Abstract IA16: New methods of PET imaging pancreas cancer
Authors: Lewis Jason S. 
Published: October 2015

The medical need to properly diagnose, stage, and treat PDAC is staggering despite research efforts in recent years. PDAC is one of the most aggressive cancers, ranking fourth as a cause of cancer mortality. Most patients do not present with symptoms until the late stages of the disease, and for that reason, 80% of patients have metastatic disease at the time of diagnosis. The overall five-year survival rate is approximately 5%, and for those who undergo surgical resection the 5-year survival rate is only 25% due to the high incidence of undiscovered metastases that are not detected using imaging modalities such as MRI and CT. The clinical options available to PDAC patients are dependent on disease progression at the time of diagnosis. Resection offers the best chance of survival, but the presence of metastases, which often escape detection using MRI and CT due to their lack of specificity, precludes patients from resection. Patients are regularly misdiagnosed or understaged, complicating treatment strategies and preventing enrollment in clinical trials. Many of these problems could be avoided if adequate diagnostic and staging procedures were available.

Positron emission tomography (PET) is a promising technological platform for the detection and staging of PDAC. Currently, PET imaging of PDAC generally utilizes the imaging agent 2-deoxy-2-[18F]-fluoro-D-glucose (18F -FDG), relying on increased tumor metabolism relative to nonmalignant cells (Warburg effect). However, despite the success of FDG as a diagnostic tool in some cancers, it lacks the sensitivity and specificity required for the staging of small primary lesions (&lt;7 mm) and liver metastases (&lt;1 cm). Additionally, in the case of PDAC, it is generally incapable of differentiating benign disease (i.e. pancreatitis, jaundice) from malignancy.

The use of FDG as a diagnostic tool for PDAC may be supplemented by assaying biomarkers from biological fluids. The diagnosis of PDAC is often based partially on the detection of elevated levels of circulating CA19.9 (also known as sialyl Lewisa) antigen in sera. CA19.9 is a ligand for epithelial leukocyte adhesion molecules, and its overexpression is a key event in invasion and metastasis of many tumors, including PDAC tumors. However, the specificity of the assays for PDAC are predominantly attenuated by antigen secretion from benign pathologies among distant organs (e.g., jaundice in the liver) or disorders of the pancreas (e.g., pancreatitis) that FDG is also not able to delineate. Thus, CA19.9 assays are useful screening tools but are not an accepted diagnostic tool due to the high occurrence of false-positive tests. Thus, the development of a radiotracer that is capable of targeting the antigen at its tissue of origin and distinguishing benign disease from malignancy is necessary to supplement antibody-based serum biomarker measurements.

Radiolabeled antibodies or antibody fragments especially those specific to surface-bound antigens expressed by tumor cells can provide the necessary specificity and sensitivity. The development of high affinity imaging agents could enhance our ability to monitor and detect micro-metastases and slow growing epithelial cancers. In the case of PDAC, the CA19.9 antigen is attractive because it is the most highly expressed tumor antigen in pancreatic cancer and is minimally expressed in healthy pancreas tissue. Moreover, multiple copies of CA19.9 are expressed on many membrane proteins, providing an advantage in terms of specificity and sensitivity compared to other tumor antigens. For those reasons, several antibody development programs have been recently initiated, leading to the development of the fully human monoclonal antibody (mAb) 5B1. The recombinant mAb 5B1 potently binds an extracellular epitope on the CA19.9 protein, providing an ideal platform for developing an immunoPET agent for imaging and staging of PDAC. One concern with 5B1 was the potential for circulating antigen to diminish its usefulness. However, initial experiments with 5B1 indicated that it was not a major concern in the case of 5B1, which provided exceptional PET images. By targeting tumor-associated CA19.9 via non-invasive PET, we will directly address these needs effectively and efficiently.

Citation Format: Jason S. Lewis. New methods of PET imaging pancreas cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA16.