Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery

Molecular Imaging and Biology, Apr 2016

Purpose The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma. Procedures The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)—score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma. Results Integrin αvβ6, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients. Conclusions The results of this study show that integrin αvβ6, CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.

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Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery

Mol Imaging Biol Selecting Tumor-Specif ic Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery Susanna W. L. de Geus 1 Leonora S. F. Boogerd 1 Rutger-Jan Swijnenburg 1 J. Sven D. Mieog 1 Willemieke S. F. J. Tummers 1 Hendrica A. J. M. Prevoo 1 Cornelis F. M. Sier 1 Hans Morreau 0 Bert A. Bonsing 1 Cornelis J. H. van de Velde 1 Alexander L. Vahrmeijer 1 Peter J. K. Kuppen 1 0 Department of Pathology, Leiden University Medical Center , Leiden , The Netherlands 1 Department of Surgery, Leiden University Medical Center , Albinusdreef 2, 2300 RC, Leiden , The Netherlands Purpose: The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma. Procedures: The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)-score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma. Results: Integrin αvβ6, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p G 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients. Conclusions: The results of this study show that integrin αvβ6, CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma. Pancreatic adenocarcinoma; Periampullary adenocarcinoma; Molecular imaging; Image-guided surgery; Immunohistochemistry; Integrin αvβ6; Carcinoembryonic antigen (CEA); Epithelial growth factor receptor (EGFR); Urokinase plasminogen activator receptor (uPAR) - Pancreatic adenocarcinoma currently ranks the fourth leading cause of cancer-related death in the Western world, with a 5-year survival rate of less than 5 % [1]. Radical surgical tumor resection is imperative to curative treatment of these patients as positive resection margins (defined as tumor cells present at the surface of the resection margins of the surgical specimen) are associated with a dramatic decrease in median overall survival [1–4]. Unfortunately, positive resection margins are common after pancreatic surgery and reported rates vary between 24 % and 76 % [5–7]. Adjuvant therapy cannot retaliate the poor survival outcome associated with residual disease [8]. The disappointing irradical resection rates after pancreatic surgery are due to our current inability to detect the true delineation of the tumor extent during surgery, which is further complicated by the intricate anatomy of the pancreas and the commonly present peritumoral inflammatory zone in pancreatic cancer. Conventional anatomic imaging modalities used for preoperative diagnosis, staging, and surgical planning include multiphase intravenous contrast-directed thin slice computed tomography, magnetic resonance imaging, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography [9, 10]. However, the translation of these preoperative imaging techniques to the surgical field remains challenging and in the theater, the surgical oncologist solely has to rely on vision and manual palpation to discriminate between malignant and healthy pancreatic tissue, assisted by ultrasonography and pathologic evaluation of frozen tissue sections [10]. Intraoperative tumor-specific imaging offers the opportunity to significantly improve current practice by increasing the capability to obtain negative resection margins and visualize residual disease during pancreatic surgery. This novel imaging approach uses labeled receptor ligands, nanoparticles, antibodies, or antibody fragments targeting cancer-specific antigens on the tumor surface detected by positron emission tomography, single-photon emission computed tomography, ultrasonography, magnetic resonance, and/or near-infrared fluorescence imaging modalities [11–13]. The feasibility of these imaging techniques has already successfully been proven in glioma and ovarian cancer surgery using respectively the fluorescent agents 5-aminolevulinic acid and folate conjugated to fluorescein isothiocyanate [11, 14]. Furthermore, the potential of image-guided surgery in pancreatic adenocarcinoma has been demonstrated by numerous preclinical studies using cancer-specific contrast agents targeting integrin αvβ6, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), human epidermal growth factor receptor (HER2), urokinase plasminogen activator receptor (uPAR), or vascular endothelial growth factor receptor 2 (VEGFR2) among others (Table 1). Nevertheless, the orthotopic mouse models used in these studies are based on a small number of pancreatic adenocarcinoma cell lines originating from single patients and (...truncated)


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Susanna W. L. de Geus, Leonora S. F. Boogerd, Rutger-Jan Swijnenburg, J. Sven D. Mieog, Willemieke S. F. J. Tummers, Hendrica A. J. M. Prevoo, Cornelis F. M. Sier, Hans Morreau, Bert A. Bonsing, Cornelis J. H. van de Velde, Alexander L. Vahrmeijer, Peter J. K. Kuppen. Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery, Molecular Imaging and Biology, 2016, pp. 807-819, Volume 18, Issue 6, DOI: 10.1007/s11307-016-0959-4