Gastrin-releasing Peptide Receptor Expression Research Articles

68Ga-RM2 PET–MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial

National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer. This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET-MRI and the detection by 68Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete. Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; 68Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported. 68Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients. The US Department of Defense.

Imaging GRPr Expression in Metastatic Castration-Resistant Prostate Cancer with [68Ga]Ga-RM2-A Head-to-Head Pilot Comparison with [68Ga]Ga-PSMA-11.

The gastrin-releasing peptide receptor (GRPr) is highly overexpressed in several solid tumors, including treatment-naïve and recurrent prostate cancer. [68Ga]Ga-RM2 is a well-established radiotracer for PET imaging of GRPr, and [177Lu]Lu-RM2 has been proposed as a therapeutic alternative for patients with heterogeneous and/or low expression of PSMA. In this study, we aimed to evaluate the expression of GRPr and PSMA in a group of patients diagnosed with castration-resistant prostate cancer (mCRPC) by means of PET imaging. Seventeen mCRPC patients referred for radio-ligand therapy (RLT) were enrolled and underwent [68Ga]Ga-PSMA-11 and [68Ga]Ga-RM2 PET/CT imaging, 8.8 ± 8.6 days apart, to compare the biodistribution of each tracer. Uptake in healthy organs and tumor lesions was assessed by SUV values, and tumor-to-background ratios were analyzed. [68Ga]Ga-PSMA-11 showed significantly higher uptake in tumor lesions in bone, lymph nodes, prostate, and soft tissues and detected 23% more lesions compared to [68Ga]Ga-RM2. In 4/17 patients (23.5%), the biodistribution of both tracers was comparable. Our results show that in our cohort of mCRPC patients, PSMA expression was higher compared to GRPr. Nevertheless, RLT with [177Lu]Lu-RM2 may be an alternative treatment option for selected patients or patients in earlier disease stages, such as biochemical recurrence.

Synaptic circuits involving gastrin-releasing peptide receptor-expressing neurons in the dorsal horn of the mouse spinal cord.

The superficial dorsal horn (SDH) of the spinal cord contains a diverse array of neurons. The vast majority of these are interneurons, most of which are glutamatergic. These can be assigned to several populations, one of which is defined by expression of gastrin-releasing peptide receptor (GRPR). The GRPR cells are thought to be "tertiary pruritoceptors," conveying itch information to lamina I projection neurons of the anterolateral system (ALS). Surprisingly, we recently found that GRPR-expressing neurons belong to a morphological class known as vertical cells, which are believed to transmit nociceptive information to lamina I ALS cells. Little is currently known about synaptic circuits engaged by the GRPR cells. Here we combine viral-mediated expression of PSD95-tagRFP fusion protein with super-resolution microscopy to reveal sources of excitatory input to GRPR cells. We find that they receive a relatively sparse input from peptidergic and non-peptidergic nociceptors in SDH, and a limited input from A- and C-low threshold mechanoreceptors on their ventral dendrites. They receive synapses from several excitatory interneuron populations, including those defined by expression of substance P, neuropeptide FF, cholecystokinin, neurokinin B, and neurotensin. We investigated downstream targets of GRPR cells by chemogenetically exciting them and identifying Fos-positive (activated) cells. In addition to lamina I projection neurons, many ALS cells in lateral lamina V and the lateral spinal nucleus were Fos-positive, suggesting that GRPR-expressing cells target a broader population of projection neurons than was previously recognised. Our findings indicate that GRPR cells receive a diverse synaptic input from various types of primary afferent and excitatory interneuron, and that they can activate ALS cells in both superficial and deep regions of the dorsal horn.

P-127 - Stabilization of 68Ga-labeled [Thz14]Bombesin(7–14) analogue for imaging gastrin-releasing peptide receptor expression with positron emission tomography

P-127 - Stabilization of 68Ga-labeled [Thz14]Bombesin(7–14) analogue for imaging gastrin-releasing peptide receptor expression with positron emission tomography

Radiometal Complexes as Pharmacokinetic Modifiers: A Potent 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonist Based on the Macrocyclic Metal Chelator NODIA-Me.

The gastrin-releasing peptide receptor (GRPr) is overexpressed in various cancer types including prostate and breast carcinomas, making it an attractive target for molecular imaging and therapy. In this work, we designed a novel GRPr antagonistic probe comprising metal chelator NODIA-Me. This 1,4,7-triazacyclononane-based chelator forms positively charged metal complexes due to its neutral methylimidazole arms. Because a positive charge at the N-terminus of GRPr conjugates is responsible for high receptor affinity as exemplified by the current gold standard DOTA-RM2, we investigated if a positively charged radiometal complex can be used as a pharmacokinetic modifier to also produce high-affinity GRPr conjugates. In this respect, the bioconjugate NODIA-Me-Ahx-JMV594 was prepared by a combination of solid-phase peptide synthesis and solution-based reactions in a 94% yield. Radiolabeling provided the 68Ga-labeled conjugate in radiochemical yields of >95% and radiochemical purities of >98% with mean molar activities of Am ∼17 MBq nmol-1. The competitive GRPr affinity of the metal-free and 69/71Ga-labeled conjugate was determined to be IC50 = 0.41 ± 0.06 and 1.45 ± 0.06 nM, respectively. The metal-free GRPr antagonist DOTA-RM2 and its corresponding 69/71Ga complex had IC50 values of 1.42 ± 0.07 and 0.98 ± 0.19 nM, respectively. Small-animal PET imaging of mice bearing GRPr(+) PC-3 tumors revealed high radioactivity accumulation in the tumors and in the pancreas as an organ with high levels of GRPr expression. These findings were corroborated by the corresponding ex vivo biodistribution data, in which the tumors and the pancreas exhibited the highest radioactivity accumulation. By coinjection of an excess of NODIA-Me-Ahx-JMV594, uptake in the tumors and GRPr(+) organs was significantly reduced, confirming specific receptor-mediated uptake. The estrogen receptor-positive tumor of a female breast cancer patient was clearly visualized by PET imaging using 68Ga-labeled NODIA-Me-Ahx-JMV594. To summarize, the positive charge at the N-terminus of the conjugate induced by the Ga(NODIA-Me) complex resulted in high GRPr affinity comparable to that of the potent antagonist DOTA-RM2. The conjugate NODIA-Me-Ahx-JMV594 is a promising probe for imaging of GRPr tumors that warrants further evaluation in larger patient cohorts as well as in combination with other radiometals.

GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms

The gastrin-releasing peptide receptor (GRPR) binds to ligands such as gastrin-releasing peptide (GRP) and plays a variety of biological roles. In this study, we investigated the therapeutic effect of a novel gastrin-releasing peptide receptor antagonist RH-1402 in hyperuricemia-induced kidney fibrosis and its underlying mechanisms. We conducted enzyme linked immunosorbent assay (ELISA) and immunohistochemical analyses and found that proGRP and GRPR expression levels were significantly increased in patients with hyperuricemic nephropathy (HN) and HN mice. GRPR knockdown significantly attenuated inflammatory and fibrotic responses in adenosine-treated human proximal tubule epithelial cells. GRPR knockout or GRPR conditional knockout in renal tubular epithelial cells significantly alleviated the decline in renal function and fibrosis in HN mice in vivo. RNA-seq and String database analysis revealed that GRP/GRPR promoted HN by suppressing the ABCG2/PDZK1 and increasing TGF-β/Smad3 levels by activating the NF-κB pathway. Overexpression of GRPR increased TGF-β/Smad3 levels, where as it reduced ABCG2/PDZK1 levels in adenosine-treated HK2 cells, which was reversed by the NF-κB inhibitor. Furthermore, we evaluated the therapeutic effects of the novel GRPR inhibitor RH-1402 on hyperuricaemia-induced renal injury and evaluated the inflammatory and fibrosis responses in vivo and in vitro. Pre-treatment with RH-1402 attenuated hyperuricaemia-induced renal injury, restored renal function, and suppressed renal inflammation and fibrosis. Taken together, GRPR enhances hyperuricaemia-induced tubular injury, inflammation, and renal fibrosis via ABCG2-dependent mechanisms and may serve as a promising therapeutic target for HN treatment.

Zhenxin Anshen formula ameliorates atopic der-matitis-like skin dysfunction in mice and regulation of transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 in Neural pathways.

To investigate the efficacy of Zhenxin Anshen formula (, ZXAS) on atopic dermatitis (AD) by transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) signalling pathway in mice and . AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice. BALB/c mice were divided into five groups: normal control, model control, cetirizine, low-, medium-, and high-dose of ZXAS. After ZXAS in-tervention, the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines. Immun-oglobulin E (IgE), interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP) were de-tected by Enzyme-linked immunosorbent assay (ELISA). The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor (GRPR), TRPV1, and TRPA1 by using immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. In addition, 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, ELISA, and Western blotting were conducted for analysis of primary dorsal root ganglia (DRG) neurons . ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score, number of scratching and epidermal thickness, accompanied by the de-creased IgE and Th2 inflammatory cytokines. ZXAS also supressed the mRNA and protein expression of GRPR, TRPV1, and TRPA1 in the spinal cord. The medicated sera of ZXAS decreased capsaicin-induced Ca influx and downregulated the expression of TRPV1, TRPA1, and phospholipase C in DRG neurons. The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca2+ signals in neurons.

GRPR versus PSMA: expression profiles during prostate cancer progression demonstrate the added value of GRPR-targeting theranostic approaches.

Central to targeted radionuclide imaging and therapy of prostate cancer (PCa) are prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals. Gastrin-releasing peptide receptor (GRPR) targeting has been proposed as a potential additional approach for PCa theranostics. The aim of this study was to investigate to what extent and at what stage of the disease GRPR-targeting applications can complement PSMA-targeting theranostics in the management of PCa. Binding of the GRPR- and PSMA-targeting radiopharmaceuticals [177Lu]Lu-NeoB and [177Lu]Lu-PSMA-617, respectively, was evaluated and compared on tissue sections of 20 benign prostatic hyperplasia (BPH), 16 primary PCa and 17 progressive castration-resistant PCa (CRPC) fresh frozen tissue specimens. Hematoxylin-eosin and alpha-methylacyl-CoA racemase stains were performed to identify regions of prostatic adenocarcinoma and potentially high-grade prostatic intraepithelial neoplasia. For a subset of primary PCa samples, RNA in situ hybridization (ISH) was used to identify target mRNA expression in defined tumor regions. The highest median [177Lu]Lu-NeoB binding was observed in primary PCa samples, while median and overall [177Lu]Lu-PSMA-617 binding was highest in CRPC samples. The highest [177Lu]Lu-NeoB binding was observed in 3/17 CRPC samples of which one sample showed no [177Lu]Lu-PSMA-617 binding. RNA ISH analyses showed a trend between mRNA expression and radiopharmaceutical binding, and confirmed the distinct GRPR and PSMA expression patterns in primary PCa observed with radiopharmaceutical binding. Our study emphasizes that GRPR-targeting approaches can contribute to improved PCa management and complement currently applied PSMA-targeting strategies in both early and late stage PCa.

Modified PROMISE criteria for standardized interpretation of gastrin-releasing peptide receptor (GRPR)-targeted PET.

There are image interpretation criteria to standardize reporting prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET). As up to 10% of prostate cancer (PC) do not express PSMA, other targets such as gastrin-releasing peptide receptor (GRPR) are evaluated. Research on GRPR-targeted imaging has been slowly increasing in usage at staging and biochemical recurrence (BCR) of PC. We therefore propose a modification of the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria (mPROMISE) for GRPR-targeted PET. [68Ga]Ga-RM2 PET data from initially prospective studies performed at our institution were retrospectively reviewed: 44 patients were imaged for staging and 100 patients for BCR PC. Two nuclear medicine physicians independently evaluated PET according to the mPROMISE criteria. A third expert reader served as standard reference. Interreader reliability was computed for GRPR expression, prostate bed (T), lymph node (N), skeleton (Mb), organ (Mc) metastases, and final judgment of the scan. The interrater reliability for GRPR PET at staging was moderate for GRPR expression (0.59; 95% confidence interval [CI] 0.40, 0.78), substantial for T-stage (0.78; 95% CI 0.63, 0.94), and almost perfect for N-stage (0.97; 95% CI 0.92, 1.00) and final judgment (0.92; 95% CI 0.82, 1.00). The interreader agreement at BCR showed substantial agreement for GRPR expression (0.70; 95% CI 0.59, 0.81) and final judgment (0.65; 95% CI 0.53, 0.78), while almost perfect agreement was seen across the major categories (T, N, Mb, Mc). Acceptable performance of the mPROMISE criteria was found for all subsets when compared to the standard reference. Interpreting GRPR-targeted PET using the mPROMISE criteria showed its reliability with substantial or almost perfect interrater agreement across all major categories. The proposed modification of the PROMISE criteria will aid clinicians in decreasing the level of uncertainty, and clinical trials to achieve uniform evaluation, reporting, and comparability of GRPR-targeted PET. Clinicaltrials.gov Identifier: NCT03113617 and NCT02624518.

GRP/GRPR enhances alcohol-associated liver injury through the IRF1-mediated Caspase-1 inflammasome and NOX2-dependent ROS pathway.

The common characteristics of alcohol-associated liver injury (ALI) include abnormal liver function, infiltration of inflammatory cells, and generation of oxidative stress. The gastrin-releasing peptide receptor (GRPR) is activated by its neuropeptide ligand, gastrin-releasing peptide (GRP). GRP/GRPR appears to induce the production of cytokines in immune cells and promotes neutrophil migration. However, the effects of GRP/GRPR in ALI are unknown. We found high GRPR expression in the liver of patients with alcohol-associated steatohepatitis and increased pro-GRP levels in peripheral blood mononuclear cells of these patients compared with that of the control. Increased expression of GRP may be associated with histone H3 lysine 27 acetylation induced by alcohol, which promotes the expression of GRP and then GRPR binding. Grpr-/- and Grprflox/floxLysMCre mice alleviated ethanol-induced liver injury with relieved steatosis, lower serum alanine aminotransferase, aspartate aminotransferase, triglycerides, malondialdehyde, and superoxide dismutase levels, reduced neutrophil influx, and decreased expression and release of inflammatory cytokines and chemokines. Conversely, the overexpression of GRPR showed opposite effects. The pro-inflammatory and oxidative stress roles of GRPR might be dependent on IRF1-mediated Caspase-1 inflammasome and NOX2-dependent reactive oxygen species pathway, respectively. In addition, we verified the therapeutic and preventive effects of RH-1402, a novel GRPR antagonist, for ALI. A knockout or antagonist of GRPR during excess alcohol intake could have anti-inflammatory and antioxidative roles, as well as provide a platform for histone modification-based therapy for ALI.

Phase I Trial of [99mTc]Tc-maSSS-PEG2-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [99mTc]Tc-maSSS-PEG2-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 µg of [99mTc]Tc-maSSS-PEG2-RM26 (600-700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [99mTc]Tc-maSSS-PEG2-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 ± 0.0007 for male patients and 0.008 ± 0.003 mSv/MBq for female patients. The accumulation of [99mTc]Tc-maSSS-PEG2-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [99mTc]Tc-maSSS-PEG2-RM26 was safe and well tolerated. [99mTc]Tc-maSSS-PEG2-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies.

[99mTc]Tc-HYNIC-RM2: A potential SPECT probe targeting GRPR expression in prostate cancers

IntroductionElevated density of gastrin releasing peptide receptors (GRPR) in prostate cancer has led to exploration of several radiolabeled peptides for imaging and staging of the disease. The GRPR antagonist peptide RM2 has been successfully conjugated with several chelators and radiolabeled with gallium-68. The goal of this study was to synthesize a 99mTc-labeled probe and investigate its potential for SPECT imaging of prostate cancer. Towards this HYNIC-RM2 peptide conjugate was synthesized, radiolabeled with 99mTc and evaluated in GRPR-positive PC3 tumor xenografts. MethodsHYNIC-RM2 was manually synthesized by standard Fmoc solid phase strategy and radiolabeled with 99mTc. In vitro cell studies were performed in GRPR-positive human prostate carcinoma (PC3) cells. Metabolic stability studies of [99mTc]Tc-HYNIC-RM2 were performed in normal mice in the presence as well as absence of neutral endopeptidase (NEP) inhibitor, phosphoramidon (PA). Biodistribution and imaging studies of [99mTc]Tc-HYNIC-RM2 were performed in SCID mice bearing PC3-xenograft. Results[99mTc]Tc-HYNIC-RM2 exhibited high binding affinity in low nanomolar range (Kd = 1.83 ± 0.31 nM). Metabolic stability studies in mice indicated that in the absence of PA, radiolabeled peptide was about 65 % intact in the blood at 15 min p.i., whereas proportion of intact radiolabeled peptide was enhanced to 90 % on co-administration of PA. Biodistribution studies in PC3 tumor bearing mice demonstrated high tumor uptake (8.02 ± 0.9%ID/g and 6.13 ± 0.44%ID/g at 1 h and 3 h p.i.). Co-administration of PA with the radiolabeled peptide resulted in further enhancement of tumor uptake (14.24 ± 0.76 % ID/g and 11.71 ± 0.59%ID/g at 1 h and 3 h p.i.). SPECT/CT images of [99mTc]Tc-HYNIC-RM2 could clearly visualize the tumor. Significant (p < 0.001) reduction in the tumor uptake with a co-injected blocking dose of unlabeled peptide ascertained the GRPR specificity of [99mTc]Tc-HYNIC-RM2. ConclusionEncouraging results obtained in biodistribution and imaging studies indicate the potential of [99mTc]Tc-HYNIC-RM2 for further exploration as GRPR targeting agent.

Early Prediction of Radiation-Induced Pulmonary Fibrosis Using Gastrin-Releasing Peptide Receptor-Targeted PET Imaging.

Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe, [64Cu]Cu-NODAGA-galacto-bombesin (BBN), an analogue peptide of GRP. In this study, we evaluated the usefulness of [64Cu]Cu-NODAGA-galacto-BBN for the early prediction of RIPF. We prepared RIPF mice and acquired PET/CT images of [18F]F-FDG and [64Cu]Cu-NODAGA-galacto-BBN at 0, 2, 5, and 11 weeks after irradiation (n = 3-10). We confirmed that [64Cu]Cu-NODAGA-galacto-BBN targets GRPR in irradiated RAW 264.7 cells. In addition, we examined whether [64Cu]Cu-NODAGA-galacto-BBN monitors the therapeutic efficacy in RIPF mice (n = 4). As a result, the lung uptake ratio (irradiated-to-normal) of [64Cu]Cu-NODAGA-galacto-BBN was the highest at 2 weeks, followed by its decrease at 5 and 11 weeks after irradiation, which matched with the expression of GRPR and was more accurately predicted than [18F]F-FDG. These uptake results were also confirmed by the cell uptake assay. Furthermore, [64Cu]Cu-NODAGA-galacto-BBN could monitor the therapeutic efficacy of pirfenidone in RIPF mice. We conclude that [64Cu]Cu-NODAGA-galacto-BBN is a novel PET imaging probe for the early prediction of RIPF-targeting GRPR expressed during the inflammatory response.

Electroacupuncture reduces chronic itch via cannabinoid CB1 receptors in the ventrolateral periaqueductal gray.

Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at “Quchi” (LI11) and “Hegu” (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch via activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch.

P-271 - Preparation and cGMP-compliant production of the bombesin analogue [68Ga]Ga-NOTA-RM26 for first-in-human clinical study of gastrin-releasing peptide receptor expression in prostate cancer

P-271 - Preparation and cGMP-compliant production of the bombesin analogue [68Ga]Ga-NOTA-RM26 for first-in-human clinical study of gastrin-releasing peptide receptor expression in prostate cancer

P-311 - Synthesis and evaluation of 68Ga-labeled [Leu13ψThz14] Bombesin(7-14) analogues for imaging gastrin-releasing peptide receptor expression with positron emission tomography

P-311 - Synthesis and evaluation of 68Ga-labeled [Leu13ψThz14] Bombesin(7-14) analogues for imaging gastrin-releasing peptide receptor expression with positron emission tomography

Radiolabeled Bombesin Analogs

Simple SummaryRecent medical advancements have strived for a personalized medicine approach to patients, aimed at optimizing therapy outcomes with minimum toxicity. In this respect, nuclear medicine methodologies have been playing increasingly important roles. For example, the overexpression of peptide receptors, such as the gastrin-releasing peptide receptor (GRPR), on tumor cells as opposed to their lack of expression in healthy surrounding tissues can be elegantly exploited with the aid of “smart” peptide carriers, such as the analogs of the amphibian 14-peptide bombesin (BBN). These molecules can bring clinically attractive radionuclides to malignant lesions in prostate, breast, and other human cancers, sparing healthy tissues. Depending upon the radionuclide in question, diagnostic imaging with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) has been pursued, identifying patients who are eligible for peptide radionuclide receptor therapy (PRRT) in an integrated “theranostic” approach. In the present review, we (i) discuss the major steps taken in the development of anti-GRPR theranostic radioligands, with a focus on those selected for clinical testing; (ii) comment on the present status in this field of research; and (iii) reflect on the current limitations as well as on new opportunities for their broader and more successful clinical applications.The gastrin-releasing peptide receptor (GRPR) is expressed in high numbers in a variety of human tumors, including the frequently occurring prostate and breast cancers, and therefore provides the rationale for directing diagnostic or therapeutic radionuclides on cancer lesions after administration of anti-GRPR peptide analogs. This concept has been initially explored with analogs of the frog 14-peptide bombesin, suitably modified at the N-terminus with a number of radiometal chelates. Radiotracers that were selected for clinical testing revealed inherent problems associated with these GRPR agonists, related to low metabolic stability, unfavorable abdominal accumulation, and adverse effects. A shift toward GRPR antagonists soon followed, with safer analogs becoming available, whereby, metabolic stability and background clearance issues were gradually improved. Clinical testing of three main major antagonist types led to promising outcomes, but at the same time brought to light several limitations of this concept, partly related to the variation of GRPR expression levels across cancer types, stages, previous treatments, and other factors. Currently, these parameters are being rigorously addressed by cell biologists, chemists, nuclear medicine physicians, and other discipline practitioners in a common effort to make available more effective and safe state-of-the-art molecular tools to combat GRPR-positive tumors. In the present review, we present the background, current status, and future perspectives of this endeavor.

LBA02-07 PROSPECTIVE STUDY OF 68 GA-RM2 PET/MRI IN PATIENTS WITH BIOCHEMICALLY RECURRENT PROSTATE CANCER AND NEGATIVE CONVENTIONAL IMAGING

You have accessJournal of UrologyLate-breaking Abstract II - Malignant1 Sep 2021LBA02-07 PROSPECTIVE STUDY OF 68GA-RM2 PET/MRI IN PATIENTS WITH BIOCHEMICALLY RECURRENT PROSTATE CANCER AND NEGATIVE CONVENTIONAL IMAGING Lucia Baratto, Hong Song, Heying Duan, Farshad Moradi, Guido Davidzon, and Andrei Iagaru Lucia BarattoLucia Baratto More articles by this author , Hong SongHong Song More articles by this author , Heying DuanHeying Duan More articles by this author , Farshad MoradiFarshad Moradi More articles by this author , Guido DavidzonGuido Davidzon More articles by this author , and Andrei IagaruAndrei Iagaru More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002149.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 68Ga-RM2 is a synthetic bombesin receptor antagonist targeting gastrin-releasing peptide receptors (GRPr) that are overexpressed in several human tumors, including prostate cancer (PC). Men with biochemical recurrence (BCR) and negative CT/MRI and bone scintigraphy were evaluated for the presence of prostate cancer. METHODS: We enrolled 127 men with BCR PC, 45-83-year-old (mean±SD: 68.3±6.9). Imaging started at 40-89 minutes (mean±SD: 51.0±8.9) after injection of 113.8-152.6 MBq (mean±SD: 140.5±6.4) of 68Ga-RM2 using a time-of-flight (TOF)-enabled simultaneous positron emission tomography (PET) / magnetic resonance imaging (MRI) scanner. RESULTS: All patients had rising PSA and negative conventional imaging prior to enrollment. 68Ga-RM2 PET identified recurrent PC in 85 of the 127 participants. Positivity rate of 68Ga-RM2 PET was: 37.9% for PSA <0.5 ng/dl (n=29), 61.1% for PSA 0.5 – 1.0 ng/dl (n=18), 64.7% for PSA 1.0 – 2.0 ng/dl (n=17), 82.6% for PSA 2.0 – 5.0 ng/dl (n=23) and 87.5% for PSA >5.0 ng/dl (n=40). PSA velocity values were 1.9±2.7 ng/ml/year (range: 0-9.1) in patients with negative PET scans and 5.8±9 ng/ml/year (range: 0.2-45.4) in patients with positive PET scans (P: 0.01). CONCLUSIONS: 68Ga-RM2 PET identifies GRPr expression in BCR PC lesions despite negative conventional imaging, indicating it is a promising PET radiopharmaceutical in this clinical scenario. 68Ga-RM2 may identify higher risk patients given the highly statistically significant difference PSA velocity values between patients with negative and positive scans and may be a complementary radiopharmaceutical to the PSMA-targeting tracers to ultimately allow for personalized medicine. Source of Funding: DoD © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1178-e1178 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lucia Baratto More articles by this author Hong Song More articles by this author Heying Duan More articles by this author Farshad Moradi More articles by this author Guido Davidzon More articles by this author Andrei Iagaru More articles by this author Expand All Advertisement Loading ...

Diagnostic role of gastrin-releasing peptide receptors in oncology

Tumor receptor-targeted diagnostic imaging is an area of research that identifies a biomarker that is overexpressed on the surface of cancer cells and binds its ligand to carriers, allowing imaging of the tumor process. The success of this approach depends on the selectivity of the receptor for certain malignant cells, as well as on its ability to specifically bind to the target ligand. This review examines the diagnostic role of the bombesin family of receptors, which focus on gastrin-releasing peptide receptors (GRPR), which are overexpressed in various cancers. For tumors expressing GRPR, the diagnostic informativeness of the detection of both primary tumor foci and metastases is high. The well-known concept of tumor heterogeneity has led to the development of bivalent prostate cancer - target peptides with the ability to target two receptors. Radiolabeled bombesin analogues are promising theranostic agents for tumors that express GRPR, which opens the possibility of early detection of primary tumors and metastatic lesions with high sensitivity and specificity. At the same time, further forward-looking clinical trials are needed to improve understanding of the relationship between GRPR expression and the biological behavior of different cancer cells. Key words: gastrin-releasing peptide receptors, bombesin, theranostic, oncology

NFAT5 Is Involved in GRP-Enhanced Secretion of GLP-1 by Sodium.

Gastrin, secreted by G-cells, and glucagon-like peptide-1 (GLP-1), secreted by L-cells, may participate in the regulation of sodium balance. We studied the effect of sodium in mice in vivo and mouse ileum and human L-cells, on GLP-1 secretion, and the role of NFAT5 and gastrin-releasing peptide receptor (GRPR) in this process. A high-sodium diet increases serum GLP-1 levels in mice. Increasing sodium concentration stimulates GLP-1 secretion from mouse ileum and L-cells. GRP enhances the high sodium-induced increase in GLP-1 secretion. High sodium increases cellular GLP-1 expression, while low and high sodium concentrations increase NFAT5 and GRPR expression. Silencing NFAT5 in L-cells abrogates the stimulatory effect of GRP on the high sodium-induced GLP-1 secretion and protein expression, and the sodium-induced increase in GRPR expression. GLP-1 and gastrin decrease the expression of Na+-K+/ATPase and increase the phosphorylation of sodium/hydrogen exchanger type 3 (NHE3) in human renal proximal tubule cells (hRPTCs). This study gives a new perspective on the mechanisms of GLP-1 secretion, especially that engendered by ingested sodium, and the ability of GLP-1, with gastrin, to decrease Na+-K+/ATPase expression and NHE3 function in hRPTCs. These results may contribute to the better utilization of current and future GLP-1-based drugs in the treatment of hypertension.