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.
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