Gastrin-releasing Peptide Research Articles (Page 1)

Recent studies have shown that pulmonary neuroendocrine tumor (NET) subgroups, defined by the transcription factors OTP and ASCL1, correlate with age, sex, and tumor location. Their relationships with histology and hormone production, however, remain unclear. We analyzed 170 pulmonary NETs classified by OTP (O) and ASCL1 (A) expression into four groups: O + /A + , O + /A-, O-/A + , and O-/A-. Subgroups were assessed for histology, hormone expression, therapy-related markers, outcomes, and matched metastases. Among 152 resected primaries, O + /A + tumors (38%) were most frequent, occurring mainly in females (median age 72years), and typically showed central or peripheral location, solid/spindle morphology with diffuse gastrin-releasing peptide (GRP), and focal ACTH/calcitonin. They also showed strong DLL3 expression and pronounced neuroendocrine cell hyperplasia. O + /A- tumors (23%) occurred predominantly in females (median age 56years) with solid/trabecular patterns, occasional/ACTH, and strong SSTR2A/5 expression. O-/A- tumors (25%) were more common in males (median age 70years), often central with solid/trabecular or oncocytic histology, serotonin expression (24%), and frequently SSTR2A-positivity. O-/A + tumors (14%) occurred across both sexes (median age 58years), were centrally located, and solid, sometimes oncocytic features with moderate DLL3/SSTR2A expression. Metastases mirrored their primaries in transcription factor and hormone profiles. In the univariate analysis, OTP-negative tumors were associated with poorer disease-free survival (DFS). However, the multivariate analysis identified Ki67-based WHO grades (G1-G3) as the only independent prognostic factors. In conclusion, integrating OTP and ASCL1 refines pulmonary NET classification into four histologically and biologically distinct subgroups, providing additional insight into tumor heterogeneity. O + /A + tumors showed solid-spindle features and diffuse GRP and frequent ACTH expression, trabecular patterns characterized ASCL1-negative tumors, while oncocytic histology predominated in OTP-negative tumors, highlighting their role in defining tumor heterogeneity.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour with limited treatment options and a poor prognosis. Hypoxia, a hallmark of solid tumours, contributes to therapeutic resistance and tumour progression. Gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in SCLC; however, its regulation under hypoxic conditions is not well described. In this study, we demonstrate that hypoxia significantly enhances GRPR expression in SCLC cell lines, COR-L24 and DMS79, as confirmed by Western blot, immunofluorescence, and flow cytometric analysis of binding with fluorescein isothiocyanate–labelled bombesin (BBN-FITC), a known GRPR ligand. To exploit this upregulation, we synthesised a previously discovered butylated neuropeptide antagonist (BU peptide) using a new method of solid-phase peptide synthesis (SPPS) by Boc chemistry and evaluated its therapeutic potential. BU peptide exhibited potent, dose-dependent cytotoxicity in both cell lines, with significantly greater efficacy under hypoxic conditions compared to normoxia. Mechanistic studies revealed that BU peptide inhibits GRP–GRPR-mediated activation of the PI3K/Akt and MAPK/ERK signalling pathways, known to be key regulators of tumour cell survival and proliferation. Moreover, BU peptide induced robust caspase 3/7-mediated apoptosis, especially under hypoxic conditions. These findings suggest that GRPR is a hypoxia-inducible target in SCLC and demonstrate that a synthetically optimised BU peptide antagonist exerts selective efficacy against hypoxic tumour cells, outperforming conventional chemotherapy agents. These findings provide new mechanistic insights into SCLC and suggest translational potential to inform the development of future treatment strategies for this and other hypoxia-driven malignancies.

GRPR Expression in Metastatic Cancers: A Review of Potential Application of GRPR-Radioligand Therapy.

Prostate-specific membrane antigen (PSMA) targeting agents have been the cornerstone of advanced prostate cancer (PCa) management in theranostics due to their high sensitivity for detecting and treating metastatic disease. However, approximately one-third of metastatic castration-resistant PCa (mCRPC) lesions may exhibit low or absent PSMA expression due to tumor heterogeneity, prior androgen deprivation therapy, or loss of androgen receptor expression, subsequently altering their response to PSMA-targeted therapy. The molecular and biological mechanisms underlying PSMA downregulation remain elusive but may include neuroendocrine differentiation or epithelial-to-mesenchymal transition (EMT). This review addresses this knowledge gap by examining recent preclinical and clinical evidence on novel radiotracers with the potential to provide alternative strategies beyond PSMA for imaging and treating PCa. The diagnostic performance and therapeutic potential of three emerging radiotracer classes are discussed, including gastrin-releasing peptide receptor (GRPR) ligands, androgen receptor (AR) ligands, and amino acid analogs. This article further highlights the complementary roles of these radiotracers along with their utility in specific patient populations, such as those with low prostate-specific antigen (PSA), biochemical recurrence (BCR), or confirmed PSMA-negative disease. For instance, GRPR-targeted radiotracers have achieved sensitivity of up to 88% and specificity of up to 90% for detecting primary tumors in PCa. The radiolabeled androgen agonist, fluorine-18 (18F)-fluoro-5α-dihydrotestosterone (FDHT), has demonstrated 98% true-positive rate in predicting lesions on positron emission tomography (PET) scans of mCRPC patients. On the other hand, the synthetic amino acid analog 18F-fluciclovine demonstrated a lesion detection rate of 84% for PSA levels at or above 5, and 62.5% for PSA levels ranging from 0.7 to less than 1. This review concludes with future directions on the paradigm of multi-tracer and dual-targeting strategies, which can effectively address challenges associated with PCa tumor heterogeneity and facilitate personalized approaches in theranostics.

Preclinical Evaluation of a ¹⁷⁷ Lu-Labeled Gastrin-Releasing Peptide Receptor Antagonist and Prostate Cancer Treatment with Monotherapy and in Combination with Everolimus

Neuropeptides are the largest class of neuromodulators. It has been shown that subpopulations of ventral tegmental area (VTA) dopamine neurons express mRNA for the neuropeptide Gastrin-releasing peptide (GRP); however, its functional relevance in mesolimbic circuits is unknown. Here we report that the GRP receptor (GRPR) is expressed in nucleus accumbens medial shell (NAc MSh) neurons, which are targeted by GRP-expressing inputs from the VTA, hippocampus, and amygdala. We show that NAc MSh GRPR-positive cells represent subpopulations of D2 receptor-expressing neurons, comprising both classical striatal projection neurons (SPNs) and eccentric SPNs. GRPR-expressing neurons have high intrinsic excitability and can be activated by GRP in vivo. NAc-specific deletion of Grpr in mice increases motivation in a progressive ratio test, demonstrating that GRPR regulates motivated behaviors. These experiments establish GRP/GRPR signaling as a potent modulator of mesolimbic circuits and advance our understanding of the diversity of cell types present in the NAc.

Linker modifications in radiolabeled RM26-based antagonists to gastrin-releasing peptide receptor (GRPR) improved tracers' pharmacokinetics.

Background/Objectives: The gastrin-releasing peptide receptor (GRPR) shows high-density expression in prostate cancer (PCa), especially in the early stages of the disease. The introduction of a safe radiotracer for assessing GRPR-expression in PCa may serve as an alternative or complementary tracer to PSMA-directed probes for patients with insufficient PSMA expression. In the present study, the tolerability and safety, biodistribution, and dosimetry of the new GRPR-targeting radiopeptide [99mTc]Tc-DB8 were investigated for the first time in male PCa patients. A mass escalation study was performed, aiming to improve tumor-to-background contrast and, thereby, to enhance diagnostic accuracy. Methods: Sixteen male patients were enrolled in a single-center diagnostic open-label exploratory Phase I clinical trial. Patients were administered a single intravenous injection of 40, 80, or 120 µg of [99mTc]Tc-DB8 peptide (n = 5–6) and underwent whole-body planar imaging (anterior and posterior) 2, 4, 6, and 24 h post-injection (pi) and SPECT-CT acquisition 2, 4, and 6 h pi. Results: Administration of [99mTc]Tc-DB8 was well tolerated at all tested peptide masses. The effective dose did not differ significantly between the injected peptide mass and was 0.005 ± 0.003 mSv/MBq. High activity uptake was observed in the pancreas and kidneys, which 3-fold decreased with an increasing injected peptide mass from 40 to 120 µg. The activity uptake in primary tumors did not differ significantly between cohorts injected with different peptide masses [SUVmax 1.65–9.96]. The tumor-to-muscle ratios increased with time and were the highest for the cohort injected with 120 µg of peptide, 7.2 ± 3.1 (4.64-11-25) at 4 h pi. Conclusions: Single intravenous administration of [99mTc]Tc-DB8, for visualization of GRPR expression in PCa using SPECT imaging was well tolerated in a peptide mass range of 40–120 µg. An injected peptide mass of 80–120 µg/patient and SPECT acquisition 2–4 h pi were found to be optimal for further clinical studies due to the significantly lower activity accumulation in the pancreas and kidneys.

Prostate-specific membrane antigen (PSMA) and Gastrin-releasing peptide receptor (GRPR) PET demonstrate hopeful results in initial staging of prostate cancer (PCa), offering potential to support precision treatment decisions. We investigated whether the dual-tracer PET/CT with [68Ga]Ga-PSMA-617 and [68Ga]Ga-RM26 could enhance prediction of biochemical recurrence (BCR) after radical prostatectomy (RP) in PCa. 102 patients from prospective cohort NCT05073653 underwent preoperative [68Ga]Ga-PSMA-617 and [68Ga]Ga-RM26 PET/CT. Tumor uptake was quantified by maximum standardized uptake value (SUVmax), with optimal cutoffs determined using maximally selected rank statistics. Biochemical recurrence-free survival (BRFS) was estimated by Kaplan-Meier analysis, and the correlations between BRFS and predictors were examined using Cox regression. Predictive values were assessed using time-dependent receiver-operating characteristic (ROC) curves. We additionally used transcriptomic data (GSE70770, n = 198) for external validation. 52 patients (51.0%) experienced BCR within the follow-up (median, 22.3 months). High PSMA-SUVmax (> 6.6) was associated with shorter BRFS (hazard ratio [HR] 3.17, p = 0.004), as was low GRPR-SUVmax (≤ 13.0) (HR 0.51, p = 0.026). Both were identified as independent predictors for BRFS. PSMA-SUVmax correlated with most of conventional clinicopathological factors (p < 0.005), whereas GRPR-SUVmax did not (p > 0.200). The combined PSMA + GRPR-SUVmax model achieved a superior time-dependent AUC of 0.73, compared with PSMA (AUC 0.63) or GRPR alone (AUC 0.62). External transcriptomic analysis corroborated that PSMAhigh/GRPRlow phenotype was associated with poorer BRFS (p = 0.029). This study provides first clinical evidence that [68Ga]Ga-RM26 PET/CT adds independent prognostic value to PSMA PET/CT for early prediction of BCR after RP. Dual-tracer PET/CT may enable more accurate risk stratification and guide personalized management in PCa patients.

IntroductionExtensive-stage small cell lung cancer (ES-SCLC) is an aggressive malignancy with a poor prognosis. This study aimed to identify and validate clinical and laboratory biomarkers for predicting treatment response and overall survival (OS) in ES-SCLC patients.MethodsWe retrospectively analyzed 101 ES-SCLC patients receiving first-line treatment. Logistic and Cox regression analyses identified independent factors influencing treatment efficacy and OS. Subgroup analysis was performed to compare white blood cell (WBC) changes between chemotherapy-alone and chemo-immunotherapy groups. Predictive models were constructed and evaluated via cross-validation, ROC, and calibration curves. Differential expression of key proteins (neuron-specific enolase (NSE), fibrinogen (FIB), and gastrin-releasing peptide precursor (ProGRP)) was validated using GEO database data.ResultsPre-chemotherapy tumor size and post-cycle 2 FIB levels were independent predictors of treatment efficacy. Pre-chemotherapy WBC count, pre-chemotherapy D-dimer, and post-cycle 2 ProGRP were independent risk factors for OS. The predictive models demonstrated strong performance. Subgroup analysis showed no significant difference in WBC changes between treatment regimens (mean change: -2.30 ± 2.47 vs. -2.08 ± 2.45, p=0.659). GEO data confirmed the differential expression of FIB and ProGRP.DiscussionOur findings establish robust and validated models based on readily available clinical metrics (tumor size, WBC, D-dimer, FIB, ProGRP) to predict outcomes in ES-SCLC, which could aid in personalizing treatment strategies. The stability of WBC trends across therapies strengthens the prognostic value of baseline WBC.

The bombesin (Bn) receptor family [Gastrin-releasing peptide (GRPR/BB2R) and Neuromedin B receptors (NMBR/BB1R)] are G-protein coupled receptors (GPCR's) with potent growth effects on normal tissues/numerous cancers, often by transactivating the ErbB receptor-tyrosine kinase (RTK) family. Whereas GRPR stimulation transactivates ErbB RTKs EGFR, HER2, and HER3 in non-small cell lung-cancer (NSCLC) cells, its effects on HER4 are unknown. This study was designed to address this question. Of 12 NSCLC's studied, 75% had HER4 mRNA expression and Western-Blotting. NCI-H522 and NCI-H661-cells had high levels of GRPR, HER4, and the HER4-ligand neuregulin (NRG1). Adding GRP to NCI-H522/NCI-H661-cells activated HER4, shown by its increased phosphorylation (P-HER4). The GRPR antagonists PD176252/BW2258U89 inhibited this increase. In NCI-H661-cells, GRP stimulated the formation of HER4-homodimers and HER2-HER4-heterodimers. Adding GRP to these NSCLC-cells increased P-ERK/P-AKT, which was inhibited by siRNA-HER4, PD176252, and ibrutinib, as well as N-acetylcysteine and Tiron, which reduce reactive-oxygen species (ROS). GRP increased secretion of NRG1 from NSCLC-cells, and NRG1 increased P-HER4 and P-ERK, which were impaired by ibrutinib. GRP and NRG1 stimulated proliferation of NSCLC-cells, which was inhibited by PD176252, siRNA-HER4, or ibrutinib and which was mediated by MAPK, not AKT/PI3K, activation. These results show GRPR activation results in HER4 transactivation in a ROS-dependent manner, which stimulates NSCLC-growth through a MAPK-mediated mechanism.

PET/CT in breast cancer.

Gastrin-releasing peptide in the paraventricular nucleus exerts hypertensive effects in preeclampsia.

Diagnostic Value of Gastrin-Releasing Peptide Receptor-Targeted PET Imaging in Oncology: A Systematic Review.

BackgroundOne of the most studied, and preclinically as well as clinically applied gastrin-releasing peptide receptor (GRPR) ligands represents the antagonist RM2 (DOTA-Pip5-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2). As an improved in vivo stability was observed for a RM2 analog comprising the unnatural amino acid α-methyl-L-tryptophan instead of L-Trp, we aimed to elucidate the impact of other unnatural amino acids (homoserine [Hse], β-(3-benzothienyl)alanine [Bta]) at the metabolically less stable Gln-Trp site. Furthermore, we conjugated either DOTA, NOTA or NODAGA to the RM2 peptide and its modified derivatives, and evaluated each analog preclinically using 68Ga and 64Cu, as well as 177Lu (only DOTA-comprising compounds).ResultsGRPR affinity and lipophilicity of RM2 derivatives were in a range of 1.2–8.4 nM and − 2.9 to − 1.1 (nat/68Ga-labeled), 1.7–33.0 nM and − 2.4 to − 1.6 (nat/64Cu-labeled), as well as 3.0–19.7 nM and − 3.2 to − 1.8 (nat/177Lu-labeled), respectively. Both, [177Lu]Lu-[Hse7]RM2 and [177Lu]Lu-[Bta8]RM2 revealed distinctly lower in vivo stability (< 20% intact at 15 min post-injection) than [177Lu]Lu-[α-Me-Trp8]RM2 (= [177Lu]Lu-AMTG) and [177Lu]Lu-RM2 (> 30% intact at 30 min post-injection). Both [68Ga]Ga-RM2 and [68Ga]Ga-AMTG exhibited high tumor (~ 15 percentage injected dose per gram, %ID/g) and pancreas uptake (> 25%ID/g), whereas [68Ga]Ga-[Hse7]RM2 and [68Ga]Ga-[Bta8]RM2 revealed lower tumor (~ 7.5%ID/g) but also substantially lower pancreas uptake (< 8%ID/g) at 1 h post-injection. At 24 h post-injection (p.i.), [177Lu]Lu-RM2 and [177Lu]Lu-AMTG exhibited high (> 8% ID/g) while [177Lu]Lu-[Hse7]RM2 and [177Lu]Lu-[Bta8]RM2 displayed low tumor retention (~ 2%ID/g). All compounds showed low activity levels in the pancreas at 24 h post-injection (< 1%ID/g).ConclusionSubstitution of the Gln-Trp site in RM2 by artificial amino acids had a distinct impact on overall pharmacokinetics. While Hse (instead of Gln) and Bta (instead of Trp) led to a decreased, α-Me-Trp (instead of Trp) led to an increased in vivo stability, which resulted in improved pharmacokinetics over time in case of the latter. However, at 1 h post-injection both [68Ga]Ga-[Hse7]RM2 and [68Ga]Ga-[Bta8]RM2 displayed slightly higher tumor-to-pancreas and tumor-to-intestine ratios, rendering homoserine and β-(3-benzothienyl)alanine potential options for the modification of GRPR ligands with regard to imaging properties.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13550-025-01241-7.

Heterotopic pancreas is a congenital malformation of various shapes and origins and is usually asymptomatic, which can simulate benign tumors on imaging, so diagnosis usually requires biopsy or surgical resection. We present a young woman with abdominal distension who was found to have a gastric mass that was suspected to be a gastrointestinal stromal tumor (GIST) by gastroscopy and enhanced CT. 68Ga-NOTA-RM26 PET/CT, a novel imaging modality targeting the gastrin-releasing peptide receptor (GRPR), also showed intense uptake in the mass. Pathology results of the resected mass demonstrated pancreatic tissue, supporting the diagnosis of heterotopic pancreas.

Alloknesis refers to itch caused by normally non itch-inducing stimuli, particularly light mechanical stimuli, such as contacts with clothes or other human bodies. This symptom occurs in patients suffering from chronic itch. While it has been mainly described in patients with atopic dermatitis, it is probably present in numerous other conditions and it could induce a severe burden. Until now, it is mainly diagnosed using Von Frey filaments and validated questionnaires are lacking. Alloknesis differs from mechanical pruritus in that it is linked to sensitization to pruritus and therefore occurs in pathological conditions, whereas mechanical pruritus (triggered by the presence of insects on the skin, for example) is a physiological phenomenon. While the role of central sensitization to pruritus in alloknesis is still poorly understood, the role of peripheral sensitization is becoming clearer. Interactions between low-threshold mechanoreceptors (LTMRs) and spinal interneurons are especially involved. Both the mechanical labelled pathway and the polymodal pathway have been shown to contribute to mechanical alloknesis. The mechanical labelled pathway comprises dedicated primary sensory neurons, spinal interneurons, and projection neurons that are functionally distinct from those involved in chemical itch. The polymodal pathway relies on a subset of primary sensory neurons traditionally associated with chemical itch, which can also transduce light mechanical stimuli through the activation of the mechanosensitive ion channel PIEZO1. Both converge onto the gastrin-releasing peptide (GRP) - GRP receptor (GRPR) chemical itch pathway in the spinal cord. Alloknesis is largely unknown to healthcare professionals and even more so to patients, and is not actively investigated. The objective of reducing alloknesis should be considered a therapeutic goal. To date, it has not been investigated in clinical trials. A novel research domain is emerging concerning this symptom, which exerts a substantial impact on the daily lives of numerous patients.

Recent advances reveal an extensive cellular diversity within the dorsal horn. How this complexity processes distinct sensations, like itch and pain, remains a fundamental question. We discovered hidden within a population of neurons expressing the gastrin-releasing peptide receptor (Grpr+), thought to be itch-specific, are highly homologous yet functionally distinct subtypes distinguished by expression of Tachykinin-1 (Tac1). While the Tac1- subtype mediates itch, the Tac1+ subtype mediates mechanical allodynia across diverse pain states. Inhibitory populations and differential sensitivities to GRP serve as key modulators of the Grpr+ neuron subtypes, shaping modality specific output. Leveraging computationally designed genomic enhancers to silence the Tac1- population reverses itch while silencing the Tac1+ subtype reverses mechanical allodynia broadly. The work demonstrates the nuance of differential sensory modality coding within the dorsal horn and the power of genomic enhancer-based strategies for modality-specific targeting.

Gastrin-releasing peptide receptor (GRPR) is overexpressed in several cancers, including prostate and breast, making it an attractive target for radiopharmaceutical development. Studies on GRPR-targeting radioligands highlight the critical role of the spacer region between the GRPR-recognition motif and radiolabeled moiety, which can significantly influence peptide pharmacokinetics and pharmacodynamics. Herein, we investigated the impact of structurally restricted spacers on the performance of RM26-based radioligands. Three novel radioligands were designed to each bear a NOTA chelator via different spacers composed of N-acetyl-lysine followed by either o-ethyltoluene (oET), o-methylanisole (oMA), or m-methylanisole (mMA) motifs. The peptides were successfully labeled with Ga-68, achieving high radiochemical yield, purity, and molar activity. The resulting [68Ga]-labeled peptides demonstrated high and GRPR-specific binding to prostate cancer PC-3 cells, antagonistic behavior, and the IC50 values to GRPR were in the single-digit nanomolar range. Biodistribution studies at 2h post-injection in PC-3 xenograft-bearing mice revealed high, GRPR-mediated tumor uptake for all three radioligands. In addition, high hepatobiliary excretion with elevated uptake in the liver and the gastrointestinal tract and pronounced pancreatic uptake were observed. Among the three radioligands, the peptide bearing the N-acetyl-lysine-oET spacer exhibited the fastest background clearance and better PET imaging of prostate cancer xenografts. The incorporation of conformationally restricted spacers is a promising strategy for developing tracers with high GRPR binding and good imaging properties, but further optimization is necessary to reduce uptake in healthy tissues.

The stomach has been a highly conserved organ throughout vertebrate evolution; however, there are now over 20 lineages composed of monotremes, lungfish and teleost fish displaying a secondary loss of stomach function and morphology. This "agastric phenotype" has evolved convergently and is typified by a loss of gastric glands and gastric acid secretion and a near-to-complete loss of storage capacity of the stomach. All agastric species have lost the genes for gastric enzymes (Pga and Pgc) and proton pump subunits (Atp4a and Atp4b), and gastrin (Gast) has been lost in monotremes. As a key gastric hormone, the conservation of gastrin has not yet been investigated in the lungfish or agastric teleosts, and it is unclear how the loss of gastrin affects the evolution and selection of the native receptor (Cckbr), gastrin-releasing peptide (Grp) and gastrin-releasing peptide receptor (Grpr) in vertebrates. Furthermore, there are still many genes implicated in gastric development and function which have yet to be associated with the agastric phenotype. We analysed the evolution, selection and conservation of the gastrin pathway and a novel gastric gene repertoire (Gkn1, Gkn2, Tff1, Tff2, Vsig1 and Anxa10) to determine the correlation with the agastric phenotype. We found that the loss of gastrin or its associated genes does not correlate with the agastric phenotype, and their conservation is due to multiple pleiotropic roles throughout vertebrate evolution. We found a loss of the gastric gene repertoire in the agastric phenotype, except in the echidna, which retained several genes (Gkn1, Tff2 and Vsig1). Our findings suggest that the gastrin physiological pathway evolved differently in pleiotropic roles throughout vertebrate evolution and support the convergent evolution of the agastric phenotype through shared independent gene-loss events.