Specifically Targeting MUC16 for Fluorescence-Guided Surgery of Pancreatic Ductal Adenocarcinoma

Pancreatic cancer is a lethal disease with a low 5-year survival rate and a high rate of resection recurrence. However, surgery remains the only treatment with curative potential for pancreatic cancer. Many factors such as high desmoplasia, a lack of intraoperative imaging, and micrometastatic disease contribute to the high rate of incomplete resections in pancreatic cancer. Fluorescence-guided surgery (FGS) is a potential intraoperative tool for application in surgical resection. FGS works through passive or active targeting of a free dye or dye-containing moiety (e.g. antibody, peptide, and nanoparticles) to specifically fluoresce the tumor compared to the surrounding normal, fibrotic, and background tissues. Mucin 16 (MUC16), a transmembrane mucin, is upregulated in 60-80% of pancreatic ductal adenocarcinoma patients, the most prevalent type of pancreatic cancer. In previous research, our group has indicated that MUC16 may be a good target for FGS through active targeting via an antibody-dye conjugate. While FGS has shown promise in pancreatic cancer resection, its use is limited by the number of patients eligible for surgical resection and the limited number of targeting moieties available. In the past two decades, neoadjuvant therapy or treatment given prior to surgery has emerged as a method to downstage the tumor and increase the number of pancreatic cancer patients eligible for surgical resection. Currently, neoadjuvant therapy most commonly consists of chemotherapeutic treatment. As chemotherapeutic treatment has been shown to impact protein expression in tissues, it is important to investigate the effect of chemotherapy treatment on biomarker expression to determine the ability to target the biomarker for FGS after treatment. Likewise, applicable targeting moieties for FGS in pancreatic cancer are often limited by the presence of high liver fluorescence. High liver background fluorescence can reduce the ability to visualize the tumor signal as well as limit the visualization of any liver micrometastatic disease. Recently, a zwitterionic dye, ZW800-1, has shown promise for application in FGS via increased tumor targeting with diminished liver background fluorescence. In this research, we investigated the expression of MUC16 after neoadjuvant chemotherapy treatment and the ability of huAR9.6-ZW800-1 to target MUC16 for FGS and diminish liver background fluorescence.