Gastrin releasing peptide

The gastrin-releasing peptide receptor (GRPR) is a cell surface receptor that belongs to the bombesin G-protein-coupled receptor family and is activated by binding to its ligand, the gastrin-releasing peptide (GRP). GRP is a neuropeptide that plays a critical role in regulating central nervous system functions such as emotional and social behavior, and memory [1, 2], as well as gastrointestinal functions such as entero-pancreatic hormone secretion and contraction of smooth muscle cells [3-5]. The activation of the GRP/GRPR axis sets a downstream signaling cascade in motion that has various physiological and biological effects. The primary signaling cascade activates phospholipase C, which leads to intracellular calcium changes, production of diacylglycerol, and activation of protein kinase C [6-8]. Other intracellular mediators that are activated by GRP/GRPR include mitogen-activated protein kinases, adhesion kinases, phosphatidylinositol 3-kinases; all can modulate the immune response by mediating neutrophil chemotaxis, releasing chemokines, cytokines, and adhesion molecules that are involved in carcinogenesis such as cell proliferation, cell differentiation, and autocrine growth stimulation [9-12].

GRPR is overexpressed in several human malignancies, including prostate [13-15], breast [16], ovarian and uterine cancer [17, 18], small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) [19], gastrointestinal stromal tumors (GIST) [20], and colon cancer [21]. Therefore, GRPR-targeting radiopharmaceuticals are considered pan tumor compounds. The highest physiological expression of GRPR is seen in the pancreas and moderate to mild expression in the gastrointestinal tract, mainly in the esophagus and rectum, while other tissues only show minimal GRPR expression [22]. This expression pattern makes GRPR an attractive target for molecular imaging and therapy, i.e., theragnostics. GRPR antagonists have gained significant interest and attention as a diagnostic imaging agent, particularly for prostate cancer and breast cancer, the two most common cancers and leading causes of cancer-related deaths in men and women, respectively [23]. Especially cancers that are characterized by high tumor heterogeneity pose a clinical challenge as they might express different molecular markers, even within the same tumor, among different metastatic sites, or tumor heterogeneity can evolve over time. Anatomical imaging with computed tomography (CT) and magnetic resonance imaging (MRI) might not be able to visualize the whole extent of disease. Molecular imaging with positron emission tomography (PET), enhanced with CT or MRI, uses radiopharmaceuticals that target specific molecular markers on the cancer cell and can thereby stratify patients to treatment that is tailored to the tumor. Theragnostics has led to a paradigm shift in medicine where you see what you treat and treat what you see, the epitome of precision medicine. GRPR-targeted radiopharmaceuticals will play a role in Theragnostics as the field will move forward.