Organoids as a Model for Precision Medicine in Malignant Pleural Mesothelioma: Where Are We Today?

SIMPLE SUMMARY: Malignant pleural mesothelioma (MPM) is an extremely lethal cancer, notoriously known for its limited treatment options, lack of targeted therapies, and catastrophic survival rates. MPM tumors are highly heterogeneous and exhibit substantial variance in the genome landscape among individual patients, characterized by widespread loss-of-function mutations of tumor suppressor genes (TSGs) that are difficult to target. Therefore, there is an urgent and unmet need for novel therapeutic targets and strategies for personalized treatment. Patient-derived organoids (PDOs), the next generation tumor models that have significantly influenced the discovery of anticancer drugs and biomarkers of response to therapies in many other cancers, are emerging and promise to play a critical role in understanding the biology of MPM and, importantly, in identifying and developing precision oncology approaches tailored to specific subsets of MPM patients. ABSTRACT: MPM is an aggressive tumor originating from pleural mesothelial cells. A characteristic feature of the disease is the dominant prevalence of therapeutically intractable inactivating alterations in TSGs, making MPM one of the most difficult cancers to treat and the epitome of a cancer characterized by a significant lack of therapy options and an extremely poor prognosis (5-year survival rate of only 5% to 10%). Extensive interpatient heterogeneity poses another major challenge for targeted therapy of MPM, warranting stratified therapy for specific subgroups of MPM patients. Accurate preclinical models are critical for the discovery of new therapies and the development of personalized medicine. Organoids, an in vitro ‘organ-like’ 3D structure derived from patient tumor tissue that faithfully mimics the biology and complex architecture of cancer and largely overcomes the limitations of other existing models, are the next-generation tumor model. Although organoids have been successfully produced and used in many cancers, the development of MPM organoids is still in its infancy. Here, we provide an overview of recent advances in cancer organoids, focusing on the progress and challenges in MPM organoid development. We also elaborate the potential of MPM organoids for understanding MPM pathobiology, discovering new therapeutic targets, and developing personalized treatments for MPM patients.