PDK1 as a Novel Target in Melanoma

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起核心作用。超过50%的人黑色素瘤存在PTEN失活和AKT/磷脂酰肌醇3-激酶（PI3K）信号通路上调。然而，尽管人们致力于开发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，PDK1是AKT和PKC信号通路的调节因子。我们的初步结果为PDK1在黑色素瘤发生发展中的重要意义提供了第一个遗传学证据，并为PDK1是黑色素瘤发生的重要调控成分和黑色素瘤治疗的新靶点的假设提供了基础。BrafV600E:Pten-/-: PDK1 -/-动物中黑色素细胞特异性缺失PDK1延迟了色素病变的发展和黑色素瘤形成的发生，同时显著延迟了肺和淋巴结转移。此外，药理PDK抑制剂也延缓黑色素瘤的发生和转移。基因表达分析强调PDK1-FOXO信号在黑色素瘤形成中的作用。TMA分析发现黑色素瘤中PDK1表达高，但痣中没有。因此，我们建议：(i)在包含WT pten模型的Nras和Braf突变黑色素瘤中证实了这些初步观察结果，这些模型代表了绝大多数人类黑色素瘤；（ii）通过绘制受PDK1影响的AGC激酶和PDK1在肿瘤微环境中的作用，表征了PDK1控制黑色素瘤发生和进展的分子机制。（iii）确定PDK1敏感肿瘤的生物标志物，并确定PDK1在黑色素瘤中表达的临床意义；（iv）开发和表征涉及PDK1抑制剂的有效组合疗法，以增加反应并降低治疗耐药性。我们提出的研究提供了一个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。

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.