Next Article in Journal
Genome-Wide Identification of the Nramp Gene Family in Spirodela polyrhiza and Expression Analysis under Cadmium Stress
Next Article in Special Issue
Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights
Previous Article in Journal
Insights into the Role of the Discontinuous TM7 Helix of Human Ferroportin through the Prism of the Asp325 Residue
Previous Article in Special Issue
Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Pancreatic Ductal Adenocarcinoma: The Dawn of the Era of Nuclear Medicine?

Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco
Institute for Research on Cancer and Aging of Nice, Centre Antoine Lacassagne, CNRS UMR 7284 and IN-SERM U1081, Université Cote d’Azur, 06200 Nice, France
LIA ROPSE, Laboratoire International Associé Université Côte d’Azur—Centre Scientifique de Monaco, 98000 Monaco, Monaco
Nuclear Medicine Department, Grenoble-Alpes University Hospital, 38000 Grenoble, France
Laboratoire Radiopharmaceutiques Biocliniques, Univ. Grenoble Alpes, INSERM, CHU Grenoble Alpes, 38000 Grenoble, France
Centre Hospitalier Princesse Grace, Nuclear Medicine Department, 98000 Monaco, Monaco
Author to whom correspondence should be addressed.
Theses authors contributed equally to this work.
Int. J. Mol. Sci. 2021, 22(12), 6413;
Received: 30 April 2021 / Revised: 18 May 2021 / Accepted: 20 May 2021 / Published: 15 June 2021
(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)


Pancreatic ductal adenocarcinoma (PDAC), accounting for 90–95% of all pancreatic tumors, is a highly devastating disease associated with poor prognosis. The lack of accurate diagnostic tests and failure of conventional therapies contribute to this pejorative issue. Over the last decade, the advent of theranostics in nuclear medicine has opened great opportunities for the diagnosis and treatment of several solid tumors. Several radiotracers dedicated to PDAC imaging or internal vectorized radiotherapy have been developed and some of them are currently under clinical consideration. The functional information provided by Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) could indeed provide an additive diagnostic value and thus help in the selection of patients for targeted therapies. Moreover, the therapeutic potential of β-- and α-emitter-radiolabeled agents could also overcome the resistance to conventional therapies. This review summarizes the current knowledge concerning the recent developments in the nuclear medicine field for the management of PDAC patients.

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) is by far the most common type of pancreatic neoplastic disease, accounting for about 90 to 95% of all pancreatic malignancies [1,2]. PDAC is an aggressive disease, representing the fourth most frequent cause of cancer-related deaths worldwide in 2018 [3,4]. The incidence of PDAC is increasing and PDAC is predicted to become the second deadliest malignancy by the year 2030. Indeed, a two-fold augmentation of PDAC cases is expected for the next ten years [5,6]. During the last decades, significant improvements have been achieved in the screening and treatment of different solid tumors, incrementing the patient’s chance to be cured. Nevertheless, insignificant modification of the mortality-to-incidence ratio has been evidenced in PDAC. PDAC has the shortest 5-year overall survival (OS) rate of all major cancers (7%) [7]. Efficacy of treatments and outcome of PDAC are largely determined by the disease stage at the diagnosis, but unfortunately PDAC patients are usually diagnosed at advanced stages, limiting the therapeutic opportunities [7]. The only curative therapy available is surgical resection followed by adjuvant therapy [8]. Unfortunately, most of the patients (80–90%) with PDAC remains asymptomatic until the disease develops to advanced stages or metastatic disease that make them ineligible to surgery [9], explaining the poor prognosis [10]. During the last 30 years, the 5-year survival of surgically resected patients has increased from 5 up to 54% [11,12,13]. However, the 5-year survival remains unchanged over the same period in unresected PDAC patients [10,14].
Differences in the molecular biology of PDAC may contribute to its early metastatic dissemination. Indeed, pre-clinical models of PDAC indicate that metastases can be detected even in the absence of any pancreatic primary tumor [15]. PDAC is therefore suggested to be a systemic pathology and multidisciplinary management of this disease becomes of great of importance. Therefore, the identification of novel therapeutic targets and the modalities to improve clinical management of the disease and life expectancy of PDAC patients are urgently needed. The diagnosis and therapeutic potential of nuclear medicine could provide new opportunities for the management of PDAC patients. Nuclear medicine indeed came up with radiopharmaceuticals that impart the ability to destroy tumor cells specifically with high-energy-emitting radionuclides [16,17]. The emergence and advent of theranostics, a combination of a single drug used for both diagnosis and therapeutic purposes, has now opened a new avenue in the field of personalized treatments. In recent years, theranostics has been successfully applied to a whole range of malignancies, including neuroendocrine tumors and prostate cancer [18,19]. In this review, we first discuss the different available molecules used in the clinic for PDAC imaging and staging, to finally emphasize the different imaging and theranostic agents that are currently under development for the management of PDAC, including radioligand therapy.

2. Radiotracers Clinically Available for PDAC Diagnosis, Staging and Monitoring

2.1. 18F-FDG

Diagnosis of suspected PDAC is based on clinical suspicion and a combination of imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI) and endoscopic ultrasound (US) [20]. Unfortunately, these imaging modalities are of limited value in the detection of small primary tumors and small-disseminated masses. Over the past two decades, the potential of positron emission tomography (PET) imaging using 18-fluorodeoxyglucose (18F-FDG) has been investigated for the diagnosis, staging and detection of recurrence of PDAC. 18F-FDG PET takes advantage of the Warburg effect, a hallmark of cancer in which proliferating tumor cells produce energy via glycolysis at higher rates as compared to normal tissues [21,22,23]. 18F-FDG PET is a sensitive imaging modality for detection, staging and response assessment in oncology in most solid tumors [24]. FDG, a glucose analogue, is transported into the cells via glucose transporters, phosphorylated by hexokinase, but does not go further into the glycolysis steps, thereby allowing its accumulation into the cells. Almost 90% of PDAC exhibit mutation of the K-Ras oncogene, promoting glucose uptake through the upregulation of hexokinase-2 or glucose transporters [25,26]. 18F-FDG uptake was investigated in mice models of PDAC and demonstrated an increased uptake throughout disease progression from pancreatic intraepithelial neoplasia precursor lesions to PDAC [27]. 18F-FDG PET has consequently been proposed as a relevant diagnosis modality for PDAC. Nevertheless, the role of 18F-FDG PET in the early detection of PDAC still remains controversial. Some guidelines indeed suggest that 18F-FDG PET has a very limited role in the diagnosis of PDAC whereas other studies reported the augmented ability of 18F-FDG PET in PDAC detection, over CT and MRI [28,29]. A systematic review of 54 studies recently reported that, while 18F-FDG PET had a superior sensitivity when compared to CT and MRI, the specificity of CT and MRI is higher [30]. However, 18F-FDG PET failed to distinguish PDAC from focal mass-forming pancreatitis, which was reported to be 18F-FDG positive in nearly 80% of cases [31]. Importantly, the most important advantages of 18F-FDG PET over CT and MRI are (1) it detects distant and potentially unknown metastases by performing a whole-body scan; and (2) it monitors early tumor responses [32]. As for other solid tumors, metabolic changes in PET precede anatomic changes in tumor size [33]. CT cannot detect small tumors [34]. Hence, following chemo/radiotherapy, 18F-FDG-PET more accurately evaluates the treatment responses compared to CT. A recent study on 22 patients showed that the response to neoadjuvant therapy in PDAC was more efficiently measured as compared to CT [35]. Several studies demonstrated the role of PET imaging in monitoring tumor recurrence. For instance, Sperti et al. showed that PET could detect earlier tumor relapse in comparison to CT, with a diagnostic accuracy of 96% and 57%, respectively [36]. Wang et al. recently confirmed these findings using 18F-FDG in resected PDAC [37]. 18F-FDG PET imaging has the ability to distinguish treatment-related fibrosis and inflammation from residual or progressive tumors, as observed by Javery et al. in a cohort of 49 patients [38]. Besides, pre-operative PET imaging predicts tumor recurrence and prognosis in PDAC patients [39]. Indeed, the high standardized uptake value (SUVmax) of patients with PDAC, which is the most common PET parameter used in the clinic, was associated with worse overall survival (OS) and progression-free survival (PFS) [29,40,41]. The emergence of a PET/MRI hybrid system and of radiomics analysis should provide added value in the management of patients with PDAC.

2.2. 18F-FLT

3-Deoxy-3-18F-fluorothymidine (18F-FLT) is a fluorinated tracer proposed as an imaging biomarker of cell proliferation. 18F-FLT is phosphorylated by thymidine-kinase-1 during the S phase and trapped inside the cells, providing an indirect measure of proliferation [42]. Pre-clinical studies carried out in mice demonstrated the ability of 18F-FLT to non-invasively image PDAC cells [43]. The role of 18F-FLT in the clinic has been investigated in several studies. 18F-FLT was found to be negative in 10 benign pancreatic lesions but 15/21 of malignant tumors display high uptake of 18F-FLT, thereby suggesting a significant diagnostic potential [44]. Nevertheless, conclusions regarding the use of 18F-FLT remain controversial. Quon et al. indeed reported a poor detectability of lesions and a decreased uptake level in the primary tumor foci [45]. Despite its poor sensitivity, a recent study however showed that initial 18F-FLT activity is correlated to poor outcomes in PDAC patients [46]. One limitation of this study is certainly the use of a stand-alone PET without any simultaneous CT acquisition. The use of hybrid PET/CT or PET/MRI may thus lead to a greater accuracy. Clinical investigations should be conducted by a dual-image modality and in a higher number of patients to conclude about the real potential role of 18F-FLT in managing patients with PDAC.

2.3. 18F-FMISO and 18F-FAZA

Hypoxia, a condition of low oxygen availability, is a common feature of solid tumors affecting many aspects of tumor biology and promoting resistance to therapy [47]. PDAC is a poorly vascularized tumor and is characterized by a strong desmoplastic reaction, which contributes to the hypoxic state. A poor blood supply is associated with poor prognosis in PDAC patients [48]. In a constitutive hypoxic microenvironment, PDAC constitutively express the hypoxia-inducible factor-1 (HIF-1). HIF-1 expression levels are associated with tumor progression and metastasis [49,50]. The hypoxic environment of PDAC thus provides the rational for imaging hypoxia and investigating its role in the management of patients. Two radiotracers, 18F-fluoromisonidazole (18F-FMISO) and 18F-fluoroazomycin arabinoside (18F-FAZA), have been evaluated in PDAC. However, their tumor uptakes were found to be weak, thereby limiting their interest in the imaging of PDAC [51,52]. However, a recent study carried out on 20 PDAC patients prior to surgery showed a prognostic value of 18F-FMISO imaging, with a significant shorter OS in 18F-FMISO-positive lesions [53]. Further investigations are therefore needed to decipher the role of hypoxia imaging in the management of PDAC patients.

2.4. 68Ga-FAPI

Cancer-associated fibroblasts (CAF) and extracellular fibrosis can contribute to up to 90% of the tumor mass [54]. CAFs differ from normal fibroblasts by their expression of fibroblast activation protein (FAP). FAP inhibitors (FAPI) were therefore developed as anti-cancer drugs and then as tumor-targeting radiotracers [55]. Several solid tumors, such as breast, lung, colorectal and PDAC cancers, were found to remarkably display high uptake of 68Ga-FAPI [56]. 68Ga-FAPI was found as a promising alternative to 18F-FDG in cancer patients. Studies of 68Ga-FAPI biodistribution demonstrated a high uptake in primary PDAC, lymph nodes and distant metastases, with low activity in healthy tissues. Indeed, a recent study revealed a higher tumor uptake of 68Ga-FAPI PET/CT as compared to 18F-FDG PET/CT in several cancers, including PDAC, as well as in more metastatic lesions [57]. In a study of 19 patients with primary or recurrent histologically confirmed PDAC, 68Ga-FAPI PET/CT showed a change in TNM stage in 10/19 (53%) patients compared to contrast-enhanced CT and a change in therapeutic management in 7 patients (37%) [58]. Recently, the tumor target volume for radiation therapy was more accurately defined with 68Ga-FAPI PET/CT as compared to the gold standard contrast-enhanced CT [59]. These preliminary results paved the way to conduct further investigations on the clinical value of 68Ga-FAPI in PDAC [60]. Moreover, the biodistribution of 68Ga-FAPI makes this tracer suitable for radioligand therapy.
The different radiotracers evaluated in clinic for PDAC imaging are depicted in Figure 1.

3. Recent Developments in Nuclear Medicine for PDAC Imaging and Treatment

Currently, the ability to interrogate the target engagement of experimental therapies and the lack of specific imaging to assess therapy response are real concerns for clinical trials. The potential of nuclear medicine to non-invasively characterize tumors at the molecular level should be considered for the follow-up of patients with PDAC. Moreover, recent advances in the molecular mechanisms of PDAC tumorigenesis, and the advent of small-animal dedicated imaging systems have led to the development of new radiotracers. Indeed, several radiotracers dedicated for staging, monitoring or for the evaluation of patients’ eligibility for a targeted therapy (companion approach), or for targeted radionuclide therapy (theranostic approach), have been developed and evaluated in several PDAC mice models. Most of the radioisotopes described here are β+ emitters (64Cu, 89Zr and 68Ga) and therefore suitable for PET imaging. They can be potentially substituted on the vector molecule by β- (177Lu and 90Y) or α-emitters (225Ac and 213Bi) isotopes for therapeutic use.

3.1. Radiotracers in Development Dedicated to Stroma Imaging

The extremely dense stroma of PDAC and its fundamental role during tumor progression gave the rationale for investigating the role of its components and the relevance of their targeting [61]. In addition to CAF targeting with the 18F-FAPI agent that could efficiently detect PDAC masses, radiotracers targeting fibronectin and matrix metalloproteinases (MMP) were recently developed for this application (Figure 1).

3.1.1. Fibronectin-Targeting Agents

Fibronectin, a major component of the extracellular matrix, is overexpressed in PDAC samples and associated with advanced stages [62]. A single-domain antibody (sdAb) targeting the fibronectin (NJB2) was recently evaluated in mice models of breast cancer and PDAC [63]. 64Cu-NJB2 demonstrated high specificity for fibronectin-expressing lesions and exhibited a high tumor-to-background ratio at early time points. Moreover, 64Cu-NJB2 allowed early detection of PDAC as well as liver metastasis, whereas 18F-FDG did not. The biodistribution profile of sdAb, with limited uptake in liver and intestine, could overcome the known limitations of conventional mAbs to image metastasis with high contrast. The ability of 64Cu-NJB2 to detect PDAC and secondary masses remains to be evaluated in future clinical studies.

3.1.2. MT1-MMP Imaging

The desmoplastic PDAC stroma contains many different proteases that play a key role in the crosstalk between cancer and stromal cells. MMPs are a family of zinc-dependent endopeptidases involved in the degradation of the ECM components. MMPs are considered as important contributors to PDAC progression [64]. Membrane-type 1 matrix metalloproteinase (MT1-MMP) upregulation promotes tumor progression and resistance to gemcitabine in a PDAC xenograft model [65]. MT1-MMP, as a candidate biomarker for non-invasive PDAC imaging, was evaluated using 89Zr-labeled antibodies (89Zr-DFO-LEM2/15). Despite liver uptake of the radiotracer, 89Zr-DFO-LEM2/15 allowed high-contrast imaging of PDAC in mice bearing orthotopically implanted, patient-derived xenograft tumors [66]. Clinical investigations of this radiotracer have not been conducted.

3.1.3. CAFs

The tumor stroma represents an attractive target for the diagnosis but also for the delivery of therapeutic compounds. The absence of fibroblast-activation protein expression in normal tissue and the biodistribution profile of 68Ga-FAPI observed in the clinic offer a very encouraging opportunity for theranostic applications [67,68,69]. A proof of concept of radioligand therapy using 90Y-FAPI-04 in two patients with final-stage breast cancer was recently assessed [70]. 90Y-FAPI-04 led to a significant decrease in pain in these patients. In parallel, FAPI was labeled with 225Ac (225Ac-FAPI) and evaluated for its therapeutic potential in preclinical models of PDAC. 225Ac-FAPI treatment of PANC-1 xenografted mice showed a significant decrease in tumor growth in comparison to control mice [69]. However, 225Ac-FAPI therapeutic potential remains to be evaluated in clinical practice.

3.2. Radiotracers Targeting Tumor Antigen: Companion and Theranostic Approaches

The radiotracers dedicated to companion and theranostic approaches currently in development are presented in Figure 2.

3.2.1. MUC1-Targeting

Most of the tracers designed for the theranostic approach target the MUC1 protein. MUC1 is a 300–600 kDa membrane-bound mucin expressed in pancreatic ductal and acinar cells. More than 60% of PDAC overexpressed MUC1 and it has a pivotal role in PDAC progression [71,72]. In tumor cells, MUC1 binds to EGFR and β-catenin to enhance cell proliferation through the MAPK, Akt or Wnt/β-catenin pathways [73,74]. Moreover, MUC1 also induces epithelial–mesenchymal transition through activation of MMP13, Stat3 and PDGFR [71]. MUC1 also favors chemoresistance in PDAC by acting as a transcriptional regulator of multidrug-resistance genes [75]. MUC1 has therefore been linked to a poor prognosis in PDAC patients [76]. Some 64Cu- and 89Zr-radiolabelled monoclonal antibodies (mAbs) were recently developed for non-invasive measurement of MUC1-expression [77,78,79]. 64Cu-DOTA-PR81 and 89Zr-Df-GGSK-1/30 were successfully validated in MUC1-expressing breast cancers with a high ratio tumor/background uptake 72 h after injection [77,78]. More recently, 89Zr-DFO-AR20.5 was validated as a valuable tracer for the visualization of tumor tissues, including metastatic lesions in a pre-clinical model of ovarian cancer [79]. Nevertheless, all these radiotracers must be first validated for PDAC imaging and then clinically transferred for an eventual application.
Numerous MUC-1-targeting radiotracers dedicated to radioimmunotherapy of PDAC have been investigated in pre-clinical and clinical studies [80]. PAM4, an anti-MUC1 mAb, was radiolabeled with 90Y and 131I, and evaluated in combination with gemcitabine in pre-clinical models of PDAC. 90Y-PM4 provided greater growth inhibition as compared to 131I-PM4, with an improved median survival time (>26 weeks in the 90Y-PM4-treated group, and 17.5 weeks for the 131I-PM4-treated group) [81]. Gold et al. further showed that a combination of 90Y-PM4 with gemcitabine enhanced tumor response in mice models of PDAC [82]. This observation led to the clinical evaluation of 90Y-PM4 in PDAC patients. 90Y-PM4 treatment was well tolerated, with manageable hematologic toxicity [83]. Low-dose gemcitabine in combination with 90Y-PM4 was evaluated in 38 advanced PDAC patients. Partial response and stable disease were found in 16% and 58% of patients, respectively [84]. Phase III was recently conducted in 334 PDAC patients but failed to demonstrate any significant improvement of OS when compared to the placebo (NCT01956812). The superior therapeutic efficacy of alpha-therapy in comparison to beta-therapy gave rise to the development of alpha-emitter radiotracers [85]. 213Bi-C595, a monoclonal antibody, was cytotoxic in vitro on PDAC cells and in vivo on a model of ovarian cancer [86,87]. Alpha-therapy remains to be evaluated in PDAC.

3.2.2. Mesothelin-Targeting with Antibody-Derived Radiotracers

Mesothelin is a 40-kDa, GPI-anchored membrane protein whose expression is very low in normal tissues (pleura, peritoneum and pericardium). However, mesothelin is overexpressed in several solid tumors, including in 80 to 85% of PDAC [88,89]. Mesothelin is a key player in sustaining cell proliferation and invasion of PDAC [89]. The limited expression of mesothelin in normal tissues as well as its overexpression in a broad range of tumors makes it an attractive and promising target for therapy. Several anti-mesothelin targeting drugs, including an antibody-based approach, immunotoxins or CAR-T cells, are under clinical investigations [90,91]. Some radiotracers serving as companion markers of anti-mesothelin therapies are currently in development. Some mAbs have been evaluated for PDAC targeting in pre-clinical mouse models and in patients. Specific signals in mesothelin-positive lesions were detected using 64Cu- and 89Zr-radiolabeled mAbs [92,93,94]. Clinical investigations showed high ability of 111In- and 89Zr-radiolabeled mAbs for the phenotypic imaging of mesothelin-expressing PDAC [95,96]. Nevertheless, hepatic elimination of mAbs and their slow blood clearance constitute important limitations. Single-chain variant (ScFv) and single-domain antibodies displaying optimal pharmacokinetics have been validated in pre-clinical studies and will thus deserve to be fully considered for clinical development [89,97,98].
In addition to their potential to serve as a companion marker for the selection of patients eligible for anti-mesothelin therapies, anti-mesothelin mAbs have been radiolabeled with alpha-emitter particles for targeted radionuclides therapy. A 227-thorium (227Th)-radiolabeled anti-mesothelin mAbs has recently been validated in pre-clinical models of ovarian cancer [99]. A Phase I trial using this compound is ongoing in patients with locally advanced or metastatic PDAC (NCT03507452).

3.2.3. Transferrin Receptor (TfR)-Targeting Agents

Transferrin receptor (TfR) is a type II transmembrane heterodimeric glycoprotein involved in iron uptake. Tumor cells are highly dependent on iron for proliferation when compared to normal cells and are more sensitive to iron deprivation [100,101]. TfR is therefore upregulated in malignant cells [102], including PDAC [97]. More generally, TfR is a key actor of several hallmarks of cancer, including cancer cell proliferation, migration and invasion [103]. TfR have consequently emerged as a candidate for antibody-mediated cancer therapy [104]. Different antibody-based strategies that target TfR in malignant cells have been developed and assessed in pre-clinical models of solid tumors. This includes in particular mAbs that can be combined to therapeutic agents (chemotherapy), toxins or radioisotopes, or ScFv [105]. Indeed, the internalization of TfR ligands opens unique opportunities for the delivery of toxic agents into malignant cells. Among the therapies, the combination of SGT-53 (nanocomplex carrying the p53 gene) with docetaxel was evaluated in 12 patients (1 PDAC) in a Phase 1b dose-escalation trial. The RECIST partial response observed in 3/12 patients and the stable disease observed in 2 patients support the Phase 2 testing this combination [106]. A Phase II study of the combination of SGT-53 and gemcitabine/nab-paclitaxel is ongoing in patients with metastatic PDAC (NCT02340117). 89Zr-TSP-A01, an anti-TfR mAb, was successfully evaluated in MiaPaCa-2-bearing mice for its ability to bind to TfR-positive tumors [107]. This antibody was also radiolabeled with 90Y (90Y-TSP-A01) and considered for radioimmunotherapy. One injection of 90Y-TSP-A01 in tumor-bearing mice (MiaPaCa-2-derived tumors) resulted in an almost complete disappearance of tumors, making it a very promising agent [108]. Nevertheless, the clinical potential of such a theranostic agent remains to be further investigated. More recently, transferrin was radiolabeled with 89Zr and evaluated for its ability to target PDAC.
Moreover, 89Zr-transferrin was evaluated for its potential to non-invasively assess the signaling downstream KRAS to stratify patients that will benefit from targeted therapies. 89Zr-transferrin was confirmed to be a valuable tool to evaluate oncogene status, as TfR is a downstream target of the KRAS pathway, and the target engagement of MYC- and ERK-targeted therapies [109,110].

3.2.4. CEACAM5-Targeting Agents

CEA, also called carcinoembryonic antigen–related cell adhesion molecule 5 (CEACAM5), is a 200-kDa protein belonging to the CEACAM family and anchored to the cell surface by a glycosylphosphatidylinositol (GPI). Despite poor sensitivity and specificity, serum CEACAM5 is a prognostic biomarker of PDAC [111]. Soluble CEACAM5 is related to tumor burden in patients with PDAC, thereby giving the rationale for its use in clinical practice [112]. Histological analysis of tumor samples revealed its ability to identify viable tumor cells before and after neoadjuvant treatment [113]. Moreover, the high tumor-to-normal ratio of CEACAM5 expression supports the development of anti-CEACAM5 imaging agents for diagnosis and staging of PDAC. That said, such potential need to be further investigated in PDAC.
Of note, the theranostic potential of anti-CEACAM5 radiolabeled antibodies was supported by a clinical pilot study carried out in five patients having metastatic colorectal cancer (mCRC) [114]. 111In-IMP288—a bispecific, engineered antibody—rapidly and selectively accumulated in tumors with a high tumor-to-tissue ratio. Administration of 177Lu-IMP288 therapeutic antibody was well tolerated without any observed adverse effect. The therapeutic potential of such an antibody remains to be demonstrated and evaluated in PDAC patients. A Phase II carried out in mCRC patients is investigating the ability of another mAb (124I-M5A) to detect liver metastasis.

3.2.5. Neurotensin Receptor-Targeting Agents

Neurotensin (NTS) is a physiological hormone, which affects the function of the gastro-intestinal tract through its cellular receptor (NTSR1). In 1998, both NTS and NTSR1 were reported to be more expressed in PDAC tissues when compared to normal samples [115]. Expression of NTSR1 correlated with histological grade and higher expression of NTSR1 was detected in patients with liver metastasis [116,117]. The signaling pathway of NTS/NTSR1 is well known in cancer—NTS/NTSR1 triggers PKC, PI3K and ERK1/2 activation, leading to aberrant survival and proliferation of tumor cells [118]. NTS/NTSR1 also activated Rho GTPases and the focal adhesion kinase, key players involved in cell migration phenomena [119,120,121]. The selective inhibition of NTSR1 in mice attenuated the tumorigenicity of the pancreatic cells [122]. Based on the selective expression of NTS/NTSR1 and its role in PDAC progression, several NTSR1-targeting agents were proposed for non-invasive imaging, treatment monitoring tools and vectorized radiotherapy [123]. 68Ga-DOTA-NT-20.3, an analogue of NTS that displays a high affinity for PDAC cells, was evaluated in orthotopic xenograft models of PDAC [124,125]. 68Ga-DOTA-NT-20.3 exhibited high tumor uptake and high contrast between the tumor and background, at early time points with a fast blood clearance. This promising result led to a recent first clinical trial in humans, where the safety, tolerability and 68Ga-DOTA-NT-20.3 uptake in PDAC (n = 3) were observed [126]. However, future investigations need to be assessed in a larger cohort of patients. Another NTS radiolabeled-analogue (99mTc-NT-XI) was previously evaluated in four PDAC patients. Despite the small number of patients, the relevance of the NTSR phenotypic imaging method has been reported [127]. A PET-dedicated radiotracer was recently developed and evaluated in prostate tumor-bearing mice. 64Cu-DOTA-NT specifically binds NTSR-expressing tumors [128]. The biochemical structure of DOTA also allows 177Lu radiolabeling, which is dedicated to targeted radiotherapy.
Twenty years ago, one of the first NTS analogues was radiolabeled with 188Re and evaluated in a radiotherapy study using HT29 colon cancer-bearing nude mice [129]. Three injections of 188Re-NT-XIX led to a 50% decrease in tumor growth. Only few studies have reported the pre-clinical efficacy of 177Lu-radiolabelled NTS in PDAC. 177Lu-FAUC469, a triazolyl-linked DOTA-derivative, was shown to display high tumor growth inhibition in PDAC-bearing mice [123]. The first patient injection of 177Lu-labelled DOTA-conjugate of NTS (177Lu-3BP-227) was performed in six PDAC patients [130]. 177Lu-3BP-227 was well tolerated and one patient achieved a partial response and experienced an improved quality of life. Despite this observation, which provides clinical evidence of 177Lu-3BP-227 treatment feasibility, it remains to be further evaluated in a Phase II study.

3.2.6. CA19.9-Targeting Agents

Serum carbohydrate antigen 19.9 (CA19.9) is regularly measured in patients with PDAC [131]. The diagnostic potential of soluble CA19.9 was evaluated in several studies. CA19.9 levels are upregulated up to 2 years prior to a PDAC diagnosis, and its level correlated with tumor stage [132,133,134]. However, CA19.9 as a soluble biomarker has limitations, including a low positive predictive value, and augmented values in pancreatico-biliary diseases [135]. Nonetheless, CA19.9 remains an attractive target for specific diagnosis and therapy as it is expressed at high levels at the surface of cancer cells. 89Zr-5B1, an anti-CA19.9 radiolabeled antibody, allowed non-invasive imaging of PDAC xenografts with an intense uptake (>100% of injected activity per gram of tissue), and notably a low activity in the liver and spleen [136,137]. Moreover, when unlabeled 5B1 was administered prior to 89Zr-5B1, the radiotracer significantly enhanced the image contrast and tumor-to-tissue ratio [137]. Due to the potential of 89Zr-5B1 to non-invasively measure CA19.9 expression, a dose-escalation trial of 89Zr-5B1 in PDAC patients was performed. This dose-escalation study confirmed these promising results in 12 patients with metastatic CA19.9-expressing tumors [138]. Anti-CA19.9 diabodies were also engineered and provided specific molecular imaging in tumor xenograft models [139,140].
The biodistribution profile of 5B1 validated the rationale for its use as a theranostic agent. A Phase I study on 177Lu-5B1 therapy was initiated and is ongoing (NCT02672917). The aim of this study is to determine the maximum tolerated dose of 177Lu-5B1, as well as its pharmacokinetics and dosimetry characteristics.

3.2.7. uPA/uPAR System

The tumor cell-associated urokinase plasminogen activator (uPA) system, including the serine protease uPA, its membrane-associated receptor uPAR and the plasminogen activator inhibitor (PAI2), play a crucial role in cell proliferation and metastasis [141,142]. uPAR binds uPA to convert inactive plasminogen to active plasmin, disrupting the ECM, and allowing invasion and metastatic spread of malignant cells [143]. Aberrant expression of the uPA-uPAR system components has been detected in a wide range of tumors [144]. Around 60% of patients with PDAC express uPAR in neoplastic or stromal cells [145]. Increased gene expression is associated with poor survival in PDAC patients [146]. Chen et al. showed that uPAR expression could discriminate between PDAC and pancreatitis [147]. Much attention has been deployed in the development of non-invasive imaging of uPA systems. The peptide antagonist AE105 and the anti-uPAR mAb ATN-658 were developed and radiolabeled with 68Ga (68Ga-AE105) and 89Zr (89Zr-ATN-658), respectively [148,149,150]. As a 1-kDa molecule, 68Ga-AE105 exhibited rapid blood clearance, thereby allowing tumor imaging at early time points with a good contrast. 89Zr-ATN-658 has a much longer half-life in the blood, offering then a possibility of acquisition at later time points. 68Ga-AE105 was evaluated in a Phase I study in patients with prostate, breast and bladder cancers [150,151]. The administration of 68Ga-AE105 was well tolerated and primary tumor uptake could be evidenced with high contrast 60 min post-injection. Moreover, the capacity of this tracer to accurately detect lymph nodes metastasis makes it suitable to allow the staging of solid tumors. To date, no evaluation in PDAC patients was performed but 177Lu-AE105 was evaluated in a disseminated metastatic prostate cancer model [152]. uPAR-targeted radionuclide therapy significantly reduced the number of metastatic lesions when compared to the vehicle and non-targeted 177Lu-groups. Targeted alpha-therapy was evaluated in a xenograft model of PDAC using the 213Bi-PAI2 radiotracer, and a significant tumor growth inhibition could then be evidenced [153]. However, further investigations are needed for PDAC and should ultimately allow a better overall understanding.

3.2.8. EGFR

Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the regulation of cell proliferation, survival and apoptosis [154]. Overexpression of EGFR was reported in a wide range of tumors, including breast, colon or lung cancers [154,155]. For PDAC, the EGFR levels ranged from 40 to 70% and its expression is associated with advanced stages and poor clinical outcomes [156,157,158,159,160]. In addition, EGFR signaling contributes to the transition of normal pancreatic epithelia to neoplasms [161]. Two classes of inhibitors have been developed for the EGFR-targeting: tyrosine kinase inhibitors (erlotinib) and EGFR mAbs (cetuximab and panitumumab). The Food and Drug Administration approved the combinatory use of erlotinib with gemcitabine as a first-line therapy for patients with advanced PDAC, since a significant improvement in OS was evidenced in comparison to gemcitabine treatment alone [162]. The measure of EGFR expression with SPECT and TEP imaging was performed using sdAbs radiolabeled with 99mTc- or 68Ga [163,164,165,166]. 99mTc-7C12 sdAb represents a valuable tool for monitoring erlotinib response in mice models of epidermoid carcinoma [166]. 89Zr-DFO-ZEGFR:2377, a radiolabeled affibody was also validated as a non-invasive tool to quantity EGFR expression in this tumor model [167]. 89Zr-cetuximab was evaluated in 10 patients with metastatic colorectal cancers and treated with cetuximab. Despite the low number of patients, a correlation between 89Zr-cetuximab uptake in secondary lesions and tumor response could be demonstrated [168]. The theranostic couple 111In- and 177Lu-panitumumab was recently evaluated for EGFR imaging in mice models of PDAC [169]. The radio-immunotherapy was further evaluated in PANC-1 xenografts. 177Lu-panitumumab strongly impedes tumor growth without any significant detected side effect (blood counts, serum alanine aminotransferase and creatinine) [170]. To date, no investigation of radioimmunotherapy targeting EGFR has been evaluated in a clinical study.

3.2.9. CDCP-1

The CUB domain-containing protein 1 (CDCP1) is a glycosylated transmembrane protein discovered 20 years ago by Scherl-Mostageer [171]. CDCP1 expression is associated with the loss of anchorage in epithelial cells during mitosis [172]. CDCP1 regulates the SRC/PKC, PI3K/Akt and RAS/ERK pathway, making it a player located at the nexus of tumorigenesis and metastasis processes [173]. Its expression has therefore been associated with a poor prognosis in several cancers, including PDAC [174,175]. These findings have stimulated the development of CDCP1-targeting agents for detection and treatment of cancers. Small molecules (Pd-Oqn) or antibodies (10D7) targeting CDCP1 have been developed and evaluated in pre-clinical studies. Peritoneal injection of Pd-Oqn in mice models was associated with a significant decrease in the peritoneal dissemination of gastric tumors [176]. The combination of 10D7 with monomethyl auristatin E cytotoxin (10D7-MMAE) reduced tumor burden in mice models of metastatic ovarian cancers [177]. 10D7 was radiolabeled with 89Zr (89Zr-10D7) and evaluated in an ovarian cancer model and a high tumor-to-background ratio could be obtained 144 h following administration [177]. Moreover, peritoneal masses were readily observable using 89Zr-10D7. Of note, 89Zr-10D7 was also found to detect PDAC tumor-derived xenografts [178]. Another antibody, 4A06, was recently radiolabeled with 89Zr (89Zr-4A06) for PET imaging of PDAC tumors but also with 177Lu- and 225Ac-, respectively, for β-- and α-emitter-targeted therapy [179]. 89Zr-4A06 detected CDCP-1 expressing PDAC (seven cell lines). Treatment with a single dose of 177Lu-4A06 significantly reduced tumor volumes in comparison to the control. Despite significant results when compared to the control conditions, the 225Ac-4A06 effect was less pronounced as compared to 177Lu-4A06. Similarly, further investigations deserve to be conducted for the clinical evaluation of these compounds.

4. Conclusions

Despite intensive efforts in the field of pancreatic cancer research, early-stage detection, treatment response monitoring and development of efficient therapeutic strategies in PDAC are still in urgent need. The field of nuclear medicine, for its ability to image a molecular-target and to treat tumors, could represent a way to improve the management of these patients. The upcoming availability of 68Ga-FAPI, with its ability to discriminate inflammation from neoplastic masses, to allow an accurate staging of patients, favors its future use in clinical routines. 68Ga-FAPI seems to overcome the known limitations of other available imaging modalities. Nonetheless, the clinical value of 68Ga-FAPI in PDAC remains to be further investigated.
The advent of theranostic and radioligand therapy in nuclear medicine has opened new opportunities for the management of solid tumors, including PDAC. More than 15 agents have been developed for the radioligand therapy of PDAC, including β- (177Lu and 90Y) and α-emitter (225Ac and 213Bi)-radiolabeled compounds. All these theranostic agents exhibit a high ability to non-invasively image PDAC with a high tumor-to-background ratio and strong anti-tumor efficacy in pre-clinical models of PDAC. Although the clinical applicability (toxicity and objective tumor response) of most of these agents remains to be further evaluated, they undoubtedly have great potential to be integrated into combination anti-cancer therapies.

Author Contributions

Conceptualization, C.M.; writing—original draft preparation, C.M. and S.C.; writing—reviewing and editing, C.M., S.C., N.D.L., J.D., M.F. and G.P.; figure preparation, C.M.; supervision, M.F. and G.P. All authors have read and agreed to the published version of the manuscript.


This work was supported by the Government of the Principality of Monaco; The Fondation François Xavier Mora; The Fondation Cordon de Vie; The Fondation Flavien; The Fondation de France; The Fondation Max et Yvonne de Foras; and La Ligue contre le Cancer—Equipe labellisée 2019.

Institutional Review Board Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


CAFCancer-associated fibroblast
CA19.9Carbohydrate antigen19.9
CDCP1CUB domain-containing protein1
CEACAM5Carcinoembryonic antigen-related cell adhesion
EGFREpidermoid growth factor receptor
FAPFibroblast activating protein
FAPIFibroblast activating protein inhibitor
FAZAFluoroazomycin arabinoside
mAbMonoclonal antibody
MMPMatrix metalloproteinase
MRIMagnetic resonance imaging
OSOverall survival
PAI2Plasminogen activator inhibitor-2
PDACPancreatic ductal adenocarcinoma
PETPositron emission tomography
PFSProgression-free survival
SdAbSingle-domain antibody
SPECTSingle-photon emission computed tomography
SUVStandardized uptake value
TfRTransferrin receptor
uPaUrokinase-type plasminogen activator


  1. Haeberle, L.; Esposito, I. Pathology of Pancreatic Cancer. Transl. Gastroenterol. Hepatol. 2019, 4. [Google Scholar] [CrossRef] [PubMed]
  2. Kleeff, J.; Korc, M.; Apte, M.; La Vecchia, C.; Johnson, C.D.; Biankin, A.V.; Neale, R.E.; Tempero, M.; Tuveson, D.A.; Hruban, R.H.; et al. Pancreatic Cancer. Nat. Rev. Dis. Primers 2016, 2, 16022. [Google Scholar] [CrossRef] [PubMed]
  3. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed][Green Version]
  4. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30. [Google Scholar] [CrossRef]
  5. Quante, A.S.; Ming, C.; Rottmann, M.; Engel, J.; Boeck, S.; Heinemann, V.; Westphalen, C.B.; Strauch, K. Projections of Cancer Incidence and Cancer-Related Deaths in Germany by 2020 and 2030. Cancer Med. 2016, 5, 2649–2656. [Google Scholar] [CrossRef] [PubMed]
  6. Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Res. 2014, 74, 2913–2921. [Google Scholar] [CrossRef] [PubMed][Green Version]
  7. Orth, M.; Metzger, P.; Gerum, S.; Mayerle, J.; Schneider, G.; Belka, C.; Schnurr, M.; Lauber, K. Pancreatic Ductal Adenocarcinoma: Biological Hallmarks, Current Status, and Future Perspectives of Combined Modality Treatment Approaches. Radiat. Oncol. 2019, 14, 141. [Google Scholar] [CrossRef] [PubMed]
  8. Manji, G.A.; Olive, K.P.; Saenger, Y.M.; Oberstein, P. Current and Emerging Therapies in Metastatic Pancreatic Cancer. Clin. Cancer Res. 2017, 23, 1670–1678. [Google Scholar] [CrossRef][Green Version]
  9. Winter, K.; Talar-Wojnarowska, R.; Dąbrowski, A.; Degowska, M.; Durlik, M.; Gąsiorowska, A.; Głuszek, S.; Jurkowska, G.; Kaczka, A.; Lampe, P.; et al. Diagnostic and Therapeutic Recommendations in Pancreatic Ductal Adenocarcinoma. Recommendations of the Working Group of the Polish Pancreatic Club. Prz. Gastroenterol. 2019, 14, 1–18. [Google Scholar] [CrossRef]
  10. Bengtsson, A.; Andersson, R.; Ansari, D. The Actual 5-Year Survivors of Pancreatic Ductal Adenocarcinoma Based on Real-World Data. Sci. Rep. 2020, 10, 16425. [Google Scholar] [CrossRef] [PubMed]
  11. Michelassi, F.; Erroi, F.; Dawson, P.J.; Pietrabissa, A.; Noda, S.; Handcock, M.; Block, G.E. Experience with 647 Consecutive Tumors of the Duodenum, Ampulla, Head of the Pancreas, and Distal Common Bile Duct. Ann. Surg. 1989, 210, 544–556. [Google Scholar] [CrossRef] [PubMed]
  12. Conroy, T.; Hammel, P.; Hebbar, M.; Ben Abdelghani, M.; Wei, A.C.; Raoul, J.-L.; Choné, L.; Francois, E.; Artru, P.; Biagi, J.J.; et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N. Engl. J. Med. 2018, 379, 2395–2406. [Google Scholar] [CrossRef]
  13. Neoptolemos, J.P.; Palmer, D.H.; Ghaneh, P.; Psarelli, E.E.; Valle, J.W.; Halloran, C.M.; Faluyi, O.; O’Reilly, D.A.; Cunningham, D.; Wadsley, J.; et al. Comparison of Adjuvant Gemcitabine and Capecitabine with Gemcitabine Monotherapy in Patients with Resected Pancreatic Cancer (ESPAC-4): A Multicentre, Open-Label, Randomised, Phase 3 Trial. Lancet 2017, 389, 1011–1024. [Google Scholar] [CrossRef]
  14. Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int. J. Mol. Sci. 2017, 18, 1338. [Google Scholar] [CrossRef]
  15. Rhim, A.D.; Mirek, E.T.; Aiello, N.M.; Maitra, A.; Bailey, J.M.; McAllister, F.; Reichert, M.; Beatty, G.L.; Rustgi, A.K.; Vonderheide, R.H.; et al. EMT and Dissemination Precede Pancreatic Tumor Formation. Cell 2012, 148, 349–361. [Google Scholar] [CrossRef] [PubMed][Green Version]
  16. Yordanova, A.; Eppard, E.; Kürpig, S.; Bundschuh, R.A.; Schönberger, S.; Gonzalez-Carmona, M.; Feldmann, G.; Ahmadzadehfar, H.; Essler, M. Theranostics in Nuclear Medicine Practice. Onco Targets 2017, 10, 4821–4828. [Google Scholar] [CrossRef][Green Version]
  17. Gomes Marin, J.F.; Nunes, R.F.; Coutinho, A.M.; Zaniboni, E.C.; Costa, L.B.; Barbosa, F.G.; Queiroz, M.A.; Cerri, G.G.; Buchpiguel, C.A. Theranostics in Nuclear Medicine: Emerging and Re-Emerging Integrated Imaging and Therapies in the Era of Precision Oncology. RadioGraphics 2020, 40, 1715–1740. [Google Scholar] [CrossRef] [PubMed]
  18. Strosberg, J.; El-Haddad, G.; Wolin, E.; Hendifar, A.; Yao, J.; Chasen, B.; Mittra, E.; Kunz, P.L.; Kulke, M.H.; Jacene, H.; et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N. Engl. J. Med. 2017, 376, 125–135. [Google Scholar] [CrossRef] [PubMed]
  19. Hofman, M.S.; Emmett, L.; Violet, J.; Y Zhang, A.; Lawrence, N.J.; Stockler, M.; Francis, R.J.; Iravani, A.; Williams, S.; Azad, A.; et al. TheraP: A Randomized Phase 2 Trial of 177 Lu-PSMA-617 Theranostic Treatment vs Cabazitaxel in Progressive Metastatic Castration-Resistant Prostate Cancer (Clinical Trial Protocol ANZUP 1603). BJU Int. 2019, 124 (Suppl. 1), 5–13. [Google Scholar] [CrossRef] [PubMed][Green Version]
  20. Elbanna, K.Y.; Jang, H.-J.; Kim, T.K. Imaging Diagnosis and Staging of Pancreatic Ductal Adenocarcinoma: A Comprehensive Review. Insights Imaging 2020, 11. [Google Scholar] [CrossRef] [PubMed][Green Version]
  21. Halbrook, C.J.; Lyssiotis, C.A. Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer. Cancer Cell 2017, 31, 5–19. [Google Scholar] [CrossRef][Green Version]
  22. Cassim, S.; Raymond, V.-A.; Dehbidi-Assadzadeh, L.; Lapierre, P.; Bilodeau, M. Metabolic Reprogramming Enables Hepatocarcinoma Cells to Efficiently Adapt and Survive to a Nutrient-Restricted Microenvironment. Cell Cycle 2018, 17, 903–916. [Google Scholar] [CrossRef]
  23. Cassim, S.; Vučetić, M.; Ždralević, M.; Pouyssegur, J. Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer. Cancers 2020, 12, 1119. [Google Scholar] [CrossRef]
  24. Boellaard, R.; Delgado-Bolton, R.; Oyen, W.J.G.; Giammarile, F.; Tatsch, K.; Eschner, W.; Verzijlbergen, F.J.; Barrington, S.F.; Pike, L.C.; Weber, W.A.; et al. FDG PET/CT: EANM Procedure Guidelines for Tumour Imaging: Version 2.0. Eur. J. Nucl. Med. Mol. Imaging 2015, 42, 328–354. [Google Scholar] [CrossRef]
  25. Bryant, K.L.; Mancias, J.D.; Kimmelman, A.C.; Der, C.J. KRAS: Feeding Pancreatic Cancer Proliferation. Trends Biochem. Sci. 2014, 39, 91–100. [Google Scholar] [CrossRef][Green Version]
  26. Pupo, E.; Avanzato, D.; Middonti, E.; Bussolino, F.; Lanzetti, L. KRAS-Driven Metabolic Rewiring Reveals Novel Actionable Targets in Cancer. Front. Oncol. 2019, 9. [Google Scholar] [CrossRef][Green Version]
  27. Serrao, E.M.; Kettunen, M.I.; Rodrigues, T.B.; Dzien, P.; Wright, A.J.; Gopinathan, A.; Gallagher, F.A.; Lewis, D.Y.; Frese, K.K.; Almeida, J.; et al. MRI with Hyperpolarised [1-13C]Pyruvate Detects Advanced Pancreatic Preneoplasia Prior to Invasive Disease in a Mouse Model. Gut 2015, 65, 465–475. [Google Scholar] [CrossRef][Green Version]
  28. Seufferlein, T.; Bachet, J.B.; Van Cutsem, E.; Rougier, P.; ESMO Guidelines Working Group. Pancreatic Adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann. Oncol. 2012, 23 (Suppl. 7), vii33–vii40. [Google Scholar] [CrossRef]
  29. Yeh, R.; Dercle, L.; Garg, I.; Wang, Z.J.; Hough, D.M.; Goenka, A.H. The Role of 18F-FDG PET/CT and PET/MRI in Pancreatic Ductal Adenocarcinoma. Abdom. Radiol. 2018, 43, 415–434. [Google Scholar] [CrossRef]
  30. Best, L.M.; Rawji, V.; Pereira, S.P.; Davidson, B.R.; Gurusamy, K.S. Imaging Modalities for Characterising Focal Pancreatic Lesions. Cochrane Database Syst. Rev. 2017, 4, CD010213. [Google Scholar] [CrossRef][Green Version]
  31. Matsumoto, I.; Shirakawa, S.; Shinzeki, M.; Asari, S.; Goto, T.; Ajiki, T.; Fukumoto, T.; Kitajima, K.; Ku, Y. 18-Fluorodeoxyglucose Positron Emission Tomography Does Not Aid in Diagnosis of Pancreatic Ductal Adenocarcinoma. Clin. Gastroenterol. Hepatol. 2013, 11, 712–718. [Google Scholar] [CrossRef] [PubMed]
  32. Lee, J.W.; O, J.H.; Choi, M.; Choi, J.Y. Impact of F-18 Fluorodeoxyglucose PET/CT and PET/MRI on Initial Staging and Changes in Management of Pancreatic Ductal Adenocarcinoma: A Systemic Review and Meta-Analysis. Diagnostics 2020, 10, 952. [Google Scholar] [CrossRef] [PubMed]
  33. Yoshioka, M.; Sato, T.; Furuya, T.; Shibata, S.; Andoh, H.; Asanuma, Y.; Hatazawa, J.; Shimosegawa, E.; Koyama, K.; Yamamoto, Y. Role of Positron Emission Tomography with 2-Deoxy-2-[18F]Fluoro-D-Glucose in Evaluating the Effects of Arterial Infusion Chemotherapy and Radiotherapy on Pancreatic Cancer. J. Gastroenterol. 2004, 39, 50–55. [Google Scholar] [CrossRef]
  34. Jain, R.K.; Lee, J.J.; Ng, C.; Hong, D.; Gong, J.; Naing, A.; Wheler, J.; Kurzrock, R. Change in Tumor Size by RECIST Correlates Linearly With Overall Survival in Phase I Oncology Studies. J. Clin. Oncol. 2012, 30, 2684–2690. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Yokose, T.; Kitago, M.; Matsusaka, Y.; Masugi, Y.; Shinoda, M.; Yagi, H.; Abe, Y.; Oshima, G.; Hori, S.; Endo, Y.; et al. Usefulness of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Predicting the Prognosis and Treatment Response of Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma. Cancer Med. 2020, 9, 4059–4068. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Sperti, C.; Pasquali, C.; Bissoli, S.; Chierichetti, F.; Liessi, G.; Pedrazzoli, S. Tumor Relapse after Pancreatic Cancer Resection Is Detected Earlier by 18-FDG PET than by CT. J. Gastrointest. Surg. 2010, 14, 131–140. [Google Scholar] [CrossRef]
  37. Wang, L.; Dong, P.; Wang, W.; Li, M.; Hu, W.; Liu, X.; Tian, B. Early Recurrence Detected by 18F-FDG PET/CT in Patients with Resected Pancreatic Ductal Adenocarcinoma. Medicine 2020, 99, e19504. [Google Scholar] [CrossRef]
  38. Javery, O.; Shyn, P.; Mortele, K. FDG PET or PET/CT in Patients with Pancreatic Cancer: When Does it Add to Diagnostic CT or MRI? Clin. Imaging 2013, 37, 295–301. [Google Scholar] [CrossRef]
  39. Yamamoto, T.; Sugiura, T.; Mizuno, T.; Okamura, Y.; Aramaki, T.; Endo, M.; Uesaka, K. Preoperative FDG-PET Predicts Early Recurrence and a Poor Prognosis after Resection of Pancreatic Adenocarcinoma. Ann. Surg. Oncol. 2015, 22, 677–684. [Google Scholar] [CrossRef]
  40. Moon, S.Y.; Joo, K.R.; So, Y.R.; Lim, J.U.; Cha, J.M.; Shin, H.P.; Yang, Y.-J. Predictive Value of Maximum Standardized Uptake Value (SUVmax) on 18F-FDG PET/CT in Patients with Locally Advanced or Metastatic Pancreatic Cancer. Clin. Nucl. Med. 2013, 38, 778–783. [Google Scholar] [CrossRef]
  41. Pimiento, J.M.; Davis-Yadley, A.H.; Kim, R.D.; Chen, D.-T.; Eikman, E.A.; Berman, C.G.; Malafa, M.P. Metabolic Activity by (18)F-FDG-PET/CT Is Prognostic for Stage I and II Pancreatic Cancer. Clin. Nucl. Med. 2016, 41, 177–181. [Google Scholar] [CrossRef][Green Version]
  42. Bollineni, V.R.; Kramer, G.M.; Jansma, E.P.; Liu, Y.; Oyen, W.J.G. A Systematic Review on [18F]FLT-PET Uptake as a Measure of Treatment Response in Cancer Patients. Eur. J. Cancer 2016, 55, 81–97. [Google Scholar] [CrossRef] [PubMed][Green Version]
  43. Von Forstner, C.; Egberts, J.H.; Ammerpohl, O.; Niedzielska, D.; Buchert, R.; Mikecz, P.; Schumacher, U.; Peldschus, K.; Adam, G.; Pilarsky, C.; et al. Gene Expression Patterns and Tumor Uptake of 18F-FDG, 18F-FLT, and 18F-FEC in PET/MRI of an Orthotopic Mouse Xenotransplantation Model of Pancreatic Cancer. J. Nucl. Med. 2008, 49, 1362–1370. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Herrmann, K.; Eckel, F.; Schmidt, S.; Scheidhauer, K.; Krause, B.J.; Kleeff, J.; Schuster, T.; Wester, H.-J.; Friess, H.; Schmid, R.M.; et al. In Vivo Characterization of Proliferation for Discriminating Cancer from Pancreatic Pseudotumors. J. Nucl. Med. 2008, 49, 1437–1444. [Google Scholar] [CrossRef] [PubMed][Green Version]
  45. Quon, A.; Chang, S.T.; Chin, F.; Kamaya, A.; Dick, D.W.; Loo, B.W.; Gambhir, S.S.; Koong, A.C. Initial Evaluation of 18F-Fluorothymidine (FLT) PET/CT Scanning for Primary Pancreatic Cancer. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 527–531. [Google Scholar] [CrossRef][Green Version]
  46. Wieder, H.; Beer, A.J.; Siveke, J.; Schuster, T.; Buck, A.K.; Herrmann, K.; Stollfuss, J.C. 18F-Fluorothymidine PET for Predicting Survival in Patients with Resectable Pancreatic Cancer. Oncotarget 2018, 9, 10128–10134. [Google Scholar] [CrossRef] [PubMed][Green Version]
  47. Muz, B.; de la Puente, P.; Azab, F.; Azab, A.K. The Role of Hypoxia in Cancer Progression, Angiogenesis, Metastasis, and Resistance to Therapy. Hypoxia 2015, 3, 83–92. [Google Scholar] [CrossRef][Green Version]
  48. Gaustad, J.-V.; Simonsen, T.G.; Wegner, C.S.; Rofstad, E.K. Vascularization, Oxygenation, and the Effect of Sunitinib Treatment in Pancreatic Ductal Adenocarcinoma Xenografts. Front. Oncol. 2019, 9. [Google Scholar] [CrossRef][Green Version]
  49. Zhao, X.; Gao, S.; Ren, H.; Sun, W.; Zhang, H.; Sun, J.; Yang, S.; Hao, J. Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin. Cancer Res. 2014, 74, 2455–2464. [Google Scholar] [CrossRef][Green Version]
  50. Matsuo, Y.; Ding, Q.; Desaki, R.; Maemura, K.; Mataki, Y.; Shinchi, H.; Natsugoe, S.; Takao, S. Hypoxia Inducible Factor-1 Alpha Plays a Pivotal Role in Hepatic Metastasis of Pancreatic Cancer: An Immunohistochemical Study. J. Hepatobiliary Pancreat Sci. 2014, 21, 105–112. [Google Scholar] [CrossRef]
  51. Metran-Nascente, C.; Yeung, I.; Vines, D.C.; Metser, U.; Dhani, N.C.; Green, D.; Milosevic, M.; Jaffray, D.; Hedley, D.W. Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake. J. Nucl. Med. 2016, 57, 361–366. [Google Scholar] [CrossRef] [PubMed][Green Version]
  52. Segard, T.; Robins, P.D.; Yusoff, I.F.; Ee, H.; Morandeau, L.; Campbell, E.M.; Francis, R.J. Detection of Hypoxia with 18F-Fluoromisonidazole (18F-FMISO) PET/CT in Suspected or Proven Pancreatic Cancer. Clin. Nucl. Med. 2013, 38, 1–6. [Google Scholar] [CrossRef] [PubMed]
  53. Yamane, T.; Aikawa, M.; Yasuda, M.; Fukushima, K.; Seto, A.; Okamoto, K.; Koyama, I.; Kuji, I. [18F]FMISO PET/CT as a Preoperative Prognostic Factor in Patients with Pancreatic Cancer. EJNMMI Res. 2019, 9. [Google Scholar] [CrossRef] [PubMed][Green Version]
  54. Siveke, J.T. Fibroblast-Activating Protein: Targeting the Roots of the Tumor Microenvironment. J. Nucl. Med. 2018, 59, 1412–1414. [Google Scholar] [CrossRef]
  55. Loktev, A.; Lindner, T.; Mier, W.; Debus, J.; Altmann, A.; Jäger, D.; Giesel, F.; Kratochwil, C.; Barthe, P.; Roumestand, C.; et al. A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts. J. Nucl. Med. 2018, 59, 1423–1429. [Google Scholar] [CrossRef]
  56. Kratochwil, C.; Flechsig, P.; Lindner, T.; Abderrahim, L.; Altmann, A.; Mier, W.; Adeberg, S.; Rathke, H.; Röhrich, M.; Winter, H.; et al. 68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer. J. Nucl. Med. 2019, 60, 801–805. [Google Scholar] [CrossRef][Green Version]
  57. Chen, H.; Zhao, L.; Hao, B.; Sun, L.; Jacobson, O.; Wu, H. Comparison of 68Ga-FAPI and 18F-FDG PET/CT for Detection, Staging, and Restaging of Various Kinds of Cancer. J. Nucl. Med. 2020, 61, 625. [Google Scholar]
  58. Röhrich, M.; Naumann, P.; Giesel, F.L.; Choyke, P.; Staudinger, F.; Wefers, A.; Liew, D.P.; Kratochwil, C.; Rathke, H.; Liermann, J.; et al. Impact of 68Ga-FAPI-PET/CT Imaging on the Therapeutic Management of Primary and Recurrent Pancreatic Ductal Adenocarcinomas. J. Nucl. Med. 2020. [Google Scholar] [CrossRef]
  59. Liermann, J.; Syed, M.; Ben-Josef, E.; Schubert, K.; Schlampp, I.; Sprengel, S.D.; Ristau, J.; Weykamp, F.; Röhrich, M.; Koerber, S.A.; et al. Impact of FAPI-PET/CT on Target Volume Definition in Radiation Therapy of Locally Recurrent Pancreatic Cancer. Cancers 2021, 13, 796. [Google Scholar] [CrossRef]
  60. Loktev, A.; Lindner, T.; Burger, E.-M.; Altmann, A.; Giesel, F.; Kratochwil, C.; Debus, J.; Marme, F.; Jaeger, D.; Mier, W.; et al. Development of Novel FAP-Targeted Radiotracers with Improved Tumor Retention. J. Nucl. Med. 2019. [Google Scholar] [CrossRef]
  61. Sperb, N.; Tsesmelis, M.; Wirth, T. Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2020, 21, 5486. [Google Scholar] [CrossRef] [PubMed]
  62. Hu, D.; Ansari, D.; Zhou, Q.; Sasor, A.; Said Hilmersson, K.; Andersson, R. Stromal Fibronectin Expression in Patients with Resected Pancreatic Ductal Adenocarcinoma. World J. Surg. Oncol. 2019, 17. [Google Scholar] [CrossRef] [PubMed]
  63. Jailkhani, N.; Ingram, J.R.; Rashidian, M.; Rickelt, S.; Tian, C.; Mak, H.; Jiang, Z.; Ploegh, H.L.; Hynes, R.O. Noninvasive Imaging of Tumor Progression, Metastasis, and Fibrosis Using a Nanobody Targeting the Extracellular Matrix. Proc. Natl. Acad. Sci. USA 2019, 116, 14181–14190. [Google Scholar] [CrossRef][Green Version]
  64. Slapak, E.J.; Duitman, J.; Tekin, C.; Bijlsma, M.F.; Spek, C.A. Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression? Biology 2020, 9, 80. [Google Scholar] [CrossRef][Green Version]
  65. Dangi-Garimella, S.; Krantz, S.B.; Barron, M.R.; Shields, M.A.; Heiferman, M.J.; Grippo, P.J.; Bentrem, D.J.; Munshi, H.G. Three-Dimensional Collagen I Promotes Gemcitabine Resistance in Pancreatic Cancer through MT1-MMP-Mediated Expression of HMGA2. Cancer Res. 2011, 71, 1019–1028. [Google Scholar] [CrossRef] [PubMed][Green Version]
  66. Morcillo, M.Á.; García de Lucas, Á.; Oteo, M.; Romero, E.; Magro, N.; Ibáñez, M.; Martínez, A.; Garaulet, G.; Arroyo, A.G.; López-Casas, P.P.; et al. MT1-MMP as a PET Imaging Biomarker for Pancreas Cancer Management. Contrast Media Mol. Imaging 2018, 2018, 8382148. [Google Scholar] [CrossRef] [PubMed]
  67. Koustoulidou, S.; Hoorens, M.W.H.; Dalm, S.U.; Mahajan, S.; Debets, R.; Seimbille, Y.; de Jong, M. Cancer-Associated Fibroblasts as Players in Cancer Development and Progression and Their Role in Targeted Radionuclide Imaging and Therapy. Cancers 2021, 13, 1100. [Google Scholar] [CrossRef] [PubMed]
  68. Cohen, S.J.; Alpaugh, R.K.; Palazzo, I.; Meropol, N.J.; Rogatko, A.; Xu, Z.; Hoffman, J.P.; Weiner, L.M.; Cheng, J.D. Fibroblast Activation Protein and Its Relationship to Clinical Outcome in Pancreatic Adenocarcinoma. Pancreas 2008, 37, 154–158. [Google Scholar] [CrossRef] [PubMed]
  69. Watabe, T.; Liu, Y.; Kaneda-Nakashima, K.; Shirakami, Y.; Lindner, T.; Ooe, K.; Toyoshima, A.; Nagata, K.; Shimosegawa, E.; Haberkorn, U.; et al. Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64Cu- and 225Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models. J. Nucl. Med. 2020, 61, 563–569. [Google Scholar] [CrossRef]
  70. Lindner, T.; Loktev, A.; Altmann, A.; Giesel, F.; Kratochwil, C.; Debus, J.; Jäger, D.; Mier, W.; Haberkorn, U. Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein. J. Nucl. Med. 2018, 59, 1415–1422. [Google Scholar] [CrossRef][Green Version]
  71. Suh, H.; Pillai, K.; Morris, D.L. Mucins in Pancreatic Cancer: Biological Role, Implications in Carcinogenesis and Applications in Diagnosis and Therapy. Am. J. Cancer Res. 2017, 7, 1372–1383. [Google Scholar]
  72. Wang, S.; You, L.; Dai, M.; Zhao, Y. Mucins in Pancreatic Cancer: A Well-Established but Promising Family for Diagnosis, Prognosis and Therapy. J. Cell. Mol. Med. 2020, 24, 10279–10289. [Google Scholar] [CrossRef] [PubMed]
  73. Tréhoux, S.; Duchêne, B.; Jonckheere, N.; Van Seuningen, I. The MUC1 Oncomucin Regulates Pancreatic Cancer Cell Biological Properties and Chemoresistance. Implication of P42-44 MAPK, Akt, Bcl-2 and MMP13 Pathways. Biochem. Biophys. Res. Commun. 2015, 456, 757–762. [Google Scholar] [CrossRef] [PubMed]
  74. Nath, S.; Roy, L.D.; Grover, P.; Rao, S.; Mukherjee, P. Mucin 1 Regulates Cox-2 Gene in Pancreatic Cancer. Pancreas 2015, 44, 909–917. [Google Scholar] [CrossRef][Green Version]
  75. Nath, S.; Daneshvar, K.; Roy, L.D.; Grover, P.; Kidiyoor, A.; Mosley, L.; Sahraei, M.; Mukherjee, P. MUC1 Induces Drug Resistance in Pancreatic Cancer Cells via Upregulation of Multidrug Resistance Genes. Oncogenesis 2013, 2, e51. [Google Scholar] [CrossRef][Green Version]
  76. Yokoyama, S.; Hamada, T.; Higashi, M.; Matsuo, K.; Maemura, K.; Kurahara, H.; Horinouchi, M.; Hiraki, T.; Sugimoto, T.; Akahane, T.; et al. Predicted Prognosis of Patients with Pancreatic Cancer by Machine Learning. Clin. Cancer Res. 2020, 26, 2411–2421. [Google Scholar] [CrossRef] [PubMed][Green Version]
  77. Alirezapour, B.; Rasaee, M.J.; Jalilian, A.R.; Rajabifar, S.; Mohammadnejad, J.; Paknejad, M.; Maadi, E.; Moradkhani, S. Development of [64Cu]-DOTA-PR81 Radioimmunoconjugate for MUC-1 Positive PET Imaging. Nucl. Med. Biol 2016, 43, 73–80. [Google Scholar] [CrossRef]
  78. Stergiou, N.; Nagel, J.; Pektor, S.; Heimes, A.-S.; Jäkel, J.; Brenner, W.; Schmidt, M.; Miederer, M.; Kunz, H.; Roesch, F.; et al. Evaluation of a Novel Monoclonal Antibody against Tumor-Associated MUC1 for Diagnosis and Prognosis of Breast Cancer. Int. J. Med. Sci. 2019, 16, 1188–1198. [Google Scholar] [CrossRef][Green Version]
  79. Fung, K.; Vivier, D.; Keinänen, O.; Sarbisheh, E.K.; Price, E.W.; Zeglis, B.M. 89Zr-Labeled AR20.5: A MUC1-Targeting ImmunoPET Probe. Molecules 2020, 25, 2315. [Google Scholar] [CrossRef]
  80. Hull, A.; Li, Y.; Bartholomeusz, D.; Hsieh, W.; Allen, B.; Bezak, E. Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature. Cancers 2020, 12, 481. [Google Scholar] [CrossRef][Green Version]
  81. Cardillo, T.M.; Ying, Z.; Gold, D.V. Therapeutic Advantage of (90)Yttrium- versus (131)Iodine-Labeled PAM4 Antibody in Experimental Pancreatic Cancer. Clin. Cancer Res. 2001, 7, 3186–3192. [Google Scholar]
  82. Gold, D.V.; Modrak, D.E.; Schutsky, K.; Cardillo, T.M. Combined 90Yttrium-DOTA-Labeled PAM4 Antibody Radioimmunotherapy and Gemcitabine Radiosensitization for the Treatment of a Human Pancreatic Cancer Xenograft. Int. J. Cancer 2004, 109, 618–626. [Google Scholar] [CrossRef]
  83. Gulec, S.A.; Cohen, S.J.; Pennington, K.L.; Zuckier, L.S.; Hauke, R.J.; Horne, H.; Wegener, W.A.; Teoh, N.; Gold, D.V.; Sharkey, R.M.; et al. Treatment of Advanced Pancreatic Carcinoma with 90Y-Clivatuzumab Tetraxetan: A Phase I Single-Dose Escalation Trial. Clin. Cancer Res. 2011, 17, 4091–4100. [Google Scholar] [CrossRef][Green Version]
  84. Ocean, A.J.; Pennington, K.L.; Guarino, M.J.; Sheikh, A.; Bekaii-Saab, T.; Serafini, A.N.; Lee, D.; Sung, M.W.; Gulec, S.A.; Goldsmith, S.J.; et al. Fractionated Radioimmunotherapy with (90) Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer: A Phase 1 Trial. Cancer 2012, 118, 5497–5506. [Google Scholar] [CrossRef][Green Version]
  85. Marcu, L.; Bezak, E.; Allen, B.J. Global Comparison of Targeted Alpha vs Targeted Beta Therapy for Cancer: In Vitro, in Vivo and Clinical Trials. Crit. Rev. Oncol. Hematol. 2018, 123, 7–20. [Google Scholar] [CrossRef]
  86. Qu, C.F.; Li, Y.; Song, Y.J.; Rizvi, S.M.A.; Raja, C.; Zhang, D.; Samra, J.; Smith, R.; Perkins, A.C.; Apostolidis, C.; et al. MUC1 Expression in Primary and Metastatic Pancreatic Cancer Cells for in Vitro Treatment by (213)Bi-C595 Radioimmunoconjugate. Br. J. Cancer 2004, 91, 2086–2093. [Google Scholar] [CrossRef][Green Version]
  87. Song, E.Y.; Qu, C.F.; Rizvi, S.M.A.; Raja, C.; Beretov, J.; Morgenstern, A.; Apostolidis, C.; Bruchertseifer, F.; Perkins, A.; Allen, B.J. Bismuth-213 Radioimmunotherapy with C595 Anti-MUC1 Monoclonal Antibody in an Ovarian Cancer Ascites Model. Cancer Biol. 2008, 7, 76–80. [Google Scholar] [CrossRef][Green Version]
  88. Nichetti, F.; Marra, A.; Corti, F.; Guidi, A.; Raimondi, A.; Prinzi, N.; de Braud, F.; Pusceddu, S. The Role of Mesothelin as a Diagnostic and Therapeutic Target in Pancreatic Ductal Adenocarcinoma: A Comprehensive Review. Target. Oncol. 2018, 13, 333–351. [Google Scholar] [CrossRef]
  89. Montemagno, C.; Cassim, S.; Trichanh, D.; Savary, C.; Pouyssegur, J.; Pagès, G.; Fagret, D.; Broisat, A.; Ghezzi, C. 99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma. Cancers 2019, 11, 1531. [Google Scholar] [CrossRef][Green Version]
  90. Hassan, R.; Thomas, A.; Alewine, C.; Le, D.T.; Jaffee, E.M.; Pastan, I. Mesothelin Immunotherapy for Cancer: Ready for Prime Time? J. Clin. Oncol. 2016, 34, 4171–4179. [Google Scholar] [CrossRef][Green Version]
  91. Montemagno, C.; Cassim, S.; Pouyssegur, J.; Broisat, A.; Pagès, G. From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2020, 21, 4067. [Google Scholar] [CrossRef]
  92. Kobayashi, K.; Sasaki, T.; Takenaka, F.; Yakushiji, H.; Fujii, Y.; Kishi, Y.; Kita, S.; Shen, L.; Kumon, H.; Matsuura, E. A Novel PET Imaging Using 64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells. J. Immunol. Res. 2015, 2015, 268172. [Google Scholar] [CrossRef][Green Version]
  93. ter Weele, E.J.; Terwisscha van Scheltinga, A.G.T.; Kosterink, J.G.W.; Pot, L.; Vedelaar, S.R.; Lamberts, L.E.; Williams, S.P.; Lub-de Hooge, M.N.; de Vries, E.G.E. Imaging the Distribution of an Antibody-Drug Conjugate Constituent Targeting Mesothelin with 89Zr and IRDye 800CW in Mice Bearing Human Pancreatic Tumor Xenografts. Oncotarget 2015, 6, 42081–42090. [Google Scholar] [CrossRef][Green Version]
  94. van Scheltinga, A.G.T.T.; Ogasawara, A.; Pacheco, G.; Vanderbilt, A.N.; Tinianow, J.N.; Gupta, N.; Li, D.; Firestein, R.; Marik, J.; Scales, S.J.; et al. Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative89 Zr-ImmunoPET. Mol. Cancer Ther. 2017, 16, 134–142. [Google Scholar] [CrossRef][Green Version]
  95. Lamberts, T.E.; Menke-van der Houven, C.W.; Weele, E.J.T.; Bensch, F.; Smeenk, M.M.; Voortman, J.; Hoekstra, O.S.; Williams, S.P.; Fine, B.M.; Maslyar, D.; et al. ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody-Drug Conjugate Treatment. Clin. Cancer Res. 2015, 22, 1642–1652. [Google Scholar] [CrossRef][Green Version]
  96. Lindenberg, L.; Thomas, A.; Adler, S.; Mena, E.; Kurdziel, K.; Maltzman, J.; Wallin, B.; Hoffman, K.; Pastan, I.; Paik, C.H.; et al. Safety and Biodistribution of 111In-Amatuximab in Patients with Mesothelin Expressing Cancers Using Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) Imaging. Oncotarget 2015, 6, 4496–4504. [Google Scholar] [CrossRef][Green Version]
  97. Montemagno, C.; Bacot, S.; Ahmadi, M.; Kerfelec, B.; Baty, D.; Debiossat, M.; Soubies, A.; Perret, P.; Riou, L.; Fagret, D.; et al. Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer. J. Nucl. Med. 2018, 59, 1056–1062. [Google Scholar] [CrossRef]
  98. Yakushiji, H.; Kobayashi, K.; Takenaka, F.; Kishi, Y.; Shinohara, M.; Akehi, M.; Sasaki, T.; Ohno, E.; Matsuura, E. Novel Single-chain Variant of Antibody against Mesothelin Established by Phage Library. Cancer Sci. 2019, 110, 2722–2733. [Google Scholar] [CrossRef] [PubMed][Green Version]
  99. Wickstroem, K.; Hagemann, U.B.; Cruciani, V.; Wengner, A.M.; Kristian, A.; Ellingsen, C.; Siemeister, G.; Bjerke, R.M.; Karlsson, J.; Ryan, O.B.; et al. Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models. J. Nucl. Med. 2019, 60, 1293–1300. [Google Scholar] [CrossRef][Green Version]
  100. Torti, S.V.; Torti, F.M. Iron: The Cancer Connection. Mol. Asp. Med. 2020, 75, 100860. [Google Scholar] [CrossRef]
  101. Basuli, D.; Tesfay, L.; Deng, Z.; Paul, B.; Yamamoto, Y.; Ning, G.; Xian, W.; McKeon, F.; Lynch, M.; Crum, C.P.; et al. Iron Addiction: A Novel Therapeutic Target in Ovarian Cancer. Oncogene 2017, 36, 4089–4099. [Google Scholar] [CrossRef] [PubMed][Green Version]
  102. Gatter, K.C.; Brown, G.; Trowbridge, I.S.; Woolston, R.E.; Mason, D.Y. Transferrin Receptors in Human Tissues: Their Distribution and Possible Clinical Relevance. J. Clin. Pathol 1983, 36, 539–545. [Google Scholar] [CrossRef][Green Version]
  103. Shen, Y.; Li, X.; Dong, D.; Zhang, B.; Xue, Y.; Shang, P. Transferrin Receptor 1 in Cancer: A New Sight for Cancer Therapy. Am. J. Cancer Res. 2018, 8, 916–931. [Google Scholar]
  104. Daniels-Wells, T.R.; Penichet, M.L. Transferrin Receptor 1: A Target for Antibody-Mediated Cancer Therapy. Immunotherapy 2016, 8, 991–994. [Google Scholar] [CrossRef][Green Version]
  105. Luria-Pérez, R.; Helguera, G.; Rodríguez, J.A. Antibody-Mediated Targeting of the Transferrin Receptor in Cancer Cells. Boletín Médico Hosp. Infant. México 2016, 73, 372–379. [Google Scholar] [CrossRef]
  106. Pirollo, K.F.; Nemunaitis, J.; Leung, P.K.; Nunan, R.; Adams, J.; Chang, E.H. Safety and Efficacy in Advanced Solid Tumors of a Targeted Nanocomplex Carrying the P53 Gene Used in Combination with Docetaxel: A Phase 1b Study. Mol. Ther. 2016, 24, 1697–1706. [Google Scholar] [CrossRef][Green Version]
  107. Sugyo, A.; Tsuji, A.B.; Sudo, H.; Nagatsu, K.; Koizumi, M.; Ukai, Y.; Kurosawa, G.; Zhang, M.R.; Kurosawa, Y.; Saga, T. Preclinical Evaluation of 89Zr-Labeled Human Antitransferrin Receptor Monoclonal Antibody as a PET Probe Using a Pancreatic Cancer Mouse Model. Nucl. Med. Commun. 2015, 36, 286–294. [Google Scholar] [CrossRef]
  108. Sugyo, A.; Tsuji, A.B.; Sudo, H.; Okada, M.; Koizumi, M.; Satoh, H.; Kurosawa, G.; Kurosawa, Y.; Saga, T. Evaluation of Efficacy of Radioimmunotherapy with 90Y-Labeled Fully Human Anti-Transferrin Receptor Monoclonal Antibody in Pancreatic Cancer Mouse Models. PLloS ONE 2015, 10, e0123761. [Google Scholar] [CrossRef][Green Version]
  109. Henry, K.; Dacek, M.; Dilling, T.; Caen, J.; Evans, M.; Lewis, J. Interrogating KRAS, ERK, and MYC Signaling in Pancreatic Cancer with Endogenous PET Imaging. J. Nucl. Med. 2018, 59, 72. [Google Scholar]
  110. Henry, K.E.; Dacek, M.M.; Dilling, T.R.; Caen, J.D.; Fox, I.L.; Evans, M.J.; Lewis, J.S. A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer. Clin. Cancer Res. 2019, 25, 166–176. [Google Scholar] [CrossRef][Green Version]
  111. Zhou, G.; Liu, X.; Wang, X.; Jin, D.; Chen, Y.; Li, G.; Li, C.; Fu, D.; Xu, W.; Wang, X. Combination of Preoperative CEA and CA19-9 Improves Prediction Outcomes in Patients with Resectable Pancreatic Adenocarcinoma: Results from a Large Follow-up Cohort. OncoTargets Ther. 2017, 10, 1199–1206. [Google Scholar] [CrossRef] [PubMed][Green Version]
  112. Ni, X.G.; Bai, X.F.; Mao, Y.L.; Shao, Y.F.; Wu, J.X.; Shan, Y.; Wang, C.F.; Wang, J.; Tian, Y.T.; Liu, Q.; et al. The Clinical Value of Serum CEA, CA19-9, and CA242 in the Diagnosis and Prognosis of Pancreatic Cancer. Eur. J. Surg. Oncol. 2005, 31, 164–169. [Google Scholar] [CrossRef]
  113. Vuijk, F.A.; de Muynck, L.D.A.N.; Franken, L.C.; Busch, O.R.; Wilmink, J.W.; Besselink, M.G.; Bonsing, B.A.; Bhairosingh, S.S.; Kuppen, P.J.K.; Mieog, J.S.D.; et al. Molecular Targets for Diagnostic and Intraoperative Imaging of Pancreatic Ductal Adenocarcinoma after Neoadjuvant FOLFIRINOX Treatment. Sci. Rep. 2020, 10, 16211. [Google Scholar] [CrossRef]
  114. Schoffelen, R.; Boerman, O.C.; Goldenberg, D.M.; Sharkey, R.M.; van Herpen, C.M.L.; Franssen, G.M.; McBride, W.J.; Chang, C.-H.; Rossi, E.A.; van der Graaf, W.T.A.; et al. Development of an Imaging-Guided CEA-Pretargeted Radionuclide Treatment of Advanced Colorectal Cancer: First Clinical Results. Br. J. Cancer 2013, 109, 934–942. [Google Scholar] [CrossRef][Green Version]
  115. Reubi, J.; Waser, B.; Friess, H.; Buchler, M.; Laissue, J. Neurotensin Receptors: A New Marker for Human Ductal Pancreatic Adenocarcinoma. Gut 1998, 42, 546–550. [Google Scholar] [CrossRef] [PubMed]
  116. Wang, J.-G.; Li, N.-N.; Li, H.-N.; Cui, L.; Wang, P. Pancreatic Cancer Bears Overexpression of Neurotensin and Neurotensin Receptor Subtype-1 and SR 48692 Counteracts Neurotensin Induced Cell Proliferation in Human Pancreatic Ductal Carcinoma Cell Line PANC-1. Neuropeptides 2011, 45, 151–156. [Google Scholar] [CrossRef] [PubMed]
  117. Körner, M.; Waser, B.; Strobel, O.; Büchler, M.; Reubi, J.C. Neurotensin Receptors in Pancreatic Ductal Carcinomas. EJNMMI Res. 2015, 5. [Google Scholar] [CrossRef] [PubMed][Green Version]
  118. Christou, N.; Blondy, S.; David, V.; Verdier, M.; Lalloué, F.; Jauberteau, M.-O.; Mathonnet, M.; Perraud, A. Neurotensin Pathway in Digestive Cancers and Clinical Applications: An Overview. Cell Death Dis. 2020, 11, 1–12. [Google Scholar] [CrossRef] [PubMed]
  119. Ouyang, Q.; Zhou, J.; Yang, W.; Cui, H.; Xu, M.; Yi, L. Oncogenic Role of Neurotensin and Neurotensin Receptors in Various Cancers. Clin. Exp. Pharmacol. Physiol. 2017, 44, 841–846. [Google Scholar] [CrossRef][Green Version]
  120. El Masri, R.; Delon, J. RHO GTPases: From New Partners to Complex Immune Syndromes. Nat. Rev. Immunol. 2021. [Google Scholar] [CrossRef]
  121. Megrelis, L.; El Ghoul, E.; Moalli, F.; Versapuech, M.; Cassim, S.; Ruef, N.; Stein, J.V.; Mangeney, M.; Delon, J. Fam65b Phosphorylation Relieves Tonic RhoA Inhibition During T Cell Migration. Front. Immunol. 2018, 9, 2001. [Google Scholar] [CrossRef]
  122. Takahashi, K.; Ehata, S.; Miyauchi, K.; Morishita, Y.; Miyazawa, K.; Miyazono, K. Neurotensin Receptor 1 Signaling Promotes Pancreatic Cancer Progression. Mol. Oncol. 2021, 15, 151–166. [Google Scholar] [CrossRef]
  123. Hodolic, M.; Ambrosini, V.; Fanti, S. Potential Use of Radiolabelled Neurotensin in PET Imaging and Therapy of Patients with Pancreatic Cancer. Nucl. Med. Commun. 2020, 41, 411–415. [Google Scholar] [CrossRef]
  124. Marenco, M.; Lodola, L.; Persico, M.G.; Frangipane, V.; Facoetti, A.; Aprile, C.; Hodolič, M. Evidence of 68Ga-DOTA-NT-20.3 Uptake in Pancreatic Adenocarcinoma AsPC-1 Cell Line—in Vitro Study. Curr. Pharm. Biotechnol. 2018, 19, 754–759. [Google Scholar] [CrossRef]
  125. Prignon, A.; Provost, C.; Alshoukr, F.; Wendum, D.; Couvelard, A.; Barbet, J.; Forgez, P.; Talbot, J.-N.; Gruaz-Guyon, A. Preclinical Evaluation of 68Ga-DOTA-NT-20.3: A Promising PET Imaging Probe To Discriminate Human Pancreatic Ductal Adenocarcinoma from Pancreatitis. Mol. Pharm. 2019, 16, 2776–2784. [Google Scholar] [CrossRef]
  126. Hodolic, M.; Wu, W.-Y.; Zhao, Z.; Yu, F.; Virgolini, I.; Wang, F. Safety and Tolerability of 68Ga-NT-20.3, a Radiopharmaceutical for Targeting Neurotensin Receptors, in Patients with Pancreatic Ductal Adenocarcinoma: The First in-Human Use. Eur. J. Nucl. Med. Mol. Imaging 2021, 48, 1229–1234. [Google Scholar] [CrossRef]
  127. Buchegger, F.; Bonvin, F.; Kosinski, M.; Schaffland, A.O.; Prior, J.; Reubi, J.C.; Bläuenstein, P.; Tourwé, D.; García Garayoa, E.; Bischof Delaloye, A. Radiolabeled Neurotensin Analog, 99mTc-NT-XI, Evaluated in Ductal Pancreatic Adenocarcinoma Patients. J. Nucl. Med. 2003, 44, 1649–1654. [Google Scholar]
  128. Deng, H.; Wang, H.; Zhang, H.; Wang, M.; Giglio, B.; Ma, X.; Jiang, G.; Yuan, H.; Wu, Z.; Li, Z. Imaging Neurotensin Receptor in Prostate Cancer With 64Cu-Labeled Neurotensin Analogs. Mol. Imaging 2017, 16. [Google Scholar] [CrossRef]
  129. Chavatte, K.; Wong, E.; Fauconnier, T.K.; Lu, L.; Nguyen, T.; Roe, D.; Pollak, A.; Eshima, D.; Terriere, D.; Mertens, J.; et al. Rhenium (Re) and Technetium (Tc)-99M Oxocomplexes of Neurotensin(8-13). J. Label. Compd. Radiopharm. 1999, 42, 415–421. [Google Scholar] [CrossRef]
  130. Baum, R.P.; Singh, A.; Schuchardt, C.; Kulkarni, H.R.; Klette, I.; Wiessalla, S.; Osterkamp, F.; Reineke, U.; Smerling, C. 177Lu-3BP-227 for Neurotensin Receptor 1-Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results. J. Nucl. Med. 2018, 59, 809–814. [Google Scholar] [CrossRef]
  131. Azizian, A.; Rühlmann, F.; Krause, T.; Bernhardt, M.; Jo, P.; König, A.; Kleiß, M.; Leha, A.; Ghadimi, M.; Gaedcke, J. CA19-9 for Detecting Recurrence of Pancreatic Cancer. Sci. Rep. 2020, 10, 1332. [Google Scholar] [CrossRef][Green Version]
  132. O’Brien, D.P.; Sandanayake, N.S.; Jenkinson, C.; Gentry-Maharaj, A.; Apostolidou, S.; Fourkala, E.-O.; Camuzeaux, S.; Blyuss, O.; Gunu, R.; Dawnay, A.; et al. Serum CA19-9 Is Significantly Upregulated up to 2 Years before Diagnosis with Pancreatic Cancer: Implications for Early Disease Detection. Clin. Cancer Res. 2015, 21, 622–631. [Google Scholar] [CrossRef][Green Version]
  133. Marchegiani, G.; Andrianello, S.; Malleo, G.; De Gregorio, L.; Scarpa, A.; Mino-Kenudson, M.; Maggino, L.; Ferrone, C.R.; Lillemoe, K.D.; Bassi, C.; et al. Does Size Matter in Pancreatic Cancer?: Reappraisal of Tumour Dimension as a Predictor of Outcome Beyond the TNM. Ann. Surg. 2017, 266, 142–148. [Google Scholar] [CrossRef] [PubMed]
  134. Imaoka, H.; Shimizu, Y.; Senda, Y.; Natsume, S.; Mizuno, N.; Hara, K.; Hijioka, S.; Hieda, N.; Tajika, M.; Tanaka, T.; et al. Post-Adjuvant Chemotherapy CA19-9 Levels Predict Prognosis in Patients with Pancreatic Ductal Adenocarcinoma: A Retrospective Cohort Study. Pancreatology 2016, 16, 658–664. [Google Scholar] [CrossRef] [PubMed]
  135. Goh, S.K.; Gold, G.; Christophi, C.; Muralidharan, V. Serum Carbohydrate Antigen 19-9 in Pancreatic Adenocarcinoma: A Mini Review for Surgeons. ANZ J. Surg. 2017, 87, 987–992. [Google Scholar] [CrossRef] [PubMed]
  136. Houghton, J.L.; Zeglis, B.M.; Abdel-Atti, D.; Aggeler, R.; Sawada, R.; Agnew, B.J.; Scholz, W.W.; Lewis, J.S. Site-Specifically Labeled CA19.9-Targeted Immunoconjugates for the PET, NIRF, and Multimodal PET/NIRF Imaging of Pancreatic Cancer. Proc. Natl. Acad. Sci. USA 2015, 112, 15850–15855. [Google Scholar] [CrossRef][Green Version]
  137. Houghton, J.L.; Abdel-Atti, D.; Scholz, W.W.; Lewis, J.S. Preloading with Unlabeled CA19.9 Targeted Human Monoclonal Antibody Leads to Improved PET Imaging with 89Zr-5B1. Mol. Pharm. 2017, 14, 908–915. [Google Scholar] [CrossRef]
  138. Lohrmann, C.; O’Reilly, E.M.; O’Donoghue, J.; Pandit-Taskar, N.; Carrasquillo, J.A.; Lyashchenko, S.K.; Ruan, S.; Teng, R.; Scholz, W.; Maffuid, P.W.; et al. Retooling a Blood-Based Biomarker: Phase I Assessment of the High-Affinity CA19-9 Antibody HuMab-5B1 for Immuno-PET Imaging of Pancreatic Cancer. Clin. Cancer Res. 2019, 25, 7014–7023. [Google Scholar] [CrossRef][Green Version]
  139. Girgis, M.D.; Federman, N.; Rochefort, M.M.; McCabe, K.E.; Wu, A.M.; Nagy, J.O.; Denny, C.; Tomlinson, J.S. An Engineered Anti-CA19-9 Cys-Diabody for Positron Emission Tomography Imaging of Pancreatic Cancer and Targeting of Polymerized Liposomal Nanoparticles. J. Surg. Res. 2013, 185, 45–55. [Google Scholar] [CrossRef][Green Version]
  140. Girgis, M.D.; Kenanova, V.; Olafsen, T.; McCabe, K.E.; Wu, A.M.; Tomlinson, J.S. Anti-CA19-9 Diabody as a PET Imaging Probe for Pancreas Cancer. J. Surg. Res. 2011, 170, 169–178. [Google Scholar] [CrossRef]
  141. Mauro, C.D.; Pesapane, A.; Formisano, L.; Rosa, R.; D’Amato, V.; Ciciola, P.; Servetto, A.; Marciano, R.; Orsini, R.C.; Monteleone, F.; et al. Urokinase-Type Plasminogen Activator Receptor (UPAR) Expression Enhances Invasion and Metastasis in RAS Mutated Tumors. Sci. Rep. 2017, 7, 9388. [Google Scholar] [CrossRef]
  142. Jaiswal, R.K.; Varshney, A.K.; Yadava, P.K. Diversity and Functional Evolution of the Plasminogen Activator System. Biomed. Pharmacother. 2018, 98, 886–898. [Google Scholar] [CrossRef] [PubMed]
  143. Li Santi, A.; Napolitano, F.; Montuori, N.; Ragno, P. The Urokinase Receptor: A Multifunctional Receptor in Cancer Cell Biology. Therapeutic Implications. Int. J. Mol. Sci. 2021, 22, 4111. [Google Scholar] [CrossRef] [PubMed]
  144. Dass, K.; Ahmad, A.; Azmi, A.S.; Sarkar, S.H.; Sarkar, F.H. Evolving Role of UPA/UPAR System in Human Cancers. Cancer Treat. Rev. 2008, 34, 122–136. [Google Scholar] [CrossRef]
  145. de Geus, S.W.; Baart, V.M.; Boonstra, M.C.; Kuppen, P.J.; Prevoo, H.A.; Mazar, A.P.; Bonsing, B.A.; Morreau, H.; van de Velde, C.J.; Vahrmeijer, A.L.; et al. Prognostic Impact of Urokinase Plasminogen Activator Receptor Expression in Pancreatic Cancer: Malignant Versus Stromal Cells. Biomark Insights 2017, 12. [Google Scholar] [CrossRef] [PubMed]
  146. Harris, N.L.E.; Vennin, C.; Conway, J.R.W.; Vine, K.L.; Pinese, M.; Cowley, M.J.; Shearer, R.F.; Lucas, M.C.; Herrmann, D.; Allam, A.H.; et al. SerpinB2 Regulates Stromal Remodelling and Local Invasion in Pancreatic Cancer. Oncogene 2017, 36, 4288–4298. [Google Scholar] [CrossRef][Green Version]
  147. Chen, Y.; Zheng, B.; Robbins, D.H.; Lewin, D.N.; Mikhitarian, K.; Graham, A.; Rumpp, L.; Glenn, T.; Gillanders, W.E.; Cole, D.J.; et al. Accurate Discrimination of Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis Using Multimarker Expression Data and Samples Obtained by Minimally Invasive Fine Needle Aspiration. Int. J. Cancer 2007, 120, 1511–1517. [Google Scholar] [CrossRef] [PubMed]
  148. Li, D.; Liu, S.; Shan, H.; Conti, P.; Li, Z. Urokinase Plasminogen Activator Receptor (UPAR) Targeted Nuclear Imaging and Radionuclide Therapy. Theranostics 2013, 3, 507–515. [Google Scholar] [CrossRef][Green Version]
  149. Yang, D.; Severin, G.W.; Dougherty, C.A.; Lombardi, R.; Chen, D.; Van Dort, M.E.; Barnhart, T.E.; Ross, B.D.; Mazar, A.P.; Hong, H. Antibody-Based PET of UPA/UPAR Signaling with Broad Applicability for Cancer Imaging. Oncotarget 2016, 7, 73912–73924. [Google Scholar] [CrossRef][Green Version]
  150. Persson, M.; Skovgaard, D.; Brandt-Larsen, M.; Christensen, C.; Madsen, J.; Nielsen, C.H.; Thurison, T.; Klausen, T.L.; Holm, S.; Loft, A.; et al. First-in-Human UPAR PET: Imaging of Cancer Aggressiveness. Theranostics 2015, 5, 1303–1316. [Google Scholar] [CrossRef][Green Version]
  151. Skovgaard, D.; Persson, M.; Brandt-Larsen, M.; Christensen, C.; Madsen, J.; Klausen, T.L.; Holm, S.; Andersen, F.L.; Loft, A.; Berthelsen, A.K.; et al. Safety, Dosimetry, and Tumor Detection Ability of 68Ga-NOTA-AE105: First-in-Human Study of a Novel Radioligand for UPAR PET Imaging. J. Nucl. Med. 2017, 58, 379–386. [Google Scholar] [CrossRef][Green Version]
  152. Persson, M.; Juhl, K.; Rasmussen, P.; Brandt-Larsen, M.; Madsen, J.; Ploug, M.; Kjaer, A. UPAR Targeted Radionuclide Therapy with (177)Lu-DOTA-AE105 Inhibits Dissemination of Metastatic Prostate Cancer. Mol. Pharm. 2014, 11, 2796–2806. [Google Scholar] [CrossRef] [PubMed]
  153. Qu, C.F.; Song, E.Y.; Li, Y.; Rizvi, S.M.A.; Raja, C.; Smith, R.; Morgenstern, A.; Apostolidis, C.; Allen, B.J. Pre-Clinical Study of 213Bi Labeled PAI2 for the Control of Micrometastatic Pancreatic Cancer. Clin. Exp. Metastasis 2005, 22, 575–586. [Google Scholar] [CrossRef] [PubMed]
  154. Ciardiello, F.; Tortora, G. EGFR Antagonists in Cancer Treatment. N. Engl. J. Med. 2008, 358, 1160–1174. [Google Scholar] [CrossRef] [PubMed][Green Version]
  155. Modjtahedi, H.; Dean, C. The Receptor for EGF and Its Ligands—Expression, Prognostic Value and Target for Therapy in Cancer (Review). Int. J. Oncol. 1994, 4, 277–296. [Google Scholar] [CrossRef] [PubMed]
  156. Tobita, K.; Kijima, H.; Dowaki, S.; Kashiwagi, H.; Ohtani, Y.; Oida, Y.; Yamazaki, H.; Nakamura, M.; Ueyama, Y.; Tanaka, M.; et al. Epidermal Growth Factor Receptor Expression in Human Pancreatic Cancer: Significance for Liver Metastasis. Int. J. Mol. Med. 2003, 11, 305–309. [Google Scholar] [CrossRef]
  157. Bloomston, M.; Bhardwaj, A.; Ellison, E.C.; Frankel, W.L. Epidermal Growth Factor Receptor Expression in Pancreatic Carcinoma Using Tissue Microarray Technique. Dig. Surg. 2006, 23, 74–79. [Google Scholar] [CrossRef] [PubMed]
  158. Guo, M.; Luo, G.; Liu, C.; Cheng, H.; Lu, Y.; Jin, K.; Liu, Z.; Long, J.; Liu, L.; Xu, J.; et al. The Prognostic and Predictive Role of Epidermal Growth Factor Receptor in Surgical Resected Pancreatic Cancer. Int. J. Mol. Sci. 2016, 17, 1090. [Google Scholar] [CrossRef][Green Version]
  159. Ueda, S.; Ogata, S.; Tsuda, H.; Kawarabayashi, N.; Kimura, M.; Sugiura, Y.; Tamai, S.; Matsubara, O.; Hatsuse, K.; Mochizuki, H. The Correlation between Cytoplasmic Overexpression of Epidermal Growth Factor Receptor and Tumor Aggressiveness: Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma. Pancreas 2004, 29, e1–e8. [Google Scholar] [CrossRef]
  160. Fagman, J.B.; Ljungman, D.; Falk, P.; Iresjö, B.-M.; Engström, C.; Naredi, P.; Lundholm, K. EGFR, but Not COX-2, Protein in Resected Pancreatic Ductal Adenocarcinoma Is Associated with Poor Survival. Oncol. Lett. 2019, 17, 5361–5368. [Google Scholar] [CrossRef][Green Version]
  161. Ardito, C.M.; Grüner, B.M.; Takeuchi, K.K.; Lubeseder-Martellato, C.; Teichmann, N.; Mazur, P.K.; Delgiorno, K.E.; Carpenter, E.S.; Halbrook, C.J.; Hall, J.C.; et al. EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis. Cancer Cell 2012, 22, 304–317. [Google Scholar] [CrossRef][Green Version]
  162. Moore, M.J.; Goldstein, D.; Hamm, J.; Figer, A.; Hecht, J.R.; Gallinger, S.; Au, H.J.; Murawa, P.; Walde, D.; Wolff, R.A.; et al. Erlotinib plus Gemcitabine Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 2007, 25, 1960–1966. [Google Scholar] [CrossRef] [PubMed]
  163. Chakravarty, R.; Goel, S.; Cai, W. Nanobody: The “Magic Bullet” for Molecular Imaging? Theranostics 2014, 4, 386–398. [Google Scholar] [CrossRef] [PubMed]
  164. Huang, L.; Gainkam, L.O.T.; Caveliers, V.; Vanhove, C.; Keyaerts, M.; De Baetselier, P.; Bossuyt, A.; Revets, H.; Lahoutte, T. SPECT Imaging with 99mTc-Labeled EGFR-Specific Nanobody for in Vivo Monitoring of EGFR Expression. Mol. Imaging Biol. 2008, 10, 167–175. [Google Scholar] [CrossRef]
  165. Vosjan, M.J.W.D.; Perk, L.R.; Roovers, R.C.; Visser, G.W.M.; Stigter-van Walsum, M.; van Bergen En Henegouwen, P.M.P.; van Dongen, G.A.M.S. Facile Labelling of an Anti-Epidermal Growth Factor Receptor Nanobody with 68Ga via a Novel Bifunctional Desferal Chelate for Immuno-PET. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 753–763. [Google Scholar] [CrossRef][Green Version]
  166. Gainkam, L.O.T.; Keyaerts, M.; Caveliers, V.; Devoogdt, N.; Vanhove, C.; Van Grunsven, L.; Muyldermans, S.; Lahoutte, T. Correlation between Epidermal Growth Factor Receptor-Specific Nanobody Uptake and Tumor Burden: A Tool for Noninvasive Monitoring of Tumor Response to Therapy. Mol. Imaging Biol. 2011, 13, 940–948. [Google Scholar] [CrossRef]
  167. Garousi, J.; Andersson, K.G.; Mitran, B.; Pichl, M.-L.; Ståhl, S.; Orlova, A.; Löfblom, J.; Tolmachev, V. PET Imaging of Epidermal Growth Factor Receptor Expression in Tumours Using 89Zr-Labelled ZEGFR:2377 Affibody Molecules. Int. J. Oncol. 2016, 48, 1325–1332. [Google Scholar] [CrossRef][Green Version]
  168. Menke-van der Houven van Oordt, C.W.; Gootjes, E.C.; Huisman, M.C.; Vugts, D.J.; Roth, C.; Luik, A.M.; Mulder, E.R.; Schuit, R.C.; Boellaard, R.; Hoekstra, O.S.; et al. 89Zr-Cetuximab PET Imaging in Patients with Advanced Colorectal Cancer. Oncotarget 2015, 6, 30384–30393. [Google Scholar] [CrossRef][Green Version]
  169. Aghevlian, S.; Lu, Y.; Winnik, M.A.; Hedley, D.W.; Reilly, R.M. Panitumumab Modified with Metal-Chelating Polymers (MCP) Complexed to 111In and 177Lu-An EGFR-Targeted Theranostic for Pancreatic Cancer. Mol. Pharm. 2018, 15, 1150–1159. [Google Scholar] [CrossRef]
  170. Aghevlian, S.; Cai, Z.; Lu, Y.; Hedley, D.W.; Winnik, M.A.; Reilly, R.M. Radioimmunotherapy of PANC-1 Human Pancreatic Cancer Xenografts in NRG Mice with Panitumumab Modified with Metal-Chelating Polymers Complexed to 177Lu. Mol. Pharm. 2019, 16, 768–778. [Google Scholar] [CrossRef]
  171. Scherl-Mostageer, M.; Sommergruber, W.; Abseher, R.; Hauptmann, R.; Ambros, P.; Schweifer, N. Identification of a Novel Gene, CDCP1, Overexpressed in Human Colorectal Cancer. Oncogene 2001, 20, 4402–4408. [Google Scholar] [CrossRef][Green Version]
  172. Spassov, D.S.; Baehner, F.L.; Wong, C.H.; McDonough, S.; Moasser, M.M. The Transmembrane Src Substrate Trask Is an Epithelial Protein That Signals during Anchorage Deprivation. Am. J. Pathol. 2009, 174, 1756–1765. [Google Scholar] [CrossRef][Green Version]
  173. Khan, T.; Kryza, T.; Lyons, N.J.; He, Y.; Hooper, J.D. The CDCP1 Signaling Hub: A Target for Cancer Detection and Therapeutic Intervention. Cancer Res. 2021. [Google Scholar] [CrossRef]
  174. Uekita, T.; Jia, L.; Narisawa-Saito, M.; Yokota, J.; Kiyono, T.; Sakai, R. CUB Domain-Containing Protein 1 Is a Novel Regulator of Anoikis Resistance in Lung Adenocarcinoma. Mol. Cell Biol. 2007, 27, 7649–7660. [Google Scholar] [CrossRef][Green Version]
  175. Miyazawa, Y.; Uekita, T.; Hiraoka, N.; Fujii, S.; Kosuge, T.; Kanai, Y.; Nojima, Y.; Sakai, R. CUB Domain-Containing Protein 1, a Prognostic Factor for Human Pancreatic Cancers, Promotes Cell Migration and Extracellular Matrix Degradation. Cancer Res. 2010, 70, 5136–5146. [Google Scholar] [CrossRef][Green Version]
  176. Nakashima, K.; Uekita, T.; Yano, S.; Kikuchi, J.-I.; Nakanishi, R.; Sakamoto, N.; Fukumoto, K.; Nomoto, A.; Kawamoto, K.; Shibahara, T.; et al. Novel Small Molecule Inhibiting CDCP1-PKCδ Pathway Reduces Tumor Metastasis and Proliferation. Cancer Sci. 2017, 108, 1049–1057. [Google Scholar] [CrossRef]
  177. Harrington, B.S.; He, Y.; Khan, T.; Puttick, S.; Conroy, P.J.; Kryza, T.; Cuda, T.; Sokolowski, K.A.; Tse, B.W.; Robbins, K.K.; et al. Anti-CDCP1 Immuno-Conjugates for Detection and Inhibition of Ovarian Cancer. Theranostics 2020, 10, 2095–2114. [Google Scholar] [CrossRef]
  178. Kryza, T.; Khan, T.; Puttick, S.; Li, C.; Sokolowski, K.A.; Tse, B.W.; Cuda, T.; Lyons, N.; Gough, M.; Yin, J.; et al. Effective Targeting of Intact and Proteolysed CDCP1 for Imaging and Treatment of Pancreatic Ductal Adenocarcinoma. Theranostics 2020, 10, 4116–4133. [Google Scholar] [CrossRef]
  179. Moroz, A.; Wang, Y.-H.; Sharib, J.M.; Wei, J.; Zhao, N.; Huang, Y.; Chen, Z.; Martinko, A.J.; Zhuo, J.; Lim, S.A.; et al. Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer. Clin. Cancer Res. 2020, 26, 3608–3615. [Google Scholar] [CrossRef]
Figure 1. Radiotracers dedicated to diagnosis, staging and therapeutic monitoring of PDAC.
Figure 1. Radiotracers dedicated to diagnosis, staging and therapeutic monitoring of PDAC.
Ijms 22 06413 g001
Figure 2. Radiotracers dedicated to companion and theranostic approaches currently in development.
Figure 2. Radiotracers dedicated to companion and theranostic approaches currently in development.
Ijms 22 06413 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Montemagno, C.; Cassim, S.; De Leiris, N.; Durivault, J.; Faraggi, M.; Pagès, G. Pancreatic Ductal Adenocarcinoma: The Dawn of the Era of Nuclear Medicine? Int. J. Mol. Sci. 2021, 22, 6413.

AMA Style

Montemagno C, Cassim S, De Leiris N, Durivault J, Faraggi M, Pagès G. Pancreatic Ductal Adenocarcinoma: The Dawn of the Era of Nuclear Medicine? International Journal of Molecular Sciences. 2021; 22(12):6413.

Chicago/Turabian Style

Montemagno, Christopher, Shamir Cassim, Nicolas De Leiris, Jérôme Durivault, Marc Faraggi, and Gilles Pagès. 2021. "Pancreatic Ductal Adenocarcinoma: The Dawn of the Era of Nuclear Medicine?" International Journal of Molecular Sciences 22, no. 12: 6413.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop