PDK1 as a Novel Target in Melanoma

PDK1 作为黑色素瘤的新靶点

基本信息

批准号：
8898742
负责人：
Ze'ev A Ronai
金额：
$ 38.17万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-12 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898742
关键词：
1-Phosphatidylinositol 3-Kinase 3-Phosphoinositide Dependent Protein Kinase-1 Ablation Affect Animals Attention BRAF gene Biological Markers Cells Clinical Clinical Trials Combined Modality Therapy Development Dominant-Negative Mutation Drug resistance Foundations Gene Expression Profiling Genes Genetic Genetic Models Genetic Transcription Genotype Health Human Immune Infiltration Interferons JUN gene Lesion Lung MAPK Signaling Pathway Pathway MEKs Maps Mediating Melanogenesis Melanoma Cell Microarray Analysis Modality Modeling Molecular Monitor Mus Mutation Neoplasm Metastasis Nevus Oncogenic Outcome PTEN gene Pathway interactions Patients Phosphoric Monoester Hydrolases Phosphotransferases Pigments Play Proto-Oncogene Proteins c-akt Resistance Role Sampling Signal Pathway Signal Transduction Stratification Therapeutic Tissue Microarray Transplantation Tumor Cell Line Up-Regulation base clinically significant cohort combinatorial cytokine genetic analysis high throughput screening human FRAP1 protein inhibitor/antagonist lymph nodes melanocyte melanoma mouse model mutant novel novel therapeutics response tensin tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Alterations in the PTEN/AKT/PI3K and BRAF/MEK/MAPK signaling pathways play a central role in the development and progression of the majority of melanomas. Over 50% of human melanomas have inactivation of PTEN and upregulation of the AKT/phosphatidylinositol 3-kinase (PI3K) signaling pathways. Yet, while considerable effort is being devoted to the development of PI3K/AKT inhibitors as possible combinatorial therapies with the currently available BRAFV600E inhibitors, little attention has been paid to the potential therapeutic importance of 3-phosphoinositide-dependent protein kinase 1 (PDK1), a regulator of the AKT and PKC signaling pathways. Our preliminary results provide the first genetic evidence for the significance of PDK1 in melanoma development and progression, and provide the foundation for our hypothesis that PDK1 is an important regulatory component in melanogenesis and a novel target for melanoma therapy. Melanocyte-specific deletion of PDK1 in BrafV600E:Pten-/-:Pdk1-/- animals delayed the development of pigmented lesions and the onset of melanoma formation with concomitant and significant delay in lung and lymph node metastasis. Further, pharmacological PDK inhibitors also delayed melanomagenesis and metastasis. Gene expression analysis highlights a role for PDK1-FOXO signaling in melanomagenesis. TMA analysis identified high PDK1 expression in melanoma, but not nevi. We therefore propose to: (i) substantiate these initial observations in Nras and Braf mutan melanoma harboring WT Pten-models representing the vast majority of human melanomas, (ii) characterize the molecular mechanisms underlying PDK1 control of melanoma development and progression through mapping the AGC kinases affected by PDK1 and the role of PDK1 in tumor microenvironment as for select subpopulations of melanoma, (iii) identify biomarkers for PDK1- sensitive tumors and determine the clinical significance of PDK1 expression in melanoma, and (iv) develop and characterize effective combinatorial therapies involving PDK1 inhibitors to increase response and reduce treatment resistance. Our proposed studies provide an unprecedented opportunity to establish the importance of PDK1 in melanoma development and its potential as novel therapeutic modality.

描述（由申请人提供）：PTEN/AKT/PI3K 和 BRAF/MEK/MAPK 信号通路的改变在大多数黑色素瘤的发生和进展中发挥着核心作用。超过 50% 的人类黑色素瘤存在 PTEN 失活和 AKT/磷脂酰肌醇 3-激酶 (PI3K) 信号通路上调。然而，尽管人们投入了大量精力开发 PI3K/AKT 抑制剂作为与现有 BRAFV600E 抑制剂的可能组合疗法，但很少有人关注 3-磷酸肌醇依赖性蛋白激酶 1 (PDK1) 的潜在治疗重要性。 AKT 和 PKC 信号通路的调节因子。我们的初步结果为PDK1在黑色素瘤发生和进展中的重要性提供了第一个遗传证据，并为我们的假设奠定了基础：PDK1是黑色素生成的重要调节成分和黑色素瘤治疗的新靶点。 BrafV600E:Pten-/-:Pdk1-/- 动物中黑素细胞特异性删除 PDK1 可延迟色素病变的发展和黑色素瘤形成的开始，同时显着延迟肺和淋巴结转移。此外，药理学PDK抑制剂还可以延迟黑色素瘤的生成和转移。基因表达分析强调了 PDK1-FOXO 信号在黑色素瘤发生中的作用。 TMA 分析发现黑色素瘤中 PDK1 高表达，但痣中则不然。因此，我们建议：（i）证实 Nras 和 Braf mutan 黑色素瘤中的这些初步观察结果，这些黑色素瘤含有代表绝大多数人类黑色素瘤的 WT Pten 模型，（ii）通过绘制 AGC 来表征 PDK1 控制黑色素瘤发展和进展的分子机制对于选定的黑色素瘤亚群，受 PDK1 影响的激酶以及 PDK1 在肿瘤微环境中的作用，(iii) 识别 PDK1 敏感肿瘤的生物标志物并确定PDK1 表达在黑色素瘤中的临床意义，以及 (iv) 开发并表征涉及 PDK1 抑制剂的有效组合疗法，以提高反应并降低治疗耐药性。我们提出的研究提供了前所未有的机会来确定 PDK1 在黑色素瘤发展中的重要性及其作为新型治疗方式的潜力。