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Research line II: Mechanisms of resistance

 

The aim of research line II is to identify and understand clinically relevant mechanisms of primary or secondary resistance to anti-angiogenic antitumor agents and to design more effective therapeutic combinations.

 

Although it was originally assumed that anti-angiogenic agents would not be susceptible to development of resistance, because they are designed to target genetically stable endothelial cells, development of resistance, in particular to anti-VEGF(R) agents may not be entirely surprising. Because of the critical nature of VEGF in homeostasis, inhibition of its signalling results in upregulation of VEGF production as well as other compensatory cytokines and growth factors, like PlGF, SDF-1 or erythropoietin, in animals as well as cancer patients (Ebos et al., Proc.Natl.Acad.Sci.USA, 2007; Vroling et al., Angiogenesis, 2009). This type of compensatory upregulation of signalling growth factors is at least partly explained by increased tumor hypoxia and consequent stabilisation of HIF-1a and increased transcription of gene programs under the control of HIF, such as SDF-1 and VEGF.

Because there is still very little firm evidence from clinical studies giving insight into mechanisms of non-responsiveness, we study the mechanisms in vitro, in tumor bearing mice and in clinical studies. For a rational application of the current clinically most useful anti-angiogenic multitargeted tyrosine kinase inhibitors (TKIs) like sunitinib or sorafenib, it will be essential to understand the critical signalling pathways affected in the context of relevant micro-environmental interactions between tumor and endothelial cells under hypoxic conditions. Combined cellular, pharmacological and phosphoproteomics and network analysis in tumor cells and ECs will provide new insights and understanding in mechanisms of response and resistance to TKIs. Our ultimate aim is to improve the clinical use of these TKIs by either circumvention of resistance with alternative (combination) treatment strategies that overcome resistance to these agents or by patient selection for treatment-based on predictive resistance markers.

 

Vasculogenic mimicry

One mechanism of resistance to angiogenesis inhibition is the escape of tumor cells through a process that is called vasculogenic mimicry. Plasticity of tumor cells may may lead to dedifferentiation into an endothelial cell-like phenotype. This tumor cell based vasculature is independent on angiogenesis and heavily associated with short survival. We intend to get more insight in the mechanisms of vasculogenic mimicry and are interested in finding therapeutic targets for the treatment of vasculogenic mimicry containing tumors (Paulis et al, BBA reviews cancer, 2010; Van der Schaft et al. Cancer Research, 2005).