Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications

Abstract

Peptide hormones of the glucagon-like peptide (GLP) family play an increasing clinical role, such as GLP-1 in diabetes therapy. Moreover, GLP receptors are overexpressed in various human tumor types and therefore represent molecular targets for important clinical applications. In particular, virtually all benign insulinomas highly overexpress GLP-1 receptors (GLP-1R). Targeting GLP-1R with the stable GLP-1 analogs (111)In-DOTA/DPTA-exendin-4 offers a new approach to successfully localize these small tumors. This non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. Malignant insulinomas, in contrast to their benign counterparts, express GLP-1R in only one-third of the cases, while they more often express the somatostatin type 2 receptors. Importantly, one of the two receptors appears to be always expressed in malignant insulinomas. The GLP-1R overexpression in selected cancers is worth to be kept in mind with regard to the increasing use of GLP-1 analogs for diabetes therapy. While the functional role of GLP-1R in neoplasia is not known yet, it may be safe to monitor patients undergoing GLP-1 therapy carefully.

Keywords: 111In-DOTA/DPTA-exendin-4; glucagon-like peptide-1; glucagon-like peptide-1 receptor; insulinoma.

FIGURE 1

Hormone and receptor determinations in vitro in a benign insulinoma. (A) Immunohistochemistry for insulin showing strongly labeled tumor cells. Bar = 0.01 mm. (B–D) In vitro GLP-1R autoradiography on consecutive insulinoma tissue sections. (B) Hematoxylin & eosin (H&E) staining showing the tumor tissue. Bar = 1 mm. (C) Autoradiogram showing total binding of ¹²⁵I-GLP-1(7-36) amide. The entire tumor is strongly positive. (D) Autoradiogram showing non-specific binding of ¹²⁵I-GLP-1(7-36) amide in the presence of 100 nM cold GLP1(7-36) amide. Reprinted from Christ et al. (2010), with permission from Elsevier.

FIGURE 2

¹¹¹In-DOTA-exendin-4 whole-body planar images (A–C) and ¹¹¹In-DOTA-exendin-4 SPECT/CT images (D,E) from the same patient. Whole-body scans were carried out 20 min (A), 4 h (B), and 3 days (C), and SPECT/CT scans were performed 4 h (D) and 3 days (E) after injection of 97 MBq ¹¹¹In-DOTA-exendin-4. Four hours after injection, there was already a focal ¹¹¹In-DOTA-exendin-4 uptake visible in the head of the pancreas (arrow) on whole-body (B) and SPECT/CT (D) scans. The tumor-to-pancreas-uptake ratio was 1.9 at 4 h after injection (D) and 3.2 at 3 days after injection of the radioligand. The longest residence times of ¹¹¹In-DOTA-exendin-4 were observed in the tumor (arrow) and kidneys (C). Reprinted from Christ et al. (2009), with permission from The Endocrine Society.