Project Summary/Abstract Soft tissue sarcomas (STS) constitute a family of mesenchymal -origin malignancies that can occur anywhere in the body. Comprising more than 50 distinct histological subtypes, STS share several distinctive features that include frequent local recurrence after definitive therapy, marked chemoresistance, and frequent metastasis, especially to the lungs. These features translate to a dismal outcome, especially for those patients harboring high grade complex karyotype STS histologies, consisting mainly of leiomyosarcoma and high grade pleomorphic sarcoma ( malignant fibrous histiocytoma and fibrosarcoma). To improve STS therapeutic outcome it will be critical to develop novel agents that capitalize on underlying STS points of molecular vulnerability; however, progress towards this urgent goal are hampered by our minimal understanding of the molecular determinants underlying STS prog ression and dissemination. Tumor cells, including STS, respond to signaling cascades that control growth regulation processes and other components of the malignant process such as motility, invasion, induction of apoptosis, etc. Among theses signaling mechanisms, the AKT kinase pathway may be particularly important in STS growth and dissemination. Phosphorylation of AKT is a critical step in this cascade, had has been associated with impaired STS prognosis when identified in STS tissues. In human STS cell lines and human STS xenografts growing in immuno -incompetent mice, AKT inhibition interferes with STS growth, perhaps by disrupting AKT interaction with vimentin, a critical structural protein that may also have oncologically-relevant functional properties. Our group is apparently the first to identify the existence of AKT -vimentin interactions. We propose to study the regulation of this interaction, hoping to learn more about the mechanisms underlying these interactions, the functional significance of this interaction regarding how it impacts on STS proliferation and metastasis in vivo, and finally to test preclinical therapeutic approaches to AKT and vimentin blockade, hoping to demonstrate preclinical relevance using human STS xenograft mouse models and murine sarcoma models.
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