I. Introduction

At the beginning of the 21^st century, pancreatic cancer remains one of the most devastating human cancers, responsible for 30,000 deaths per year in the USA (Jemal et al, 2004). The lack of specific symptoms until late in the pathology, as well as the high proliferative and metastatic potential of the disease hamper early diagnosis and consequently, effective treatment. As a result, disease prognosis is poor, with a 5-year survival rate of only around 4% (Jemal et al, 2004).

The only potentially curative treatment remains surgical resection. At the time of presentation, approximately 15-20% of patients have resectable disease. Nevertheless, despite the possibility for radical intervention, due to the aggressive nature of the disease, only 20% of these patients survive to 5 years. Adjuvant chemotherapy and radiation therapy only provide marginal palliative benefits due to the low chemosensitivity of the disease with response rates to conventional agents of less than 10% (Kollmannsberger et al, 1998).

Despite significant efforts to improve the prognosis associated with this disease, progress towards the management of pancreatic cancer over the past 50 years has been limited and still close to 100% of patients diagnosed with pancreatic cancer will develop metastases and die. This outlook, however, can be improved dramatically by the availability of early diagnostics. An essential element of diagnosis is represented by non-invasive imaging. Imaging techniques are in active development both in the laboratory and the clinic, since the conception of novel approaches ultimately leading to therapy for pancreatic cancer is an urgent priority.

II. Pancreatic cancer: molecular course

The progression to pancreatic cancer appears to follow the Vogelstein model described for colorectal cancers (Vogelstein et al, 1988). Namely, tumorigenesis is the result of the violation of multiple checkpoints controlling cell proliferation, differentiation, and death. This process, characterized by serial perturbations in a variety of cell signaling pathways, ultimately leads to the acquisition of a survival and growth advantage by select cells which escape the normal safeguards to uncontrollable proliferation and invasiveness, and consequently results in carcinogenesis (Cowgill and Muscarella, 2003).

Pancreatic cancer, in particular, is believed to originate from mutations in pancreatic duct cells. Pancreatic intraepithelial neoplasia (PanIN) is defined as the increased incidence of abnormal ductal structures seen in patients with pancreatic carcinoma. The similarity in spatial distribution between PanIN lesions and malignant tumors led to the hypothesis that these lesions in fact represent incipient pancreatic adenocarcinomas. Morphologically, PanIN lesions are quite heterogeneous and can be classified based on graded stages of increasingly dysplastic growth (Bardeesy and DePinho, 2002).

Both tumor suppressor genes, responsible for arresting cell growth at critical points in the cell’s life, and oncogenes, promoting cell division, have been identified as possible culprits for the development of pancreatic cancer. Some of these have been reviewed in more detail (Cowgill and Muscarella, 2003).

One of the most frequently mutated genes in pancreatic cancer is the k-ras oncogene, altered in nearly 90% of pancreatic malignancies (Almoguera et al, 1988). k-ras is a key element in cell-growth signaling cascades, linking growth factor and hormone receptors to downstream mediators of cell proliferation and differentiation. In pancreatic carcinomas, k-ras mutations are generally the first detected alterations in the progression series. In fact, k-ras mutations are seen in about 30% of early pancreatic lesions and increase in frequency with disease progression (Bardeesy and DePinho, 2002). However, k-ras, is also altered in some benign conditions, which makes it a poor candidate for a diagnostic marker.

The tumor suppressor gene, p16, which is part of the well-characterized Rb tumor-suppressive pathway, responsible for global cell-cycle regulation, is also commonly mutated in pancreatic malignancy. p16 inactivation has been identified in 27% to 82% of primary tumors (Caldas et al, 1994). Furthermore, p16 inactivation has been linked to prognosis, altered more frequently in short term survivors (85% of the cases) compared to long-term survivors (50% of the cases) (Gerdes et al, 2002).

Another tumor suppressor, p53, is inactivated in between 40% and 75% of pancreatic cancers (Pellegata et al, 1994). p53 is a mediator of DNA-damage induced cell-cycle arrest and programmed cell death. Interestingly, in pancreatic carcinomas, p53 is often found mutated in association with k-ras mutations, suggesting cooperativity between the two genes in pancreatic cancer tumorigenesis (Scarpa et al, 1993). Still, p53 is a later marker of tumorigenesis, mutated in PanINs which demonstrate a high degree of dysplasia.

DPC4, a component of the TGF-beta signaling pathway, is deleted in approximately 50% of pancreatic adenocarcinomas (Hahn et al, 1996). It has been suggested that mutations in DPC4 correlate with invasiveness (Takaku et al, 1998). Still, the precise role of this tumor suppressor in the development of pancreatic cancer is poorly understood.

In addition to classical oncogenes and tumor-suppressor genes implicated in the development of pancreatic cancer, many growth factors and growth factor receptors have been found to be overexpressed in carcinomas of the pancreas. Among them are: the epidermal growth factor (Korc, 1998), vascular endothelial growth factor (Shi et al, 2001), fibroblast growth factor (Yamanaka et al, 1993), as well as multiple cytokines, including transforming growth factor beta (Kleeff et al, 1999), interleukin 1 (Blanchard et al, 2000), interleukin 6 (Saito et al, 1998), tumor necrosis factor alpha (Watanabe et al, 1997), and interleukin 8 (Shi et al, 1999) reviewed in (Li et al, 2004). For some of these molecules, a direct link has been established between their upregulated expression and pancreatic cancer. Vascular endothelial growth factor for instance is a key angiogenic factor regulated by hypoxia, common to most solid tumors, among which is pancreatic cancer (Li et al, 2004). Angiogenesis is one mechanism conducive to local and systemic expansion of the tumor mass and as a result is implicated in primary tumor growth and indirectly, metastasis.

Pancreatic cancer is characterized by its high invasivenes and metastatic potential. The molecules involved in the metastatic process fall into two groups: cell adhesion molecules and extracellular proteases. One cell adhesion molecule mutated in pancreatic cancers is E-cadherin (Karayiannakis et al, 2001). E-cadherin couples adjacent cells via E-cadherin bridges and in that way is directly implicated in the transmission of antigrowth signals in response to cell-cell contacts. Loss of E-cadherin function is thus one mechanism leading to cancer cell invasion and metastasis. Adhesion molecules overexpressed in pancreatic cancer include ICAM-1, VCAM-1 (Tempia-Caliera et al, 2002), and integrins (Keleg et al, 2003). Overexpression of these adhesion molecules imparts to cancer cells the ability to migrate and home in to distant sites where they form metastatic lesions.

Another class of molecules also implicated in cancer invasiveness and metastasis are extracellular proteases. Extracellular proteases facilitate the invasion of cancer cells into the adjacent stroma, across blood vessels and to a metastatic site by mediating the degradation of the extracellular matrix. Studies on pancreatic cancer have clearly established the tendency for upregulation of proteases, downregulation of protease inhibitors and conversion of inactive zymogens into active enzymes (Coussens and Werb, 1996). Evidence exists for induction of urokinase expression in stromal cells (Cantero et al, 1997) and overexpression of a variety of matrix metalloproteinases (MMPs) in pancreatic cancer (Gress et al, 1995) reviewed in (Keleg et al, 2003).

Understanding of the genetic alterations contributing to the progression to pancreatic cancer is an essential starting point for future research, which would hopefully lead to the construction of a detailed map of the intricate molecular interactions characterizing the disease. It is clear now that the aggressive nature of the disease necessitates early intervention as the most promising treatment strategy. Commonly used clinical tests for pancreatic cancer tumor markers are serum-based immunoassays for tumor-specific antigens, such as CA19-9, which is a mucin-associated marker (Ringel and Lohr, 2003). This test, however, is not specific to pancreatic cancer, since elevated marker levels are also present in pancreatitis and other cancers. Therefore, timely diagnosis and characterization of the malignancy through non-invasive imaging of the pancreas is an essential first step towards disease management. Targeted imaging which utilizes the molecular alterations specific to pancreatic cancer, has the potential to advance our capacity for identification and characterization of the malignancy in its initial stages.

III. Imaging of pancreatic cancer

A. Clinical imaging of pancreatic cancer

Currently pancreatic cancer imaging in the clinic relies on nontargeted morphologically-based modalities. Ultrasonographic methods, such as abdominal ultrasonography, endoscopic ultrasonography, as well as helical CT and MRI have evolved as the major tools for pancreatic cancer detection and staging (Rosewicz and Wiedenmann, 1997; Hosten et al, 2000). More recently, these techniques have been complemented by the biochemically-based detection procedure of FDG-PET.

1. Abdominal ultrasonography (US)

Ultrasonography is the most widely used clinical imaging modality because of its low cost, availability, and safety. Ultrasound images are obtained when high-frequency (>20-kHz) sound waves are emitted from a transducer placed against the skin and the ultrasound is reflected back from the internal organs under examination.

Contrast in the images obtained depends on the imaging algorithm used, backscatter, attenuation of the sound, and sound speed. Some of the drawbacks of ultrasound imaging, however, extend from the presence of bone and air artefacts, due to the tendency of air and bone to not transmit sound waves. Consequently ultrasound is characterized by limited depth penetration.

Abdominal ultrasonography represents a good initial screening tool. However, US has a fairly low sensitivity and specificity of 67% and 40%, respectively for pancreatic cancer (Rosch, 1995). Furthermore, US is operator-dependent and affected by local artefacts. Nevertheless, US is suitable for detection of tumors over 2 cm in diameter, dilated biliary and pancreatic ducts, and extrapancreatic spread (Furukawa, 2002).

2. Endoscopic ultrasonography

Endoscopic ultrasonography is a sensitive and reliable modality for the detection, staging, and surgical evaluation of pancreatic cancer. It uses a high-frequency sonographic transducer that is introduced into the gastrointestinal tract by a side-viewing endoscope. This setup permits the operator to obtain real-time cross-sectional images of the gastrointestinal wall and soft-tissue (Tamm et al, 2003). Endoscopic ultrasound overcomes some of the drawbacks of abdominal ultrasonography based on the endoscopic positioning of the ultrasound probe adjacent to the pancreas. This allows the detailed assessment of local anatomy and permits the identification of small lesions normally not detected by abdominal ultrasound.

The reported sensitivity, specificity, and accuracy of endoscopic ultrasonography are significantly higher than conventional CT, with an accuracy of 85-100%, compared to 64-66% for CT and 61-64% for abdominal ultrasound (Rosch et al, 1992; Palazzo et al, 1993; Yasuda et al, 1993). The superiority of endoscopic ultrasonography over CT is particularly evident for lesions smaller than 3 cm in size.

Furthermore, endoscopic ultrasound is a good staging tool for pancreatic cancer. Generally, staging is based on a TNM classification. T stage refers to tumor characteristics including vascular involvement. N stage reflects regional lymph node involvement, and M stage assesses metastatic spread. Endoscopic ultrasound is reliable for the identification of certain types of vascular involvement of the portal and splenic veins into the tumor. However, despite its sensitivity in terms of T and N staging, endoscopic ultrasound is not suitable for assessing M stage due to its limited tissue penetration (Santo, 2004).

3. Endoscopic ultrasonography guided fine needle aspiration (EUS-FNA)

EUS-FNA combines the ability to visualize primary tumors, lymph nodes, and the liver with the capacity to obtain a tissue sample during the diagnostic procedure. Its sensitivity ranges from 45% to 100%. Its specificity approaches 100% (Pinto et al, 1988). Still the diagnostic benefits of the procedure are limited by the ability to visualize the lesion in the first place, since endoscopic ultrasound cannot differentiate between inflamed and metastasis-bearing lymph nodes as well as focal pancreatitis from a tumor (Hawes et al, 2000).

The major advantage of this procedure lies in its relative noninvasiveness. Traditionally, the high mortality and morbidity associated with pancreatidoduodenectomy has discouraged the progress to surgery without tissue diagnosis. The morbidity associated with percutaneous FNA has been minimal, despite fears that percutaneous biopsy would lead to peritoneal seeding of tumor cells along the needle tract (Clarke et al, 2003). Obtaining a tissue sample would allow one to distinguish pancreatitis from malignancy, and in cases where adjuvant chemo- or radiotherapy is implemented, biopsy of a suspected lesion is necessary and beneficial.

4. Computerized tomography (CT)

CT is the most commonly used modality for the initial diagnosis, staging, and evaluation of response to therapy of pancreatic cancer. The reported accuracy of CT in determining that a tumor is unresectable approaches 100%. However, about a third of the cases considered resectable based on CT, in fact are unresectable (Freeny et al, 1988; Freeny et al, 1993; Bluemke et al, 1995).

Signal in computed tomography (CT) results from differential absorption of X-rays by component tissues and media, namely, bone, air, fat, and water. Volumetric data are collected as an X-ray source and a detector rotate around the subject. Limiting factors affecting the level of resolution of this imaging modality include the pixel sampling size, the size of the X-ray source, and blurring in the phosphor screen which constitutes an element in the signal detector system (Massoud and Gambhir, 2003). A major drawback of CT is the poor soft tissue contrast, which necessitates the administration of iodinated contrast agents which pass through different tissues at different rates. CT has a relatively high spatial resolution (50mm) and is characterized by fast acquisition times (Weissleder, 2002). CT is a commonly applied clinical imaging modality and is traditionally used as a cancer diagnostic tool.

More recently modifications of the CT procedure have shown improved sensitivity and diagnostic accuracy. Helical CT provides thin-section, motion-free images. It permits imaging of the entire pancreas and tissues adjacent to it in different circulatory phases. The different phases are defined by variability in scan delay. The pancreatic phase (scan delay of 40 s) has an enhanced capacity to differentiate between pancreatic parenchyma and blood vessels, compared to portal-vein phase imaging (scan delay 60-70 s) (Bluemke et al, 1995). On the other hand, imaging during the portal-vein phase is best for imaging of liver metastases. Therefore, the assessment of tumor stage and metastasis is derived from a “dual-phase” technique. However, circulation times vary between patients, which is a source of error in the use of this application. The reported accuracy of helical CT for T staging is 77%, for N staging 58%, and for M staging 79% (Zeman et al, 1997).

Thin section helical CT reduces the obscuring impact of volume averaging on the detection of small lesions. Typically slices ranging between 3 and 5 mm in thickness are obtained using this procedure (Tamm et al, 2003).

In general, helical CT can reveal the presence of the tumor and its location in relation to surrounding structures, such as the superior mesenteric artery and vein, the portal vein, and the coeliac axis. The evaluation of resectability is therefore dependent on the capacity of CT to determine whether the tumor is invading the superior mesenteric artery and the coeliac axis, as well as to detect liver and distant metastases, which is an indicator of unresectability (Li et al, 2004).

The latest advance in CT imaging of the pancreas combines volume rendering of CT data with a three-dimensional display and is referred to as multidetector CT (MDCT). The advantages of this technique lie in the ability of the operator to optimize the visualization of structures, which allows key elements of the anatomy to be enhanced. Still, the accuracy and reliability of this procedure remain to be determined. Furthermore, its demand for extensive computer memory and relative expense make it less popular (Clarke et al, 2003).

5. Endoscopic retrograde cholangio pancreatography (ERCP)

ERCP with stent placement is a relatively invasive procedure which identifies visual symptoms of biliary and pancreatic duct stenosis. It is recommended for patients who present with symptoms of obstructive jaundice, i.e., renal failure or cholangitis, and is a way of alleviating biliary obstruction.

ERCP has several drawbacks as a diagnostic tool. Due to the indirect determination of parenchymal abnormalities, a normal pancreatogram does not exclude the possibility for the presence of a tumor. Chronic pancreatitis and pancreatic cancer cannot be differentiated predictably. Lesions in certain areas of the pancreas are less likely to be detected by this method (Clarke et al, 2003).

Improvements in ERCP utilize the capacity of the procedure to obtain tissue specimens from the location of interest. ERCP with secretin stimulation and brush biopsy have been utilized in order to collect material for further analysis (Davis et al, 1975; Warshaw and Fernandez-del Castillo, 1992). However, the use of EUS-FNA as a diagnostic/sampling tool will likely replace ERCP due to its limited invasiveness and enhanced specificity.

6. Magnetic resonance imaging (MRI)

The principle behind MRI is founded upon the tendency of unpaired nuclear spins (dipoles), e.g. hydrogen atoms in water and organic molecules, to align themselves along an externally applied magnetic field. This external field is produced by a strong magnet surrounding the subject. Following the magnetic pulse delivered by the magnet, the dipoles return to their baseline orientation. That event is detected as a change in electromagnetic flux and is characterized by a differential rate of magnetic relaxation depending on the local environment. For example, fat and hydrocarbon-rich environments have short relaxation times, whereas aqueous environments have relatively long relaxation times. The measurement of dipole relaxation is translated into an MR signal with contrast provided by the differential nature of relaxation rate (Massoud and Gambhir, 2003).The most commonly used timing parameters are known as T1 and T2 and reflect the differential relaxation of the dipoles in the longitudinal and transverse directions, respectively.

Whereas the resolution of MRI is high (10-100 mm), its sensitivity is quite low (10^-3-10^-5 moles/L). Nevertheless, the capacity to derive both anatomical and molecular/physiologic information simultaneously through MRI make it one of the most promising imaging modalities. Its application in the clinic is expanding despite its relatively high cost. Furthermore, as a research tool, MRI has been used to image specific molecular interactions by the use of chemical agents capable of altering MR signal intensity. Paramagnetic metal cations, such as gadolinium or superaparamagnetic iron oxide nanoparticles have been used as targeted MRI probes (Moore et al, 1997, 2000). Still, the low sensitivity of MRI makes it necessary to deliver very high concentrations of probe at the target site in order to achieve sufficient contrast for reliable imaging. Nevertheless, magnetic resonance imaging has been used for multiple applications included but not limited to cell trafficking (Josephson et al, 1999; Moore et al, 2002), and imaging of gene expression (Weissleder et al, 2000; Moore et al, 2001).

Originally, conventional MRI had a limited diagnostic value for pancreatic cancer due to motion artifacts (respiratory, vascular, peristaltic). Recently, however, the use of more advanced MRI techniques, such as dynamic contrast enhanced MRI, has led to considerable sensitivity levels, surpassing even those reported for dual-phase helical CT. A comparative study found that MRI had an accuracy of 96% for predicting resectability vs. 81% for helical CT (Sheridan et al, 1999). Compared to endoscopic ultrasound, MRI was found to have a positive predictive value of 77% vs. 69% for EUS. In determining resectability, the negative predictive value (defining unresectability) was 76% (Ahmad et al, 2000). Furthermore, MR imaging is reported to have higher sensitivity for small liver metastases compared to CT (Santo, 2004). Additional advantages of MRI over CT derive from the fact that it offers better soft-tissue contrast, prior to the administration of iodinated contrast agents and that images can be acquired in multiple planes. However, CT reportedly provides higher spatial resolution (Tamm et al, 2003).

The imaging protocols for detection of pancreatic malignancy involve both T1 and T2-weighted sequences, or dynamically-enhanced T1-weighted sequences. On T1-weighted images, the normal pancreas has higher signal intensity than any other abdominal organ. Its short T1 relaxation time has been attributed to the abundant protein and rough endoplasmic reticulum contained within it. Fat-saturated T1-weighted sequences are useful for distinguishing normal from abnormal pancreatic parenchyma (Winston et al, 1995). Also, T1-weighted sequences have been shown to be more efficient at reducing motion artifacts than T2-weighted sequences (Steiner et al, 1989). T2-weighted sequences are typically used to differentiate between benign and malignant liver lesions. Dynamic contrast-enhanced MRI estimates blood flow using a computational algorithm. Its capability to identify pancreatic malignancy rests on the fact that pancreatic cancers are hypovascular relative to normal pancreas (Siegelman et al, 1995).

With its high sensitivity and tissue contrast, specifically in applications involving contrast agents, e.g. gadolinium as a T1 contrast agent, and its capability to simultaneously provide anatomical and functional information, as well as by the diversity of its applications, i.e. pancreatography by means of MRCP and angiography by means of dynamic contrast-enhanced MRI, the magnetic resonance imaging modality is likely to replace other imaging tools, such as helical CT for instance, as the method of choice in the diagnosis of pancreatic cancer.

7. Magnetic resonance cholangio pancreatography (MRCP)

MRCP is a noninvasive procedure, which is replacing ERCP for diagnosis of the biliary and pancreatic ducts. It is based on magnetic resonance imaging and utilizes T2 weighted imaging with long echo times to deliver optimal contrast between the hyperintense signal of pancreatic juice and bile and the hypointense signal produced by blood and solid organs (Furukawa, 2002).

The sensitivity of MRCP for diagnosis of pancreatic and biliary duct abnormalities is 93-100% (Soto et al, 1995). As a result, MRCP is suitable for the assessment of obstructive jaundice. Still, its limited diagnostic potential necessitates the complementary use of alternative imaging modalities.

8. Positron emission tomography (PET)

One of the most sensitive imaging modalities is positron emission tomography (PET). The sensitivity of PET ranges between 10^-11 and 10^-12 mole/L and is independent of the location depth of the contrast-producing probe. This makes PET a very attractive modality for metabolic/physiological characterization of the tumor microenvironment. The principle of PET relies on the labeling of biological molecules with a positron-emitting isotope, such as ¹⁵O, ¹³N, ¹¹C, ¹⁸F, ¹⁴O, ⁶⁴Cu, ¹²⁴I, ⁷⁶Br, ⁸²Rb, and ⁶⁸Ga. This positron-emitting isotope is capable of generating two g-rays by releasing a positron from its nucleus. The released positron subsequently annihilates with an electron in its vicinity which results in the production of two g rays located at 180° apart. These emitted rays are detected using scintigraphic equipment, which converts the energy of the g rays into visible light (Massoud and Gambhir, 2003).

Alternatively g emitting isotopes, such as ^99mTc, ¹¹¹In, ¹²³I, and ¹³¹I, can be used for imaging but require different equipment, namely gamma cameras, which can generate tomographic information by rotating around the subject. This modality is known as single photon emission computed tomography (SPECT). SPECT is at least a log less sensitive than PET, less quantitative compared to PET but allows the simultaneous detection of multiple molecular events since it is capable of detecting several isotopes with different energy g rays (Massoud and Gambhir, 2003).

Unlike the imaging modalities listed above, which largely rely on morphological parameters to detect and assess, PET delivers biochemical/metabolic information about tumor biology. For detection of pancreatic cancer, PET traditionally uses FDG, a glucose analogue, labeled with the radioisotope ¹⁸F. The principle behind the preferential uptake of this contrast agent by cancers is the enhanced metabolic activity associated with malignancy. FDG enters cells in the same manner as glucose, and is trapped there after being phosphorylated by endogenous kinases to a form, which cannot be further metabolized.

On PET, pancreatic cancer appears as an intense region of radiotracer uptake. The reported values for PET sensitivity and specificity vary greatly and range between 64% and 100% for specificity and 71% to 100% for sensitivity (Zimny and Schumpelick, 2001). The main advantage of PET over other imaging modalities is its enhanced capacity to identify metastatic disease and clarify uncertain CT findings in the liver (Mertz et al, 2000). PET can detect lesions less than 2 cm in diameter (Clarke et al, 2003).

One major drawback of PET imaging is its poor spatial resolution and anatomic accuracy compared to MRI and CT. Novel combined PET-CT scanners, however, can overcome that weakness. A case study in which FDG-PET results were superimposed on CT-generated scans permitted the identification of a region of atrophy visible on CT as a tumor by virtue of its increased FDG uptake (Hosten et al, 2000).

The application of PET to pancreatic cancer imaging is an exciting and very promising new strategy, particularly in view of the recent progress in developing multimodal PET-CT technology for image collection and analysis. The sensitivity of PET combined with the good spatial resolution of CT could become one of the leading strategies for diagnosis and staging of this malignancy.

B. Molecular imaging of pancreatic cancer

Molecular imaging is a novel field which attempts to combine the global anatomical/physiologic scale of in vivo imaging with the detailed molecular/cellular scale of biochemistry and cell and molecular biology in order to obtain a visual representation and characterization of biological processes at the cellular/sub-cellular level in living subjects (Massoud and Gambhir, 2003). This approach would allow the unraveling of complex disease pathways, the diagnosis of disease at the earliest causative stages characterized by the first signs of metabolic or molecular disturbance, and the noninvasive real-time monitoring of disease progression as well as response to therapy in authentic physiologic environments.

There are very few described attempts at imaging pancreatic cancer using targeted molecular approaches. All of these studies have been conducted in murine models and will be discussed below.

1. Nuclear imaging of pancreatic cancer

The majority of studies investigating the potential of nuclear imaging for pancreatic cancer targeting have focused on the use of radiolabeled tumor-specific antibodies.

A recent investigation uses PAM4 which is an antibody targeting the tumor-associated MUC-1 antigen (Cardillo et al, 2004). The basis for the study is the success of initial clinical trials utilizing ¹³¹I- and ^99m Tc-lebeled PAM4 whole IgG (Mariani et al, 1995; Gold et al, 2001). Cardillo et al. used a bispecific chimeric antibody consisting of PAM4 Fab’ and murine anti-indium-diethylenetriaminepentaacetic acid Fab’ fragments to target subcutaneously implanted pancreatic cancer employing a pretargeting enhancement strategy. The pretargeting strategy exploits the use of a primary targeting monoclonal antibody carrying a secondary recognition moiety, which is targeted later with a radiolabeled hapten. This system achieves high tumor:nontumor signal ratios after injection of the hapten, and rapid tumor penetration and clearance from the circulation (Figure 1).

In addition to the traditional methods for pancreatic cancer imaging by PET involving a radiolabeled glucose analogue, different groups have reported the use of radiolabeled nucleotide or amino-acid tracers for PET or SPECT imaging exploiting the increased metabolic rate of tumors (Seitz et al, 2001; Samnick et al, 2004). These investigations show good tumor localization and kinetics. Furthermore, tumor uptake is directly related to proliferative rate, unlike imaging with radiolabeled glucose analogues.

Currently, we are undertaking studies to evaluate the CLIO-EPPT probe as a diagnostic tool for monitoring the response of orthotopically-implanted pancreatic tumors to various forms of chemotherapy. Our progress on multimodal imaging of pancreatic cancer combines the sensitivity of optical imaging with the high resolution of MR imaging and allows not only the detection of primary tumor and metastases (MUC-1 is overexpressed and underglycosylated on metastatic lesions) but also, potentially, the tracking of tumor progression and response to therapy non-invasively. The development of new therapeutics for pancreatic cancer can be very costly. Therefore, there has been an increased demand for accurate and non-invasive assessment of their effectiveness that can be achieved using our approach.

IV. Future outlook

Carcinogenesis of pancreatic cancer is a multistep signal transduction process, in which the most likely early events involve activation of oncogenes, such as k-ras (Kawesha et al, 2000), overexpression of growth signal receptors, the EGFR (Korc, 1998) in particular, and mutations in various tumor suppressor genes, including DPC4 (Takaku et al, 1998), p53 (Rozenblum et al, 1997), and p16 (Gerdes et al, 2002). Based on the currently available information regarding tumor origin and progression, there is an abundance of potential strategies for targeting malignancy, whether for the purpose of imaging or therapy. Monoclonal antibodies to the EGFR, probes/inhibitors of tumor-upregulated proteases, apoptosis-related molecules, such as caspase-3 and tumor necrosis factor family members, all constitute prospective targets and are actively being investigated.

Detailed knowledge about these targets and their interactions represents the basis upon which one can design various diagnostic approaches by combining the specificity and selectivity of molecular interrogation of malignancy with the capacity of the presently available imaging modalities to provide a real-time global view of anatomical characteristics and physiologic processes in a living subject. The potential implications of these methodologies for the management of pancreatic cancer become obvious in view of the aggressiveness of the disease and its high mortality rate.

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Research Article

Received: 24 August 2004; Accepted: 08 September 2004; electronically published: September 2004

I. Introduction

II. Pancreatic cancer: molecular course

III. Imaging of pancreatic cancer

References