Gastrin-releasing peptide receptor (GRPR)

Class

Targeted alpha-particle radioligand therapy (²¹²Pb-DOTAM-conjugated GRPR antagonist)

Pathway

GRPR-expressing tumor targeting; alpha-emitter (lead-212) induced DNA damage

Gastrin-releasing peptide receptor (GRPR) is a cell-surface receptor belonging to the bombesin receptor family that is expressed at low levels in normal tissue but becomes markedly overexpressed on several solid tumors, most notably prostate and certain breast cancers. Because of this expression pattern, GRPR serves as a homing beacon: a molecule designed to bind it selectively can be used to deliver a cytotoxic payload directly to tumor cells while largely sparing healthy tissue. In this approach, a small-molecule antagonist that binds GRPR is chemically linked to a chelating group (DOTAM) carrying lead-212, an isotope that emits alpha particles as it decays. Alpha particles carry substantial energy and travel only a very short distance in tissue, so the radiation dose is concentrated almost entirely within and immediately around the cells that have bound the radioligand. This alpha radiation produces dense clusters of DNA damage, including breaks in both strands of the double helix, which are difficult for cells to repair and typically lead to cell death. The overall rationale unites receptor-based tumor targeting with a highly localized, high-potency form of radiation, an approach broadly relevant to cancers characterized by GRPR overexpression.