Targeting Pten - An Upstream, Downstream and Offstream Approach

过去几年的遗传学研究发现，超过80%的浑南黑色素瘤携带控制MEK/MAPK信号通路的B-Raf或N-Ras癌基因突变。现在很明显，针对这一途径的组成部分开发的第二代和第三代抑制剂无法有效地抑制黑色素瘤的发展/进展，这突显了迫切需要确定在这种肿瘤类型中解除调控的其他途径(S)。在可能增强去调控的MEK/MAPK信号的主要途径中，Pten/Akt信号通路就是其中之一。在黑色素瘤中，30%的肿瘤具有失活的Pten，50%的肿瘤表达结构性活性的Akt。该计划项目代表了一种高度集成的方法，以将与 黑色素瘤中的PTEN/Akt信号通路。这一提议的总体假设是，了解Pten介导的黑色素瘤肿瘤发生和进展的潜在机制为针对其频繁失活的后果提供了独特的机会。为了实现这一目标，该计划 该项目联合了一个国际知名的合作者小组，他们将跨越学科界限，为Pten/Akt介导的黑色素瘤的发展提供新的见解，并为Pten/Akt靶向肿瘤治疗开发新的策略。我们将首次定义泛素连接酶Siah的作用 在黑色素瘤中表达上调，在黑色素瘤的发展和转移中是必需的，以及识别和表征与Pten/Akt通路相关的代谢通量。我们还建议在新药靶点的验证、基于结构的药物设计和分子签名的识别方面做出高度集中的努力，以表明患者将对REN/Akt靶向治疗有反应。 在三个核心的综合支持下，这三个项目将共同解决以下Pten生物学的中心问题。JL项目：确定Pten/Akt如何通过E3连接酶Siah2调节肿瘤的发生和转移。项目2：定义由Pten/Akt调节的中枢碳代谢的各个方面，并评估这些代谢中心是否为Pten Null的有效药物靶点 肿瘤。项目3：使用基于结构的药物设计来开发针对AKT和Siah2的新药。除行政核心(核心A)外，还将支持siRNA构建和文库(核心B)、人类肿瘤细胞系和TMA的分析，以确定拟议研究过程中确定的标记的分子签名，以及分析针对2D、3D培养和动物模型研究的每一种成分开发的抑制剂(核心C)。 总体而言，分子生物学、生物化学、代谢组学和基于结构的药物设计的这种结合，为以关键的Tumo[抑制基因Pten/Akt]为中心的肿瘤生物学中的关键悬而未决的问题和恶性黑色素瘤的研究提供了一个无与伦比的机会。

Genetic studies over the past few years have identified that over 80% of hunnan melanomas carry mutations in B-Raf or N-Ras oncogenes, which control the MEK/MAPK signaling pathway. It is now apparent that second and third generation inhibitors developed against components of this pathway fail to elicit effective inhibition of melanoma tumor development/progression, highlighting the urgent need to identify additional pathway(s) that are deregulated in this tumor type. Among primary pathways that are likely to augment deregulated MEK/MAPK signaling is the Pten/Akt signaling cascade. In melanoma, 30% of tumors have inactivated Pten and 50% of tumors express a constitutively active Akt. This program project represents a highly integrated approach to translate basic science findings pertaining to the Pten/Akt signaling pathway in melanoma. The overall hypothesis of this proposal is that understanding mechanisms underlying the Pten mediated melanoma tumor development and progression offers unique opportunities for targeting the consequence of its frequent inactivation. To achieve this goal, this Program Project unites an internationally renowned group of collaborators who will cross disciplinary boundaries to provide novel insights into Pten/Akt-mediated melanoma development and to develop new strategies for Pten/Akt-targeted tumor therapy. For the first time we will define the role of the ubiquitin ligase Siah which is upregulated in melanoma and is required for its development and metastasis, as well as identify and characterize metabolic fluxes that are linked to the Pten/Akt pathway. We also propose highly focused efforts in the validation of new drug targets, structure-based drug design, and the identification of molecular signatures to indicate patients that will respond to Ren/Akt-targeted therapy. With the integrated support of the three cores, the three projects will work together to address the following central questions in Pten biology. Project jl: Determine how Pten/Akt regulates tumorigenesis and metastasis through the E3 ligase Siah2. Project 2: Define aspects of central carbon metabolism that are regulated by Pten/Akt, and assess whether these metabolic hubs are valid drug targets in Pten null tumors. Project 3: Use structure-based drug design to develop novel drugs targeting AKT and Siah2. In addition to the administrative core (Core A), support will be provided for siRNA constructs and libraries (Core B), and analysis of human tumor cell lines and TMAs for molecular signatures of markers identified in the course of the proposed studies and for analysis of inhibitors developed against each of the components studied in 2D, 3D cultures and animal rriodel (Core C). Overall, this combination of molecular biology, biochemistry, metabolomics, and structure based drug design offers a second to none opportunity for integrated studies that address critical unanswered questions in tumor biology centered on key tumo[ suppressor gene Pten/Akt with focus on malignant melanoma.