Inhibition of the pro-tumorigenic effects of TGFbeta in tumor therapy


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Carl-Henrik Heldin1
1Uppsala University

Abstract

Transforming growth factor-beta (TGFbeta) regulates growth, survival and differentiation of most cell types. It signals by binding to type I and type II serine/threonine kinase receptors, leading to activation of Smad molecules that form complexes which act as transcription factors in the nucleus. TGFbeta also activates non-Smad pathways, including Erk1/2, JNK and p38 MAP kinases, Src, phosphatidylinositol 3ยด-kinase (PI3K), and formation of a soluble intracellular domain of the type I receptor (TbetaRI-ICD). In cancer, TGFbeta is initially a tumor suppressor, but acquires tumor promoting activities at later stages of tumor progression, including induction of epithelial-mesenchymal transition (EMT), which is correlated to increased invasiveness and metastasis. We aim at developing selective TGFbeta inhibitors which inhibit only the tumor promoting effects of TGFbeta. For this purpose, we are identifying the pathways involved, e.g. TbetaRI-ICD, PI3K Erk1/2 MAPK kinases and Src, and the mechanisms whereby TGFbeta induces these pathways. Moreover, we have screened for low molecular weight inhibitors of TGFbeta-induced EMT. Our aim is to explore whether such compounds, or other selective inhibitors of the pro-tumorigenic effects of TGFbeta which we are developing, can be used for improved treatment of patients with advanced cancers.