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Frontiers in Medicine 2023Breast Cancer (BC) is the most common cancer worldwide and, despite the advancements made toward early diagnosis and novel treatments, there is an urgent need to reduce... (Review)
Review
Breast Cancer (BC) is the most common cancer worldwide and, despite the advancements made toward early diagnosis and novel treatments, there is an urgent need to reduce its mortality. The Gastrin-Releasing Peptide Receptor (GRPR) is a promising target for the development of theranostic radioligands for luminal BC with positive estrogen receptor (ER) expression, because GRPR is expressed not only in primary lesions but also in lymph nodes and distant metastasis. In the last decades, several GRPR-targeting molecules have been evaluated both at preclinical and clinical level, however, most of the studies have been focused on prostate cancer (PC). Nonetheless, given the relevance of non-invasive diagnosis and potential treatment of BC through Peptide Receptor Radioligand Therapy (PRRT), this review aims at collecting the available preclinical and clinical data on GRPR-targeting radiopeptides for the imaging and therapy of BC, to better understand the current state-of-the-art and identify future perspectives and possible limitations to their clinical translation. In fact, since luminal-like tumors account for approximately 80% of all BC, many BC patients are likely to benefit from the development of GRPR-radiotheranostics.
PubMed: 38020178
DOI: 10.3389/fmed.2023.1250799 -
Pharmaceutics Nov 2023Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on... (Review)
Review
Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. Bombesin receptor ligands are effective drugs for the treatment of rheumatoid arthritis or gastrointestinal diseases. However, most diseases are complex, and the use of polytherapy may lead to pharmacokinetic and pharmacodynamic drug-drug interactions, resulting in side effects. Therefore, there is a need to develop effective compounds that also contain BN or its analogs, which are combined with other structural entities, thus generating a so-called hybrid drug. Hybrid drugs that contain bombesin pharmacophore(s) may be proposed as a solution to the problem of polytherapy or the lack of an effective cure. Such structures have now demonstrated the desired efficacy, though information on these aforementioned compounds is relatively scarce. Therefore, our paper aims to encourage researchers to focus on bombesins. Herein, we indicate that the hybrid approach should also be firmly applied to bombesins and the BN receptor family. This paper's structure is divided into two main sections demonstrating bombesins and their properties, as well as recent data on bombesin-based hybrid compounds and their potential usefulness in medicine. Overall, it refers to the discovery and synthesis of modified bombesin-based hybrid compounds.
PubMed: 38004575
DOI: 10.3390/pharmaceutics15112597 -
EMBO Reports Oct 2023A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in...
A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergic ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1 ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1 neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1 neurons form synapses with GRP receptor-expressing (GRPR ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1 neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1 neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.
Topics: Humans; Receptors, Bombesin; Gastrin-Releasing Peptide; Spinal Cord; Glutamic Acid; Dopamine; Pruritus; Dopaminergic Neurons; Receptors, AMPA
PubMed: 37522391
DOI: 10.15252/embr.202256098 -
Annals of Medicine Dec 2024This comprehensive review aims to explore the potential applications of Gastrin-releasing peptide receptor (GRPR) in the diagnosis and treatment of prostate cancer.... (Review)
Review
This comprehensive review aims to explore the potential applications of Gastrin-releasing peptide receptor (GRPR) in the diagnosis and treatment of prostate cancer. Additionally, the study investigates the role of GRPR in prognostic assessment for individuals afflicted with prostate cancer. The review encompasses a thorough examination of existing literature and research studies related to the upregulation of GRPR in various tumor types, with a specific focus on prostate. The review also evaluates the utility of GRPR as a molecular target in prostate cancer research, comparing its significance to the well-established Prostate-specific membrane antigen (PSMA). The integration of radionuclide-targeted therapy with GRPR antagonists is explored as an innovative therapeutic approach for individuals with prostate cancer. Research findings suggest that GRPR serves as a promising molecular target for visualizing low-grade prostate cancer. Furthermore, it is demonstrated to complement the detection of lesions that may be negative for PSMA. The integration of radionuclide-targeted therapy with GRPR antagonists presents a novel therapeutic paradigm, offering potential benefits for individuals undergoing treatment for prostate cancer. In conclusion, this review highlights the emerging role of GRPR in prostate cancer diagnosis and treatment. Moreover, the integration of radionuclide-targeted therapy with GRPR antagonists introduces an innovative therapeutic approach that holds promise for improving outcomes in individuals dealing with prostate cancer. The potential prognostic value of GRPR in assessing the disease's progression adds another dimension to its clinical significance in the realm of urology.
Topics: Male; Humans; Receptors, Bombesin; Prostatic Neoplasms; Biomarkers; Up-Regulation; Radioisotopes
PubMed: 38442298
DOI: 10.1080/07853890.2024.2320301 -
Cancer Imaging : the Official... Jan 2024GRPR is a type of seven-transmembrane G-protein coupled receptor that belongs to the bombesin protein receptor family. It is highly expressed in various cancers,... (Review)
Review
GRPR is a type of seven-transmembrane G-protein coupled receptor that belongs to the bombesin protein receptor family. It is highly expressed in various cancers, including prostate cancer, breast cancer, lung cancer, gastrointestinal cancer, and so on. As a result, molecular imaging studies have been conducted using radiolabeled GRPR ligands for tumor diagnosis, as well as monitoring of recurrence and metastasis. In this paper, we provided a comprehensive overview of relevant literature from the past two decades, with a specific focus on the advancements made in radiolabeled GRPR ligands for imaging prostate cancer and breast cancer.
Topics: Male; Humans; Positron Emission Tomography Computed Tomography; Receptors, Bombesin; Bombesin; Prostatic Neoplasms; Breast Neoplasms
PubMed: 38279185
DOI: 10.1186/s40644-024-00658-y -
Seminars in Nuclear Medicine Mar 2024The gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in breast cancer, making it a promising target for both imaging and therapy within a... (Review)
Review
The gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in breast cancer, making it a promising target for both imaging and therapy within a theranostic framework. Various radioligands targeting GRPR have undergone investigation in preclinical and clinical studies related to breast cancer. This systematic scoping review aimed to assess the current evidence on GRPR-targeted radioligands for diagnostic and therapeutic applications in breast cancer. The methodology followed the PRISMA-ScR protocol. The literature search was conducted in September 2023 and encompassed MEDLINE, Embase, Cochrane, and Scopus databases. We included original peer-reviewed studies focused on breast cancer patients or in vivo breast cancer models. Two reviewers performed the study selection process independently. Data were extracted, synthesized, and categorized into preclinical and clinical studies, further subdivided based on radioligand properties. A total of 35 original studies were included in the review, with three of them evaluating therapeutic outcomes. The results indicated that GRPR-radioantagonists are superior to GRPR-agonists, exhibiting preferable in vivo stability, rapid, specific tumor targeting, and enhanced retention. Both preclinical and clinical evaluations demonstrated renal excretion and high uptake in normal GRPR-expressing tissue, primarily the pancreas. A significant positive correlation was observed between GRPR and estrogen-receptor expression. In the clinical setting, GRPR-radioligands effectively detected primary tumors and, to a lesser extent, lymph node metastases. Moreover, GRPR-targeted radioantagonists successfully identified distant metastases originating from various sites in advanced metastatic disease, strongly correlated with positive estrogen receptor expression. Preclinical therapeutic evaluation of GRPR-radioligands labeled with lutetium-177 showed promising tumor responses, and none of the studies reported any observed or measured side effects, indicating a safe profile. In conclusion, the evidence presented in this review indicates a preference for GRPR-targeted antagonists over agonists, owing to their superior kinetics and promising diagnostic potential. Clinical assessments suggested diagnostic value for GRPR-targeted theranostics in breast cancer patients, particularly those with high estrogen receptor expression. Nevertheless, in the therapeutic clinical context, paying attention to the radiation dose administered to the pancreas and kidneys is crucial.
Topics: Humans; Female; Receptors, Bombesin; Breast Neoplasms; Precision Medicine; Receptors, Estrogen
PubMed: 38342656
DOI: 10.1053/j.semnuclmed.2024.01.004 -
Bioengineering & Translational Medicine Jul 2023We aimed to develop a new biocompatible gastrin-releasing peptide receptor (GRPR) targeted optical probe, IRDye800-RM26, for fluorescence image-guided surgery (FGS) of...
We aimed to develop a new biocompatible gastrin-releasing peptide receptor (GRPR) targeted optical probe, IRDye800-RM26, for fluorescence image-guided surgery (FGS) of brain malignancies in near-infrared window II (NIR-II) imaging. We developed a novel GRPR targeting probe using a nine-amino-acid bombesin antagonist analog RM26 combined with IRDye800CW, and explored the fluorescent probe according to optical properties. Fluorescence imaging characterization in NIR-I/II region was performed in vitro and in vivo. Following simulated NIR-II image-guided surgery, we obtained time-fluorescent intensity curves and time-signal and background ratio curves. Further, we used histological sections of brain from tumor-beating mice model to compare imaging specificity between 5-aminolevulinic acid (5-ALA) and IRDye800-RM26, and evaluated biodistribution and biocompatibility. IRDye800-RM26 had broad emission ranging from 800 to 1200 nm, showing considerable fluorescent intensity in NIR-II region. High-resolution NIR-II imaging of IRDye800-RM26 can enhance the advantages of NIR-I imaging. Dynamic and real time fluorescence imaging in NIR-II region showed that the probe can be used to treat brain malignancies in mice between 12 and 24 h post injection. Its specificity in targeting glioblastoma was superior to 5-ALA. Biodistribution analysis indicated IRDye800-RM26 excretion in the kidney and liver. Histological and blood test analyses did not reveal acute severe toxicities in mice treated with effective dose (40 μg) of the probe for NIR-II imaging. Because of the considerable fluorescent intensity in NIR-II region and high spatial resolution, biocompatible and excretable IRDye800-RM26 holds great potentials for FGS, and is essential for translation into human use.
PubMed: 37476052
DOI: 10.1002/btm2.10532 -
Theranostics 2024Lower-grade gliomas (LGGs) are a group of infiltrative growing glial brain tumors characterized by intricate intratumoral heterogeneity and subtle visual appearance... (Clinical Trial)
Clinical Trial
Lower-grade gliomas (LGGs) are a group of infiltrative growing glial brain tumors characterized by intricate intratumoral heterogeneity and subtle visual appearance differences from non-tumor tissue, which can lead to errors in pathologic tissue sampling. Although 5-ALA fluorescence has been an essential method for visualizing gliomas during surgery, its effectiveness is limited in the case of LGGs due to low sensitivity. Therefore, we developed a novel PET/NIR dual-modality image probe targeting gastrin-releasing peptide receptor (GRPR) in glioma cells to enhance tumor visualization and improve the accuracy of sampling. A prospective, non-randomized, single-center feasibility clinical trial (NCT03407781) was conducted in the referral center from October 21, 2016, to August 17, 2018. Consecutive enrollment included patients suspected of having LGGs and considered suitable candidates for surgical removal. Group 1 comprised ten patients who underwent preoperative Ga-IRDye800CW-BBN PET/MRI assessment followed by intraoperative fluorescence-guided surgery. Group 2 included 42 patients who underwent IRDye800CW-BBN fluorescence-guided surgery. The primary endpoints were the predictive value of preoperative PET imaging for intraoperative fluorescence and the sensitivity and specificity of fluorescence-guided sampling. Thirty-nine patients were included in the in-depth analysis of endpoints, with 25 (64.1%) exhibiting visible fluorescence, while 14 (35.9%) did not. The preoperative positive PET uptake exhibited a greater accuracy in predicting intraoperative fluorescence compared to MRI enhancement (100% [10/10] 87.2% [34/39]). A total of 125 samples were harvested during surgery. Compared with pathology, subjective fluorescence intensity showed a sensitivity of 88.6% and a specificity of 88.2% in identifying WHO grade III samples. For WHO grade II samples, the sensitivity and specificity of fluorescence were 54.7% and 88.2%, respectively. This study has demonstrated the feasibility of the novel dual-modality imaging technique for integrated pre- and intraoperative targeted imaging via the same molecular receptor in surgeries for LGGs. The PET/NIR dual-modality probe exhibits promise for preoperative surgical planning in fluorescence-guided surgery and provides greater accuracy in guiding tumor sampling compared to 5-ALA in patients with LGGs.
Topics: Humans; Receptors, Bombesin; Brain Neoplasms; Prospective Studies; Glioma; Aminolevulinic Acid; Positron-Emission Tomography
PubMed: 38169486
DOI: 10.7150/thno.91554 -
European Journal of Nuclear Medicine... Nov 2023NeoB and RM2 are the most investigated gastrin-releasing peptide receptor (GRPR)-targeting radiotracers in preclinical and clinical studies. Therefore, an extensive... (Comparative Study)
Comparative Study
INTRODUCTION
NeoB and RM2 are the most investigated gastrin-releasing peptide receptor (GRPR)-targeting radiotracers in preclinical and clinical studies. Therefore, an extensive side-by-side comparison of the two radiotracers is valuable to demonstrate whether one has advantages over the other. Accordingly, this study aims to compare the in vitro and in vivo characteristics of radiolabeled NeoB and RM2 to guide future clinical studies.
METHOD
The stability of the radiolabeled GRPR analogs was determined in phosphate buffered saline (PBS), and commercially available mouse and human serum. Target affinity was determined by incubating human prostate cancer PC-3 cells with [Lu]Lu-NeoB or [Lu]Lu-RM2, + / - increasing concentrations of unlabeled NeoB, RM2, or Tyr-bombesin (BBN). To determine uptake and specificity cells were incubated with [Lu]Lu-NeoB or [Lu]Lu-RM2 + / - Tyr-BBN. Moreover, in vivo studies were performed to determine biodistribution and pharmacokinetics. Finally, radiotracer binding to various GRPR-expressing human cancer tissues was investigated.
RESULTS
Both radiotracers demonstrated high stability in PBS and human serum, but stability in mouse serum decreased substantially over time. Moreover, both radiotracers demonstrated high GRPR affinity and specificity, but a higher uptake of [Lu]Lu-NeoB was observed in in vitro studies. In vivo, no difference in tumor uptake was seen. The most prominent difference in uptake in physiological organs was observed in the GRPR-expressing pancreas; [Lu]Lu-RM2 had less pancreatic uptake and a shorter pancreatic half-life than [Lu]Lu-NeoB. Furthermore, [Lu]Lu-RM2 presented with a lower tumor-to-kidney ratio, while the tumor-to-blood ratio was lower for [Lu]Lu-NeoB. The autoradiography studies revealed higher binding of radiolabeled NeoB to all human tumor tissues.
CONCLUSION
Based on these findings, we conclude that the in vivo tumor-targeting capability of radiolabeled NeoB and RM2 is similar. Additional studies are needed to determine whether the differences observed in physiological organ uptakes, i.e., the pancreas, kidneys, and blood, result in relevant differences in organ absorbed doses when the radiotracers are applied for therapeutic purposes.
Topics: Animals; Humans; Male; Mice; Biological Transport; Bombesin; Cell Line, Tumor; Prostatic Neoplasms; Receptors, Bombesin; Tissue Distribution
PubMed: 37584725
DOI: 10.1007/s00259-023-06364-4