Patient-Derived Organotypic Tumor Spheroids Facilitate Precision Medicine Advances in Therapeutic Screening for Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited curative treatment, common tumor recurrence, and poor prognosis. Given the fatal nature of this disease and limited effectiveness of conventional therapies, novel approaches to treatment are essential. To this end, in prior research we demonstrated that utilization of 3D microfluidic cell culture in combination with patient-derived organotypic tumor spheroids (PDOTS) can serve as a model to study the tumor microenvironment and cellular responses to treatment in cancer. Through this study, we pursued three aims: (1) evaluate pre-analytical variables from the operating room to the lab bench predicted to have an effect on generation of PDOTS; (2) perform short term comparative analysis of tumor responses to standard chemotherapy (cisplatin/pemetrexed) and immunotherapy treatments; (3) assess predictability of our 3D platform system in guiding personalized medicine approaches for mesothelioma by comparing patients-specific chemotherapy responses to ex vivo culture experiments. Through investigation of these goals, we found that in treatment naïve mesothelioma specimens, evaluation of pre-analytical variables demonstrated that prolonged ischemic times are associated with decreased tissue viability, lower tumor content, and decreased generation of spheroids. Treated specimens are consistently associated with low tissue viability, regardless of ischemic times. Separately, short-term analysis of drug therapies led to the treatment of mesothelioma samples with standard chemotherapy, revealing significant responses to this regimen in 3 of 5 samples. Experimental treatment with immunotherapy was also analyzed in one sample, however the response was not statistically significant (p = 0.561). Lastly, comparison of ex vivo and in vivo treatment responses demonstrated that 4 of 5 samples treated with standard chemotherapy had concordant responses to those of patients who received the same or similar post-operative therapy. As evaluated by our first aim, these data highlight the importance of streamlining human tissue collection and optimizing variables affecting the formation of PDOTS prior to ex vivo treatment analysis. Moreover, per our findings to aims two and three, the concordance observed in 3D cell culture and in vivo patient responses demonstrate the potential of this system to serve as predictive platform guiding future efforts in precision medicine.