The occurrence of severe side effects and the development of resistance are two of the biggest problems facing modern cancer therapy. Even the latest, highly targeted cancer drugs such as the tyrosine kinase inhibitors Tarceva® or Sutent® are affected by these problems, which can ultimately lead to treatment having to be stopped. The effect of this class of inhibitors is based on the specific inhibition of proteins that are over-activated in cancer cells and which drive abnormal cell growth. However, clinical practice has shown that, as a result of the physiological functions of these proteins in healthy tissue, their inhibition can cause severe side effects. As a result, there is an acute need for strategies to restrict the effect of these highly promising new drugs more selectively to the malignant tumour.
The aim of the research was to develop an improved tyrosine kinase inhibitor that is actually inactive and which is only activated selectively in the malignant tissue. This is intended to prevent damage to healthy tissue and therefore minimise side effects for patients. As part of the paper published in the highly respected journal "Angewandte Chemie [Applied Chemistry], International Edition", a new inhibitor has been successfully synthesised and coordinated to cobalt(III). This leads to initial drug inactivation and, thus, no activity under normal physiological conditions. Only in tumour tissue where, due to the rapid growth, unusually low-oxygen conditions prevail, the inactive cobalt(III) compound is reduced to cobalt(II) and as a result releases the active drug. The tumour-selective effectiveness of this approach has been demonstrated both in living cells and in tumor-bearing organisms.
The development of this complex idea and strategy was made possible by the outstanding interdisciplinary collaboration organised in the context of the "Translational Cancer Therapy Research" platform led by Bernhard Keppler, Dean of the Faculty of Chemistry at the University of Vienna, and Walter Berger, Professor at the Medical University of Vienna. This research platform promotes constant scientific exchange between synthetic chemists at the University of Vienna and cancer researchers at the Medical University of Vienna. It is only through these opportunities that the team of university assistants Christian Kowol (University of Vienna) and Petra Heffeter (Medical University of Vienna) has been able, based on two diploma theses (by Claudia Karnthaler-Benbakka, MSc., and Diana Groza, MSc.), to produce these results. The study was funded by the City of Vienna fund for "innovative interdisciplinary cancer research", the Austrian Science Fund (FWF) and COST CM1105. In view of the highly promising results, the new combination class has been patented by the two universities and currently a partner for further (clinical) development is searched.
So far there has been no comparable strategy for reducing the (severe) side effects of tyrosine kinase inhibitors. As a result, there is hope that, in future, the approach presented here will improve the tolerance of the therapy and allow this treatment to benefit patients who have previously had to discontinue it.
Publikation in "Angewandte Chemie, International Edition":
Tumor-Targeting of EGFR Inhibitors by Hypoxia-Mediated Activation: C. Karnthaler-Benbakka, D. Groza, K. Kryeziu, V. Pichler, A. Roller, W. Berger, P. Heffeter und C. R. Kowol. 2014.
» Englisch onlinelibrary.wiley.com/doi/10.1002/anie.201403936/abstract
» Deutsch onlinelibrary.wiley.com/doi/10.1002/ange.201403936/abstract