Current Status of Therapeutic Targeting of Developmental Signalling Pathways in Oncology

Tobias      Kiesslich; Frieder      Berr; Beate      Alinger; Ralf      Kemmerling; Martin      Pichler; Matthias      Ocker; Daniel      Neureiter

Abstract

Signalling pathways such as Hedgehog (Hh), Wnt, Notch, bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β) hold a central position in regulation of vertebrate development by controlling vital processes such as migration, differentiation and proliferation. Insights into the mechanistic aspects of cancer initiation and progression have pointed to striking similarities between tumourigenesis and embryonic development. These observations can partly be explained by the fact that similar cellular signalling mechanisms are employed in both situations. This review focuses on the role and therapeutic potential of Hh, Wnt, Notch and BMP/TGF-β signalling and discusses i) their signal transduction mechanisms during development and tumourigenesis, ii) evidence of pathway activation in different types of cancers, and, iii) strategies for pharmacological targeting. Numerous studies have demonstrated a crucial role of developmental signalling in a variety of tumours, where their signalling mechanisms contribute to oncogenic properties such as tumour cell proliferation, apoptosis inhibition and / or metastatic migration. From the literature available, it is obvious that the relative importance and the oncogenic mechanisms of developmental pathways vary with the tumour type, the stage of the disease as well as the interaction with the tumour microenvironment, thus highlighting the complexity of cellular signalling strategies employed during tumourigenesis. Intensive research activities are devoted to identification of drugs that interfere with oncogenic signalling by developmental pathways. First clinical data for such compounds – e.g. GDC-0449 for the Hh pathway – are promising and indicate that targeted therapy of developmental signalling pathways has potential for future anti-cancer therapies.

Keywords: Apoptosis, BMP, cancer, developmental signalling pathway, hedgehog, notch, TGF-β, Wnt, cancer initiation, tumourigenesis, signal transduction mechanisms, apoptosis inhibition