and the development of small molecule inhibitors to these proteins. The group proposes to pursue the following goals 1. Target oncogenic BRAF for therapy of melanoma. The oncogenic BRAF mutant, BRAFV600E, has evolved as, arguably, the most important target in melanoma. We will use several approaches to explore the use of BRAF , as a target for therapy: We will: i. Use currently available inhibitors of the MARK pathways with activity for either BRAF or MEK using complex in vitro and orthotopic in vivo models (Project 1); ii. Induce specific cellular immunity against BRAF that leads to tumor growth inhibition in a melanoma model in mice (Project 2); iii. Develop a new generation of inhibitors for BRAFV600E based on the crystal structure of BRAF (Project 3); and iv. Develop new organic inhibitors and a new generation of organometallic inhibitors using a ruthenium pyridocarbazole molecular scaffold to BRAFV600E with increased specificity and efficacy (Projects 3 and 4). We expect the development of new therapies of melanoma that focus on BRAFV600E as a molecular target to result from these combined biological, immunological, structural and chemical studies. 2. Target the PI3 kinase pathway with a new generation of inhibitors and use these in combination with BRAF inhibitors for therapy of melanoma. Based on preliminary studies in project 1, we hypothesize that PI3a kinase pathways are highly important for melanoma cell survival. Projects 3 and 4 combine structural and chemical strategies to identify a novel generation of inhibitors to the PI3Ka/? isoforms. The inhibitors will be developed based on the organometallic scaffold described above for the BRAF kinases (Project 4), and supported by inhibitor screens in vitro (Project 4) and in vivo (Projects 1) and x-ray crystal structures of PI3K? inhibitor complexes (Project 3). In addition, we will explore novel Akt/PKB inhibitors using in vitro and in vivo models and investigate how they synergize with BRAF inhibitors (Projects 1 and 2). 3. Target GSK3? for induction of apoptosis. We have found that targeting GSK3? with organometallic inhibitors (developed in Project 4) has surprising apoptosis-inducing activities on melanoma cells (Project 1). Based on these preliminary studies we will now investigate the mechanisms of apoptosis induction, which may occur through activation of p53 (Project 1). We will also continue to prepare more potent and specific organometallic GSK3? inhibitors in project 4 for treatment of melanoma cells in project 1. Most melanomas are not mutated in GSK3?, but p53 can also be downregulated by HDM2, which is frequently overexpressed in melanoma. Together, the collaborations among members of the Program Project will combine expertise in tumor biology, tumor immunology, biochemistry, chemistry and structural biology to generate unique approaches and reagents for use in melanoma therapy.

描述(由申请人提供)：该计划项目的长期目标是开发治疗黑色素瘤的新策略，其基础是对与疾病相关的关键蛋白质的机理了解，以及对这些蛋白质的小分子抑制剂的开发。该小组建议追求以下目标1.靶向致癌的BRAF用于黑色素瘤的治疗。致癌的BRAF突变体BRAFV600E已经进化为黑色素瘤最重要的靶点。我们将使用几种方法来探索使用BRAF作为治疗的靶点：i.使用目前可用的对BRAF或MEK具有活性的Mark通路的抑制剂，使用复杂的体外和体内原位模型(项目1)；ii.诱导针对BRAF的特异性细胞免疫，从而抑制小鼠黑色素瘤模型中的肿瘤生长(项目2)；根据BRAF的晶体结构开发新一代BRAFV600E抑制剂(项目3)；开发新的有机缓蚀剂和新一代有机金属缓蚀剂，使用Ru吡咯咔唑分子支架来提高BRAFV600E的特异性和有效性(项目3和4)。我们预计，以BRAFV600E为分子靶点的黑色素瘤新疗法的开发将源于这些生物学、免疫学、结构和化学的综合研究。2.用新一代抑制剂靶向PI3激酶通路，并与BRAF抑制剂联合用于黑色素瘤的治疗。基于项目1中的初步研究，我们假设PI3a激酶通路对黑色素瘤细胞的生存非常重要。项目3和4结合了结构和化学策略，以确定新一代的PI3Ka/？抑制剂。异构体。这些抑制剂将基于上述用于BRAF激酶的有机金属支架(项目4)开发，并由体外(项目4)和体内(项目1)的抑制剂筛选和PI3K？缓蚀剂复合体(项目3)。此外，我们将利用体外和体内模型探索新型Akt/PKB抑制剂，并研究它们如何与BRAF抑制剂协同作用(项目1和2)。3.目标GSK3？用于诱导细胞凋亡。我们发现靶向GSK3？使用有机金属抑制剂(在项目4中开发)对黑色素瘤细胞具有惊人的诱导凋亡活性(项目1)。在这些初步研究的基础上，我们现在将探讨诱导细胞凋亡的机制，这可能是通过激活P53而发生的(项目1)。我们还将继续制备更有效、更特异的有机金属GSK3？项目4中的抑制剂用于治疗项目1中的黑色素瘤细胞。大多数黑色素瘤在GSK3中没有突变，但P53也可以被Hdm2下调，Hdm2在黑色素瘤中经常过表达。该计划项目成员之间的合作将结合肿瘤生物学、肿瘤免疫学、生物化学、化学和结构生物学方面的专业知识，以产生用于黑色素瘤治疗的独特方法和试剂。