Preclinical targeting of the tumor microenvironment: Possibilities and consequences

Metastatic disease is currently the main cause of all cancer induced deaths. Therefore, there is an ongoing search for new treatment strategies that may increase treatment effects. However, the importance of the tumor microenvironment as a contributor to tumor growth and metastatic disease has become more evident. This provides the rational for targeting not only the cancer cells, but also the tumor microenvironment, in order to aim to improve cancer treatment. To enable accurate targeting, it is essential to identify key targets present in the tumor microenvironment. Two potential targets present in the tumor microenvironment are transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF).

The tumor and its microenvironment are reproduced in preclinical models consisting of both stromal and cancer cells. These in vitro and in vivo models show that stromal cells are needed to exert the TGF-β mediated anti-breast cancer effect of the bisphosphonate zoledronic acid. In addition, the preclinical development of a TGF-β tracer is described. With this technique, a radiolabeled antibody can be depicted with the help of positron emission tomography (PET). With the use of the TGF-β tracer it was possible to portray the presence of TGF-β in tumors.
For VEGF, the effect of anti-VEGF therapy on tumor uptake of drugs was evaluated with the help of PET imaging. Anti-VEGF therapy reduced tumor uptake of other drugs in two preclinical models.

In conclusion, this thesis describes the possibilities and consequences of targeting factors present in the tumor microenvironment.