Selecting Potential Targetable Biomarkers for Imaging Purposes in Colorectal Cancer Using TArget Selection Criteria (TASC): A Novel Target Identification Tool

Abstract

Peritoneal carcinomatosis (PC) of colorectal origin is associated with a poor prognosis. However, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is available for a selected group of PC patients, which significantly increases overall survival rates up to 30%. As a consequence, there is substantial room for improvement. Tumor targeting is expected to improve the treatment efficacy of colorectal cancer (CRC) further through 1) more sensitive preoperative tumor detection, thus reducing overtreatment; 2) better intraoperative detection and surgical elimination of residual disease using tumor-specific intraoperative imaging; and 3) tumor-specific targeted therapeutics. This review focuses, in particular, on the development of tumor-targeted imaging agents. A large number of biomarkers are known to be upregulated in CRC. However, to date, no validated criteria have been described for the selection of the most promising biomarkers for tumor targeting. Such a scoring system might improve the selection of the correct biomarker for imaging purposes. In this review, we present the TArget Selection Criteria (TASC) scoring system for selection of potential biomarkers for tumor-targeted imaging. By applying TASC to biomarkers for CRC, we identified seven biomarkers (carcinoembryonic antigen, CXC chemokine receptor 4, epidermal growth factor receptor, epithelial cell adhesion molecule, matrix metalloproteinases, mucin 1, and vascular endothelial growth factor A) that seem most suitable for tumor-targeted imaging applications in colorectal cancer. Further cross-validation studies in CRC and other tumor types are necessary to establish its definitive value.

Figure 1

Selection of biomarkers upregulated in CRC.

Figure 2

The TASC. The blue flag represents the selected biomarker. I. Extracellular localization of the biomarker, cell membrane-bound, or in close proximity of tumor cell. II. Diffuse up-regulation of the target throughout tumor tissue. III. T/N ratio greater than 10. Blue cells represent tumor cells; normal cells are green. IV. Up-regulation of the biomarker in most patients. V. A biomarker that has previously successfully been used in in vivo imaging studies. VI. Enzymatic activity facilitating the use of activatable probes. Shown are cleaving enzymes (yellow) that activate the imaging agent. VII. Internalization of probe for accumulation of imaging agent.