BRCA1/MAD2L1 deficiency disrupts the spindle assembly checkpoint to confer vinorelbine resistance in mesothelioma

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.Pathogenesis and treatment of chronic pulmonary disease

The search for new treatment strategies for malignant pleural mesothelioma

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. 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. LUMC / Geneeskunde Repositoriu

Chemical Profiling of Primary Mesothelioma Cultures Defines Subtypes with Different Expression Profiles and Clinical Responses

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Trophoblast Glycoprotein is Associated With a Favorable Outcome for Mesothelioma and a Target for Antibody Drug Conjugates

Chemical Immunolog