Over the last two decades, several lines of experimental evidence have suggested that the gastrin-releasing peptide (GRP) may act as a growth factor in many types of cancer. For that reason, gastrin-releasing peptide receptor (GRPR) antagonists have been developed as anticancer candidate compounds, exhibiting impressive antitumoral activity both in vitro and in vivo in various murine and human tumors. In this article, the GRPR cell surface expression profile in human malignancies is reviewed aiming at the identification of potential tumor types for future clinical trials with GRP analogues and antagonists. In this review, we summarize the current literature regarding the GRPR status in human malignancies. Source data were obtained by searching all published material available through Medline, PubMed and relevant articles from 1971 to 2006. The data available demonstrated a high expression of GRPRs in a large spectrum of human cancers, demonstrating the potential relevance of this intracellular signaling pathway in various human tumor models. The GRPR may be an interesting target for therapeutic intervention in human malignancies, as carriers for cytotoxins, immunotoxins or radioactive compounds, being also a potential tool for tumor detection.
Growth factor receptors are involved in all steps of tumor progression, enhancing angiogenesis, local invasion and distant metastases. Furthermore, the overexpression of growth factor receptors on the cell surface of malignant cells might be associated with a more aggressive behavior and a poor prognosis. For these reasons, tumor-related growth factor receptors can be considered potential targets for therapeutic interventions. The interference with epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF)-dependent cell surface signaling are examples of experimental therapeutic approaches that showed evidence of antitumor activity in patients with various types of malignancies, such as breast, colorectal and renal cancer.
Over the last two decades, several lines of experimental evidence have suggested that the gastrin-releasing peptide (GRP) and other bombesin-like peptides (BLPs) may act as growth factors in many types of cancer. For that reason, GRP-preferring receptor [gastrin-releasing peptide receptor (GRPR)] antagonists have been developed as anticancer candidate compounds, exhibiting impressive antitumor activity both in vitro and in vivo in various murine and human tumors. Notably, the inhibition of GRPR was demonstrated to interfere with other relevant growth factor pathways such as the EGF- and VEGF-dependent signaling pathways. RC-3095 is a GRPR antagonist of this series, which showed a very favorable toxicity profile and antitumor activity in preclinical models. RC-3095 is currently undergoing clinical trials in our institution. Recently, a phase I trial with this compound was carried out in patients with advanced malignancies, confirming its favorable toxicity. In this context, a review of GRPR cell surface profile in human malignancies is an issue of critical relevance, recognizing tumor types expressing sufficient amounts of these receptors for potential clinical applications of GRP analogues and antagonists.
Bombesin is a14-amino acid peptide first isolated from frog skin. BLPs were identified in mammalian and the highest levels were observed in pulmonary neuroendocrine cells. One major pulmonary BLP was determined to be GRP, a 27-amino acid homolog of frog bombesin. GRP and bombesin share a highly conserved 7-amino-acid COOH-terminal sequence, which is required for immunogenicity and for high-affinity binding to the GRP-preferring receptor. Consequently, GRP and bombesin have essentially identical physiologic actions.
Three mammalian BLP receptors have been cloned: GRPR, neuromedin B receptors (NMBR) and the orphan bombesin receptor subtype 3 (BRS-3). These receptors are coupled to G-protein via their intracellular domain and, thus, belong to the G-protein receptor superfamily. Through the binding of GRPRs multiple cellular signal transduction pathways are activated, including mitogen-activated protein kinase, protein kinase C, tyrosine phosphorylation of focal adhesion kinase, paxillin, p130 cas and calcium mobilization, resulting in cell proliferation and growth.
GRP plays an important role in regulating smooth muscle contraction, releasing hormones in the gastrointestinal (GI) tract, secreting pancreatic enzymes and serving as a neurotransmitter in the central nervous system. These peptides are also thought to have pathogenic effects. Using animal models, Roesler et al. have conducted several preclinical studies investigating the role of BLPs and the GRPR in regulating brain function and discussing the implications of the GRPR for neurological and psychiatric disorders.
The GRPR system seems to have a functional interaction with other neurotransmitter and receptor systems (GABA, dopamine and glucocorticoid recept
