Individuals with glioblastoma multiforme (GBM), one of the most aggressive types of brain tumor, have an extremely poor prognosis. Although pre-clinical studies indicated therapeutics inhibiting a group of proteins known as receptor tyrosine kinases (RTKs) would likely be beneficial to individuals with GBM, these RTK inhibitors have met with limited clinical success — only a small proportion of patients respond to such treatment and most subsequently relapse after only a short time.
New data, generated by Andrew Kung and colleagues, at the Dana-Farber Cancer Institute, Boston, have now provided insight into the mechanism by which GBM cells become resistant to RTK inhibitors and have suggested a way to improve the efficacy of RTK inhibitors in this clinical setting. The researchers report their findings in the Aug. 1 issue of the Journal of Clinical Investigation.
In the study, human GBM cells exposed in vitro to an inhibitor of the RTK PDGFR activated a cellular pathway that usually induces cells to undergo a form of cell death known as apoptosis, but the final steps of the pathway were not completed, meaning that the cells did not die.
Further analysis revealed that the final steps of this pathway were blocked by a group of proteins known as IAPs. Consistent with this, if the PDGFR inhibitor was combined with an IAP inhibitor the GBM cells underwent apoptosis. Further, this drug combination showed enhanced efficacy at inhibiting tumor growth in an orthotopic mouse model of GBM. The authors therefore suggest that combining drugs targeting IAPs with RTK inhibitors might prove beneficial to individuals with GBM.
- Ziegler et al. Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins. Journal of Clinical Investigation, 2008; DOI: 10.1172/JCI34120
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