Gastrin-releasing peptide (GRP)

Gastrin-releasing peptide (GRP) Overview

Gastrin-releasing peptide (GRP) is a neuropeptide found in the central and peripheral nervous systems, as well as in various tissues throughout the body. It is the mammalian equivalent of bombesin, a tetradecapeptide originally isolated from amphibian skin. GRP acts as a growth factor for several cell types and plays a crucial role in regulating a wide array of physiological functions, including gastrointestinal motility, exocrine and endocrine secretions, smooth muscle contraction, and cell proliferation.

Beyond its normal physiological roles, GRP and its receptors (GRPR) are frequently overexpressed in various human cancers, making them attractive targets for both diagnostic imaging and therapeutic interventions in oncology.

GRP Biology and Function

GRP is a 27-amino acid peptide derived from a larger precursor molecule. It exerts its biological effects by binding to specific G protein-coupled receptors, primarily the gastrin-releasing peptide receptor (GRPR), also known as bombesin receptor subtype 2 (BB2).

Key biological functions of GRP include:

1. Gastrointestinal Regulation:
   • Stimulates the release of gastrin from G cells in the stomach, which in turn promotes gastric acid secretion.
   • Influences pancreatic exocrine secretion, gall bladder contraction, and intestinal motility.
2. Neurotransmission: Acts as a neurotransmitter and neuromodulator in the central nervous system, involved in processes such as thermoregulation, satiety, pain perception, and anxiety.
3. Cell Growth and Proliferation: GRP is a potent mitogen for various cell types, including fibroblasts, epithelial cells, and a wide range of cancer cells. It promotes cell growth, survival, and differentiation through activation of intracellular signaling pathways such as the ERK/MAPK and PI3K/Akt pathways.
4. Inflammation and Immunity: Plays a role in inflammatory responses and immune modulation.

Clinical Significance of GRP

The widespread distribution and diverse actions of GRP make it clinically significant in several areas:

• Gastrointestinal Disorders: Dysregulation of GRP signaling can contribute to conditions like peptic ulcers, irritable bowel syndrome (IBS), and pancreatitis.
• Neurological Conditions: Research is exploring GRP's involvement in anxiety, depression, and other neuropsychiatric disorders.
• Cancer: The most significant clinical interest in GRP stems from its role in cancer development and progression. GRPR is overexpressed in numerous human malignancies, including prostate cancer, breast cancer, lung cancer, colorectal cancer, and pancreatic cancer.

GRP as a Tumor Marker

While GRP itself is not typically used as a circulating tumor marker in routine clinical practice, the **gastrin-releasing peptide receptor (GRPR)** is an important target in oncology.

• Overexpression in Cancers: GRPR is found in high density on the surface of various cancer cells, while its expression in most healthy tissues is low or absent, particularly in adult organs. This differential expression makes GRPR an excellent target for cancer-specific imaging and therapy.
• Growth Factor for Tumors: Autocrine and paracrine GRP/GRPR signaling pathways are implicated in promoting tumor cell proliferation, angiogenesis, and metastasis.

The detection of GRPR overexpression is often achieved through immunohistochemistry on biopsy samples or, more increasingly, through molecular imaging techniques.

Diagnostic Applications of GRP

Radiolabeled GRP receptor agonists or antagonists are being developed and used for **molecular imaging** of GRPR-positive tumors, primarily using Positron Emission Tomography (PET) or Single-Photon Emission Computed Tomography (SPECT).

• PET Imaging: Radiopharmaceuticals such as ⁶⁸Ga-labeled bombesin analogs (e.g., ⁶⁸Ga-RM2, ⁶⁸Ga-NeoBOMB1) are used for PET imaging to detect and stage GRPR-positive tumors, particularly prostate cancer. This allows for non-invasive assessment of tumor burden, identification of metastases, and monitoring treatment response.
• Theranostics: The high and specific expression of GRPR in many cancers also paves the way for theranostics – combining diagnostic imaging with targeted radionuclide therapy. For example, using a therapeutic radioisotope (e.g., ¹⁷⁷Lu, ⁹⁰Y) conjugated to a GRPR-targeting peptide can deliver radiation directly to tumor cells.

These imaging agents offer advantages in certain cancers by providing more sensitive and specific detection compared to conventional imaging modalities.

Therapeutic Potential of GRP Antagonists

Given the role of GRP/GRPR signaling in tumor growth, **GRP receptor antagonists** are being investigated as potential anti-cancer therapies. These molecules aim to block the binding of endogenous GRP to its receptor, thereby inhibiting tumor cell proliferation and survival.

• Direct Anti-tumor Effects: By blocking GRPR, antagonists can directly inhibit the growth-promoting signals in cancer cells.
• Radiolabeled Antagonists for Therapy: Similar to diagnostic agents, therapeutic radionuclides can be attached to GRPR antagonists for targeted radiotherapy. Antagonists may offer advantages over agonists for therapy due to different internalization kinetics and receptor binding properties, potentially leading to better tumor retention and reduced uptake in non-target tissues.

Clinical trials are ongoing to evaluate the efficacy of GRPR-targeted therapies in various GRPR-expressing cancers.

Frequently Asked Questions (FAQ)

References

1. Sun, B., et al. (2007). Bombesin-like peptides and their receptors in gastrointestinal cancer. *Peptides*, 28(12), 2419-2426.
2. Reubi, J. C., & Maecke, H. R. (2008). Peptide-based radionuclides for cancer therapy and imaging. *J Nucl Med*, 49(11), 1735-1738.
3. Liu, Z., et al. (2009). Gastrin-releasing peptide receptor targeted imaging and therapy. *Theranostics*, 1, 107-119.
4. Guo, W., et al. (2014). Gastrin-releasing peptide receptor (GRPR) as a novel target for cancer therapy. *Biochem Pharmacol*, 87(1), 1-9.
5. Conti, M., et al. (2020). Bombesin receptor subtype 2 (BB2/GRPR) targeting: Current status and future perspectives. *Mol Imaging Biol*, 22(1), 1-13.
6. Schuster, D. M., et al. (2020). ⁶⁸Ga-RM2 PET/CT for prostate cancer: an overview. *J Nucl Med*, 61(10), 1369-1375.