Modeling Epidermal Growth Factor Inhibitor‐mediated Enhancement of Photodynamic Therapy Efficacy Using 3D Mesothelioma Cell Culture1. (7th January 2019)

• Record Type: Journal Article
• Authors: Cramer, Gwendolyn; Shin, Michael; Hagan, Sarah; Katz, Sharyn I; Simone, Charles B.; Busch, Theresa M.; Cengel, Keith A.
• Is Part Of: Photochemistry and photobiology. Volume 95:Number 1(2019)
• Page Start: 397
• Page End: 405
• Publication Date: 2019-01-07
• Subjects: Photochemistry -- Periodicals; Light -- Physiological effect -- Periodicals; 541.35
• DOI: 10.1111/php.13067
• Languages: English
• ISSNs: 0031-8655

Abstract

Abstract: We have demonstrated that lung‐sparing surgery with intraoperative photodynamic therapy (PDT) achieves remarkably extended survival for patients with malignant pleural mesothelioma (MPM). Nevertheless, most patients treated using this approach experience local recurrence, so it is essential to identify ways to enhance tumor response. We previously reported that PDT transiently activates EGFR/STAT3 in lung and ovarian cancer cells and inhibiting EGFR via erlotinib can increase PDT sensitivity. Additionally, we have seen higher EGFR expression associating with worse outcomes after Photofrin‐mediated PDT for MPM, and the extensive desmoplastic reaction associated with MPM influences tumor phenotype and therapeutic response. Since extracellular matrix (ECM) proteins accrued during stroma development can alter EGF signaling within tumors, we have characterized novel 3D models of MPM to determine their response to erlotinib combined with Photofrin‐PDT. Our MPM cell lines formed a range of acinar phenotypes when grown on ECM gels, recapitulating the locally invasive phenotype of MPM in pleura and endothoracic fascia. Using these models, we confirmed that EGFR inhibition increases PDT cytotoxicity. Together with emerging evidence that EGFR inhibition may improve survival of lung cancer patients through immunologic and direct cell killing mechanisms, these results suggest erlotinib‐enhanced PDT may significantly improve outcomes for MPM patients. Abstract : Here, we report the development of a novel 3‐D malignant pleural mesothelioma cell culture model using a patient‐derived cell line and its use to quantify photodynamic therapy (PDT) dose–response (figure). The translational potential of this system in further demonstrated in evaluating efficacy of molecularly targeted therapeutics in combination with PDT.