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：
8563220
负责人：
Ze'ev A Ronai
金额：
$ 40.88万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8563220
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 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 public health relevance 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信号通路的变化在大多数黑色素瘤的发展和发展中起着核心作用。超过50％的人黑色素瘤灭活了PTEN和AKT/磷脂酰肌醇3-激酶（PI3K）信号通路的上调。 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.我们的初步结果为PDK1在黑色素瘤发育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，即PDK1是黑色素生成中的重要调节成分，也是黑色素瘤治疗的新颖靶标。 brafv600e中PDK1的黑色素细胞特异性缺失：PTEN - / - ：PDK1 - / - 动物延迟了色素病变的发育以及黑色素瘤形成的发作，并随着肺和淋巴结转移的伴随和显着延迟。此外，药理学PDK抑制剂还延迟了黑色素作和转移。基因表达分析强调了PDK1-福克斯信号在黑色素作用中的作用。 TMA分析鉴定了黑色素瘤中的高PDK1表达，但没有NEVI。因此，我们提出：（i）证实这些最初观察到的NRAS和BRAF突变性黑色素瘤含有代表绝大多数人黑色素瘤的WT PTEN模型，（ii）表征了PDK1在PDK1控制中的分子机制的特征。黑色素瘤（III）的生物标志物的生物标志物鉴定出用于PDK1敏感性肿瘤的生物标志物，并确定PDK1表达在黑色素瘤中的临床意义，（iv）发展并表征涉及PDK1抑制剂的有效组合疗法以增加反应并降低治疗耐药性。我们提出的研究为确定PDK1在黑色素瘤发育中的重要性及其作为新型治疗方式的潜力提供了前所未有的机会。