Mucins are a family of glycoproteins that have recently been the focus of intense investigation for fluorescence-guided surgery of cancer due to their overexpression in many malignancies. In pancreatic cancer alone there are at least twelve mucins that are upregulated or uniquely expressed. In our group, we have been developing a near infrared fluorescent labelled mAb, NIRF-AR9.6, that targets MUC16, which is overexpressed in 60-80% of pancreatic cancers. We have previously reported that in an orthotopic xenograft model of pancreatic cancer, NIRF-AR9.6 resulted in a 3.7-fold enhancement of tumor compared to surrounding pancreas, while the isotype IgG control resulted in a 2-fold increase. We also demonstrated that NIRF-AR9.6 could enhance PDAC xenografts, even with lower levels of MUC16. Moreover, initial studies showed that NIRF-AR9.6 could enhance a PDX pancreatic cancer model, consistent with MUC16 staining throughout the tumor. We are now investigating the feasibility for NIRF-AR9.6 for fluorescence-guided surgery after neoadjuvant therapy, implementing orthotopic PDX models of varying MUC16 expression, and investigating targeting multiple mucins to account for tumor heterogeneity.
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Up to 20% of patients are candidates for resection, which is currently the only potentially curative treatment option. However, pancreatic cancer patients have high rates of recurrence after resection due in part to cells left behind at the surgical margin. Fluorescence guided surgery (FGS) has emerged as a method to improve surgical resection. For pancreatic cancer patients eligible for surgical resection, intraoperative imaging would serve two purposes. For patients with resectable disease, image-guidance could help delineate tumor tissue to achieve complete resection. Of critical value, fluorescence guided surgery (FGS) could be used to identify locally metastatic disease, which could spare the patient from major, unnecessary surgery and move directly to other treatments. Recent studies demonstrated that MUC16 is overexpressed in 60-80% of pancreatic cancers, but this biomarker has not yet been explored for FGS of pancreatic cancer. Herein, we describe the validation and development of a near infrared fluorescence antibody that recognizes MUC16 for surgical imaging.
Nerve injuries that significantly affect a patient’s quality of life are a common complication of major surgeries. Fluorescence-guided surgery (FGS) has become increasingly popular because it allows physicians to position their instruments precisely during surgeries to spare nerves, for example, in radical prostatectomies. Visualization of nerves during oncological surgeries is an unmet clinical need that is under investigation. Here, we address this unmet need with a contrast agent that is selective for peripheral nerves. Our contrast agent combines an existing near infrared (NIR) dye that fluoresces in the 800 region with a naturally-occurring protein of the human nervous system, nerve growth factor (NGF) – a combination termed Nervelight. Due to the fact that exogenously administered NGF localizes to the distal ends of nerves due to guidance by high affinity receptors, our contrast agent binds specifically to, then is endocytosed, and is transported up the nerve via retrograde axonal transport. In the clinical setting during nerve sparing surgeries, the area in question would be incised, and the surgeon could intra-operatively apply the agent to at-risk nerves before removing the tumor. In preliminary studies, after we directly applied the contrast agent to the nerve of interest, the targeted nerve was clearly labeled by this fluorescent imaging agent. In these experiments, visualization was obtained after 10 minutes. Other studies suggest that nerves may be seen for the duration of at least one hour and likely longer. These results suggest that Nervelight can serve as a fluorescence-guided surgical tool that will improve the visualization of at-risk nerves during radical prostatectomies, and possibly other oncological surgeries.
Breast cancer patients that experience complete removal of the primary tumor, or negative surgical margins (NSMs), benefit from decreased rates of local recurrence and increased survival. However, intraoperative margin detection is limited to visualization, palpation, and experience to identify malignant vs. healthy tissue. As a result, roughly 1/3 of patients treated with breast conserving surgery (BCS) have residual cancer cells left at the resection border, or positive surgical margins (PSMs). Fluorescence image-guided surgery (FIGS) is a promising alternative for intraoperative margin detection, providing surgeons with real-time feedback on tumor location, increasing the likelihood of achieving NSMs. Our past work has demonstrated that the use of self-assembled hyaluronic acid (HA) nanoparticles improves the delivery of indocyanine green (ICG) to breast tumors, enhancing intraoperative tumor signal and contrast. This study built upon these findings by assessing the surgical efficacy of ICG-loaded HA nanoparticles (NanoICG) for the image-guided resection of orthotopic iRFP+/luciferase+ 4T1 breast tumors in BALB/c mice. Tumors were resected with FIGS in mice treated with ICG or NanoICG and compared to bright light surgery (BLS) or sham controls. Tumor growth and recurrence were monitored with bioluminescence imaging. NanoICG improved complete resection and prolonged tumorfree survival. Additionally, NanoICG provided greater intraoperative contrast in malignant tissue than ICG or BLS. Furthermore, NanoICG demonstrated a greater ability to identify small, occult lesions than ICG. Overall, the use of NanoICG for the fluorescence image-guided resection of breast tumors could potentially decrease PSM rates and improve complete tumor removal.
Improved methods to determine tumor localization and disease extension are critical factors in the management of pancreatic ductal adenocarcinoma (PDAC). Thus, contrast-enhanced fluorescence-guided detection of these lesions could improve the treatment of PDAC. A current limitation to fluorescence enhancement of PDAC is non-specific signal due to the clearance of the imaging dye, e.g. indocyanine green, like the liver, spleen or other local, intraperitoneal organs where metastatic spread may be present. We report surgical imaging agents that provide strong enhancement of PDAC compared to healthy tissue, but also have significantly reduced nonspecific background signal in clearance organs of the peritoneal cavity.
Aberrant metabolism mechanisms are a well-established hallmark of cancer. Exploiting tumor metabolism as a therapeutic target is being actively pursued. De novo synthesis of fatty acids by fatty acid synthase (FASN) is a particularly attractive mechanism to target because increased lipid synthesis is associated with more aggressive tumor. In particular, our work focuses on the reformulation of orlistat, an FDA-approved lipase inhibitor that also inhibits the thioesterase domain of FASN. We report on the rationale, synthesis, efficacy, delivery, and limitations of a novel nanoparticle formulation of orlistat in the goal of targeting the FASN pathway.
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