Malignant pleural mesothelioma (MPM) is a cancer of the pleura with few treatment options and an infaust prognosis. We developed a short-term primary tumor culture model from tumor cells derived... Show moreMalignant pleural mesothelioma (MPM) is a cancer of the pleura with few treatment options and an infaust prognosis. We developed a short-term primary tumor culture model from tumor cells derived from pleural fluid of MPM patients and performed drug screening on these cultures to guide treatment decisions of corresponding patients. We observed a high concordance between in vitro results and clinical outcomes and defined three subgroups responding differently to the anti-cancer drugs tested. Gene expression profiling yielded distinct signatures that segregated these subgroups and demonstrated that the fibroblast growth factor pathway was most prominently involved. Pharmacogenomic profiling revealed a subgroup of immortalized and primary MPM lines that appeared highly sensitive to FGFR inhibition. BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples. Furthermore, 34 patients were treated in a clinical trial with nivolumab which demonstrated meaningful clinical efficacy and a manageable safety profile in pretreated patients with mesothelioma. PD-L1 expression did not predict for response in this population. Show less
Malignant pleural mesothelioma (MPM) is an aggressive tumor of the mesothelial cells lining the pleura. The poor prognosis of patients indicates the importance to find more effective treatments.... Show moreMalignant pleural mesothelioma (MPM) is an aggressive tumor of the mesothelial cells lining the pleura. The poor prognosis of patients indicates the importance to find more effective treatments. Therefore, this thesis focused on finding new treatment strategies for MPM. We present a method in which primary MPM cultures were chemically profiled to determine second-line treatment for patients. With this personalized treatment strategy we were able to predict individual patient responses to selected drugs. Based on the chemical profiles of all tumor cultures, these cultures could be divided in three groups. Transcriptomic analysis of these groups identified a unique genetic profile separating these groups and identifying the fibroblast growth factor receptor (FGFR) as a new target for the treatment of MPM. The cultures sensitive to FGFR inhibitors were dependent on FGFR3 mediated signaling which was regulated by BAP1, indicating BAP1 can serve as a biomarker for this treatment. Another target explored in this thesis was 5T4. We showed that 5T4 was only expressed in the tumor cells and that antibody-drug conjugates effectively kill high 5T4 expressing MPM cells. Altogether we present different promising novel strategies in the treatment of MPM, which could improve the survival outcome of these patients. Show less