Volatile biomarkers for malignant pleural mesothelioma

Ondertitel:from discovery to translation and validation

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-induced thoracic cancer, with a very poor prognosis. As MPM is usually diagnosed in an advanced stage, it is believed that patient survival can be improved by early detection. Analysis of volatile organic compounds (VOCs) in exhaled breath has emerged as a new, innovative approach to this end. Although different studies have shown the potential of VOCs as non-invasive biomarkers for MPM, clinical implementation has been hampered by a lack of independent validation and limited knowledge about the underlying biochemical origin. The overall aim of this PhD was to contribute to these necessary next steps, building further on the discovery studies that were previously conducted by our research group. Part II of this thesis covered the results of the biological translation in vitro, which aimed to gain insights into the biological origin of VOCs. The first study characterized the VOCs in the headspace of different MPM and lung cancer cell lines. Comparative analysis identified VOC profiles that were able to differentiate between the different cell types, suggesting the existence of tumor- and subtype-specific VOCs. Despite these interesting results, limited correlations with exhaled VOCs of MPM patients were observed, which was hypothesized to be the consequence of the difference in oxygen levels between in vivo and standard in vitro conditions. Therefore, we investigated in a second study the influence of in vivo-like hypoxic cell culture conditions on the VOC profile generated by MPM cells. The headspace VOC profiles of MPM cells cultured under both normoxic (21% O2) and hypoxic (1% O2) conditions were compared, revealing significant alterations in many VOCs upon hypoxic exposure. This study thus demonstrated the importance of hypoxic cell culture conditions in VOC research, as it better simulates the in vivo situation and has been shown to significantly impact the VOC profile. Part III of this thesis was related to the results of the external validation of a previously developed breath VOC-based prediction model for MPM. This external validation revealed poor predictive performance of the original model in the validation cohort, which could substantially be improved by updating the model. This was reflected by a high sensitivity and NPV, demonstrating the model’s potential for screening purposes. However, its predictive performance should be reconfirmed in a new cohort. Although this doctoral research has yielded interesting findings, further studies are clearly warranted before a ready-to-use breath test can be implemented in practice.

Jaar van publicatie:2023

Trefwoorden:Doctoral thesis

Toegankelijkheid:Embargoed