Targeting tumour angiogenesis by targeting Angiopoietin/Tie signalling: from vascular regression over vascular normalisation to stromal reprogramming therapies

Hellmut G. Augustin1

1Vascular Oncology and Metastasis, German Cancer Research Center, Heidelberg (DKFZ-ZMBH Alliance); Vascular Biology and Tumour Angiogenesis, Medical Faculty Mannheim (CBTM), Heidelberg University; Germ, Germany, Germany

Abstract

Anti-angiogenesis was originally proposed to ‘starve tumours to death' by driving the tumour-associated vasculature into regression. This bold ambition did not materialise, but combination therapies involving VEGF/VEGFR targeting drugs have become part of standard tumour therapy for several types of tumours. With more than 10 years into the clinic, their efficacy in terms of progression free survival (PFS) and overall survival (OS) continues to be limited. Yet, the implementation of anti-angiogenic therapy marks a fundamental change-of-paradigm as the first proof-of-principle that stromal targeting can be of therapeutic benefit. Today, it is widely recognised that the MOA of anti-angiogenic intervention in human tumours can only partially be explained by global regression of the tumour-associated vasculature. Instead, anti-VEGF/VEGFR therapies prune particularly the immature tumour vasculature thereby facilitating chemotherapy by functionally normalising the pruned tumour vascular tree. Progress in anti-angiogenic intervention can be expected from combination therapies that broaden the therapeutic window of established anti-angiogenic VEGF/VEGFR targeting therapies. Moreover, the facilitation effect on other forms of therapy, not just chemotherapy, but in the future most likely also immunotherapies, promises to substantially advance vascular targeting tumour therapies. In fact, it can be foreseen that the concepts of anti-angiogenesis and vascular normalisation may be transformed towards stromal reprogramming therapies that systematically alter the tumour microenvironment to enhance the efficacy of tumoricidal drugs. The Angiopoietin/Tie system acts in concert with VEGF/VEGFR signalling. It is high up in the hierarchy of events the control vascular responses and paracrine-acting vascular-derived growth factors. The presentation will focus on the development of Ang/Tie targeting therapies for the improvement of established anti-angiogenic therapies and for the eventual development of stromal targeting therapies.