P3.03-027 Growth Factor and Inflammatory Signaling Pathway Interactions Influence Outcomes Following Multimodality Therapy for Mesothelioma: Topic: Mesothelioma Transitional

Abstract

Photodynamic therapy (PDT) and external beam radiotherapy (RT) have been used as adjuvant therapies directed at increasing local control in patients undergoing surgical resection for malignant pleural mesothelioma (MPM). In patients with MPM treated with a surgically-based multimodality treatment program that involves intraoperative PDT and postoperative RT for MPM, we have previously demonstrated that expression/activation of epidermal growth factor receptor (EGFR)/STAT3 signaling correlates with increased pleural recurrence rates and decreased overall survival. We assessed if activation of STAT3 through EGFR pathway activation mediates resistance of lung cancer cells to either PDT or ionizing RT. Tumor samples from patients with MPM undergoing lung-sparing surgery/intraoperative PDT and postoperative RT were analyzed for expression of growth factor and inflammatory signaling pathways using both IHC and Nanostring techniques. For in vivo assays, Balbc mice with syngeneic Ab12 MPM tumors were treated with partial surgical resection followed by PDT. In vitro studies involved human MPM cell lines derived from subjects enrolled on tissue acquisition with a pTRIPZ expression vector designed to allow doxycycline-induced STAT3 or EGFR shRNA expression. Ninety-three consecutive patients were assessed. Patients undergoing surgery/PDT and RT with median time to local recurrence of <12 months demonstrated elevated EGFR/STAT3 expression levels and increased plasma IL-6 after tumor resection as compared to patients with a median time to local recurrence of > 12 months. In vivo studies in Balbc mice undergoing incomplete surgical resection of Ab12 MPM flank tumors demonstrated activation of STAT3 and EGFR signaling as well as increased plasma IL-6. Moreover, this activation was associated with decreased efficacy of postoperative PDT as compared to mice bearing equivalent sized tumors undergoing PDT without surgery and the effects of surgery on PDT were abolished by pretreating animals with the Cox-2 inhibitor celecoxib. Finally, using a novel 3D in vitro MPM cell culture system, we found that activation of EGFR/STAT3/Cox-2 signaling pathways significantly decreased PDT and RT mediated cellular cytotoxicity. Conversely, inhibition of these pathways enhanced PDT and RT efficacy. Both EGFR and STAT3 are activated in the wound healing/inflammatory response to surgical injury, and EGFR/STAT3 activation leads to increased cox-2 expression. Taken with the above results, this suggests that surgically mediated activation of these pathways, possibly through STAT3-mediated growth factor/inflammatory signaling pathways, impairs the potential efficacy of intraoperative/post-operative PDT and RT and that inhibition of this response to surgery might enhance clinical outcomes in patients with MPM.