SelectiveTGFb-inhib SIGNED

Project "SelectiveTGFb-inhib" data sheet

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 Project objective

Transforming growth factor-b (TGFb) is a multifunctional cytokine which has important functions during embryonal development and in tissue homeostasis. In cancer, TGFb is often overexpressed and has both tumor suppressor effects (induction of growth arrest and apoptosis) and tumor promoting effects (stimulation of epithelial-mesenchymal transition (EMT) of tumor cells, stimulation of angiogenesis and cancer associated fibroblasts, and suppression of immune surveillance). Our aim is to elucidate the mechanisms for the pro-tumorigenic effects of TGFb and to develop selective inhibitors which can be used to suppress tumor invasiveness and metastasis in animal models, and later on for treatment of patients with advanced cancer. We think it is important to develop selective inhibitors, which do not affect the tumor suppressive effects of TGFb, since complete inhibition of TGFb may cause severe side effects and may even promote tumorigenesis. We plan to: 1. perform a systematic analysis of posttranslational modifications and interactors of the TGFb receptor I (TbRI) and II (TbRII), and determine their functional importance for the induction of various pro-tumorigenic pathways; 2. determine the mechanism whereby TGFb activates the tyrosine kinase Src, and its role in invasiveness and metastasis; 3. attempt to selectively inhibit the activation of phosphatidylinositol 3´-kinase by TGFb, in order to inhibit tumor cell survival and migration; 4. elucidate the functional role in the nucleus of the cleaved intracellular domain of TbRI, and attempt to inhibit its formation and thereby tumor metastasis; 5. determine the cellular compartment where the pro-tumorigenic signaling pathways are activated; 6. elucidate mechanisms for TGFb-induced EMT and develop candidate low molecular weight inhibitors that we have obtained from a screen, aiming at using them in vivo to suppress metastasis; 7. develop biomarkers to identity patient cohorts for treatment with selective TGFb inhibitors.