Preclinical Evaluation of Cetuximab and Benzoporphyrin Derivative-Mediated Intraperitoneal Photodynamic Therapy in a Canine Model.

Peritoneal carcinomatosis (PC) can occur as an advanced consequence of multiple primary malignancies. Surgical resection, radiation or systemic interventions alone have proven inadequate for this aggressive cancer presentation, since PC still has a poor survival profile. Photodynamic therapy (PDT), in which photosensitive drugs are exposed to light to generate cytotoxic reactive oxygen species, may be an ideal treatment for PC because of its ability to deliver treatment to a depth appropriate for peritoneal surface tumors. Additionally, epidermal growth factor receptor (EGFR) signaling plays a variety of roles in cancer progression and survival as well as PDT-mediated cytotoxicity, so EGFR inhibitors may be valuable in enhancing the therapeutic index of intraperitoneal PDT. This study examines escalating doses of benzoporphyrin derivative (BPD)-mediated intraperitoneal PDT combined with the EGFR-inhibitor cetuximab in a canine model. In the presence or absence of small bowel resection (SBR) and cetuximab, we observed a tolerable safety and toxicity profile related to the light dose received. Additionally, our findings that BPD levels are higher in the small bowel compared with other anatomical regions, and that the risk of anastomotic failure decreases at lower light doses will help to inform the design of similar PC treatments in humans.

Modeling Epidermal Growth Factor Inhibitor-mediated Enhancement of Photodynamic Therapy Efficacy Using 3D Mesothelioma Cell Culture.

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.