Creatie van nieuwe onderzoeksmodellen en in vivo testen van de doeltreffendheid van nieuwe behandelingsstrategieën voor resistente gastrointestinale stromale tumoren

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors in the digestive tract. The majority of these tumors are characterized by activating mutations in the receptor tyrosine kinases KIT or platelet derived growth factor receptor alpha (PDGFRA). Advanced or metastatic GIST are currently treated with tyrosine kinase inhibitors which are developed based on the genetic alterations driving the development and progression of GIST. These drugs which include imatinib (first line), sunitinib (second line) and regorafenib (third line) have revolutionized the treatment and survival of GIST patients with an advanced disease. However, with time nearly all patients show disease progression due to the emergence of heterogeneous resistance to these drugs. Hence, the development of new treatment options for resistant GIST is of major importance and requires reliable, preclinical GIST models to be used for preclinical drug testing. We plan to establish new patient-derived xenograft models of GIST and to assess the in vivo efficacy of several innovative compounds with broad mechanism of actions against resistance. The main goal of this PhD project is to identify new compounds which would have promising preclinical efficacy in resistant GIST models. These results would potentially facilitate clinical trials, especially in patients with tumors resistant to currently available lines of treatments. In addition we believe that our study would broaden our knowledge on resistance mechanisms in GIST, and allow identifying novel potential targets for further preclinical investigation.nrpages: 203status: publishe