GIST research in the Duensing Lab

Gastrointestinal stromal tumors (GISTs) are a prototypical example of a solid tumor entity that was fatal in the past but that can now be successfully treated with a novel class of drugs, called small molecule protein kinase inhibitors. Imatinib mesylate (Gleevec) is the first and most prominent inhibitor that belongs to this group. It targets the KIT and PDGFRA protein kinases, which are mutated in GISTs and drives tumorigenesis. Imatinib rapidly shuts down aberrant KIT and PDGFRA signaling activity, but it needs to be emphasized that the precise molecular events that lead to GIST cell eradication are unknown. Elucidating these mechanisms would not only allow to develop a better imatinib that is even more effective and does not lead to therapy resistance, a problem that is more and more encountered in GIST patients. Moreover, understanding the mode of action of imatinib and why it is so effective in GISTs will be instrumental to develop novel small molecule protein kinase inhibitors and to identify other proteins that can be targeted therapeutically.
Towards these aims, we have begun to study the role of a protein involved in DNA damage signaling, histone H2AX. We found a massive and hitherto unrecognized induction of histone H2AX expression in GIST cells treated with imatinib. This upregulation was found to correspond with GIST cell death, and we discovered that H2AX is directly causing this process in a manner that is not necessarily dependent on its well-established role in DNA damage signaling.
We are currently investigating how exactly H2AX can stimulate GIST cell death and looking into the possibility to modulate the levels of this protein in GIST cells by different means in order to eradicate tumor cells faster and more effectively. Moreover, we are studying how KIT signaling interferes with H2AX levels and how imatinib treatment causes its upregulation.
These experiments are complemented by efforts to identify additional signaling molecules in drug-induced GIST cell death and cell cycle arrest. It has been observed that not all GIST cells that are treated with Gleevec undergo apoptosis but rather seem to be dormant. We are currently exploring the role of Gleevec in this pathway that involves an arrest of the cell division cycle and how it can be targeted therapeutically.
Our ultimate goal is to generate a framework for future translational studies to improve the therapeutic options for GIST patients. With this framework we hope to be able to develop innovative strategies to treat GISTs more effectively, to achieve more long-term remissions and eventually to overcome Gleevec resistance.
The support by GCRF is absolutely critical for us to continue and intensify our studies. Without fundraising by GCRF it would have not been possible for us to pursue our work on GIST, in particular in the current funding situation and regarding the fact that we are just starting out as an independent laboratory. We anticipate that funding by GCRF will help us to obtain additional grants from other funding agencies such as the NIH or the ACS and we are extremely grateful for this opportunity.

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