Date Published: April 15, 2008
Publisher: Public Library of Science
Author(s): Kimberly A Kelly, Nabeel Bardeesy, Rajesh Anbazhagan, Sushma Gurumurthy, Justin Berger, Herlen Alencar, Ronald A DePinho, Umar Mahmood, Ralph Weissleder, Sanjiv Gambhir
Abstract: BackgroundPancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents.Methods and FindingsHere, a phage display approach was used in a mouse model of PDAC to screen for peptides that specifically bind to cell surface antigens on PDAC cells. These screens yielded a motif that distinguishes PDAC cells from normal pancreatic duct cells in vitro, which, upon proteomics analysis, identified plectin-1 as a novel biomarker of PDAC. To assess their utility for in vivo imaging, the plectin-1 targeted peptides (PTP) were conjugated to magnetofluorescent nanoparticles. In conjunction with intravital confocal microscopy and MRI, these nanoparticles enabled detection of small PDAC and precursor lesions in engineered mouse models.ConclusionsOur approach exploited a well-defined model of PDAC, enabling rapid identification and validation of PTP. The developed specific imaging probe, along with the discovery of plectin-1 as a novel biomarker, may have clinical utility in the diagnosis and management of PDAC in humans.
Partial Text: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States and shows a rapid clinical course, with a median survival of 6 mo and a 5-y survival rate of only 3% . As chemotherapy and radiotherapy have only modest benefits, and surgery is only possible in 20% of patients, early detection that allows surgical resection offers the best hope for longer survival . Indeed, the detection of PDAC or high-grade precursors in high-risk patient groups (e.g., hereditary cancer syndromes, chronic pancreatitis, and new-onset diabetes) represents a critical unmet need in the cancer diagnostic portfolio [3,4]. Additionally, tools to distinguish PDAC from benign cystic lesions frequently detected incidentally on cross-sectional imaging would be clinically useful by diminishing the need for invasive procedures. Currently, serum CA-19–9 is the only clinically used biomarker; however, it lacks the sensitivity needed to detect early-stage PDAC . In addition, cross-sectional abdominal imaging has proven to be unreliable to detect early-stage PDAC in high-risk patients . Therefore, considerable ongoing efforts aimed at identifying new PDAC detection biomarkers are currently being pursued using a variety of approaches including serum proteomics, expression profiling of tumor tissue, genetic analysis of pancreatic fluid, and methods using combinatorial chemistry [5,7–10].
Using a phage display screen and exploiting the experimental merits of a refined genetically engineered mouse model of PDAC, we successfully generated a multimodal nanoparticle-based targeted imaging agent, PTP-NP, that allows imaging of PDAC in the background of normal, mucinous, and ductal metaplasia of the pancreas. The imaging agent has potential use for both MRI and endoscopy in high-risk patients. Important issues in the development of improved diagnostics for PDAC include the need to distinguish pancreatic neoplasia from regions of pancreatic damage and the need for methods that identify earlier stages of tumor progression . The imaging probes identified in this study home to the neoplasm while showing no appreciable colocalization with adjacent areas or acinar-ductal metaplasia. This specificity could be used to possibly reduce “false-positives” in diagnostic tests. Further, these new imaging probes bind to PanINs as well as to advanced cancers. The capacity to detect such premalignant lesions could enable the development of new approaches in the management of this disease. Although liver and kidney uptake is high, the tomographic imaging techniques that would be used with this probe (i.e., MRI, single photon emission computed tomography [SPECT]/CT, or optical) would allow the resolution of the pancreas in the context of both organs.