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Associated Methods
Published in Lars-Inge Larsson, Immunocytochemistry: Theory and Practice, 2020
I believe that the techniques for studying ligand binding to fixed tissue sections by immunocytochemistry will never be universally accepted. Thus, as already stated, kinetic parameters cannot readily be obtained. Much unspecific binding of ligands will occur in most situations and enzymes, binding proteins, and other unspecific factors all will operate. Evidence for binding of gastrin-releasing peptide [14-27] to hypothalamic magnocellular neurons has been presented and considered to be due to binding to neurophysin.80 Moreover, if a real interaction takes place, it is reasonable to assume that part of the ligand structure will become masked by the receptor protein. This was directly shown for the a subunit of human chorionic gonadotropin.74 Therefore, most antibodies would be unable to detect the ligand-receptor complex. This was realized by Lackie et al.59 who employed a dimeric ligand for studying bombesin receptors on small cell carcinoma cells of lung. In this study, Lys3-bombesin was dimerized by glutaraldehyde. It was felt that one part of the dimer would interact with the receptor on live cultured cells and that the other part would be free to interact with a monoclonal bombesin antibody which subsequently was detected by indirect immunogold staining.59 Staining of cells was obtained and could be competed for by monomeric bombesin.59 The biological activity of the bombesin dimer was not given.
Non-FDG radionuclide imaging and targeted therapies
Published in Anju Sahdev, Sarah J. Vinnicombe, Husband & Reznek's Imaging in Oncology, 2020
Luigi Aloj, Ferdia A Gallagher
Gastrin-releasing peptide (GRP)/bombesin receptors are another target of interest for cancer diagnosis and therapy. These G-protein coupled regulatory peptide receptors have high physiological expression in the pancreas but low levels in other normal tissues. Overexpression of these receptors has been documented in cancers with endocrine features, most notably prostate and breast cancers (37,38). Originally, technetium-99m labelled peptides were developed (39), and more recently 68Ga labelling has been utilized (40,41). There are examples of early clinical application in prostate cancer (40,42) and in breast cancer (43). There is evidence that these receptors are more prominently expressed in well-differentiated prostate tumours and could be useful in initial staging (44). In breast cancer, expression of these targets is related to integrity and response of the oestrogen receptor pathway. Imaging with these agents may be utilized to characterize lesions where oestrogen receptor positivity is retained (43).
Radiolabeled Agents for Molecular Imaging and/or Therapy
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Dimitrios Psimadas, Eirini A. Fragogeorgi
Slightly modified analogs of the universal BN ligand (Pradhan et al. 1998) bind with high affinity to all bombesin receptor subtypes and were coupled to diethylenetriaminepentaacetic acid (DTPA) and DOTA using γ-aminobutyric acid as a spacer. The resulting panbombesin analogs radiolabeled with 111In, 177Lu, or 90Y exhibited high and specific uptake in GRPR-positive tissue (pancreas) and tumor (Zhang et al. 2004).
Imaging of pancreatic neuroendocrine tumors: recent advances, current status, and controversies
Published in Expert Review of Anticancer Therapy, 2018
Lingaku Lee, Tetsuhide Ito, Robert T. Jensen
In general, all of this has changed. It is now clear that panNETs as well as NETs in other locations are increasing in frequency, and whether it is because of increased detection or increased occurrence is not clear [293]. Also, there have been large strides in the pathology of NETs, with the development of classification/grading systems that have prognostic value and can influence patient management [1,2]. Insights from these pathologic studies have begun to have an impact on therapeutic approaches in other more frequent, aggressive tumors such as prostate cancer [294–296]. From the pathological studies of panNETs and other NETs, it has become clear that they frequently over-express G-protein-coupled receptors from a number of families (especially somatostatin, GLP1, bombesin) and from that arose the concept that these could be used to localize these tumors, as well as later, to treat them [99]. From these observations developed the use of radiolabeled somatostatin analogs to imagine the tumors, which is now the most sensitive localization method available [20,99]. Furthermore, using other radiolabeled somatostatin analogs, it has been possible to treat these tumors, because almost all overexpress somatostatin receptors, if well differentiated [96,99]. This latter point has been shown in a recent Phase-3 study [97]. This methodology is now being investigated for the diagnosis, imaging and treatment of prostate cancer using radiolabeled bombesin receptor analogs [294,295]. Furthermore, it is now realized that a significant proportion of panNETs and NETs in other locations pursue an aggressive course, and can cause considerable morbidity [1–3]. This has led to a number of double-blind Phase-3 studies of antitumor treatment for malignant panNETs and/or patients with other NETs in other locations with advanced diseases [297–300]. These include studies demonstrating the antiproliferative efficacy of somatostatin analogs; the mTOR inhibitor, everolimus and the tyrosine kinase inhibitor, sunitinib [297–300].
Lack of bombesin receptor-activated protein homologous protein impairs hippocampal synaptic plasticity and promotes chronic unpredictable mild stress induced behavioral changes in mice
Published in Stress, 2023
Xueping Yao, Xiaoqun Qin, Hui Wang, Jiaoyun Zheng, Zhi Peng, Jie Wang, Horst Christian Weber, Rujiao Liu, Wenrui Zhang, Ji Zeng, Suhui Zuo, Hui Chen, Yang Xiang, Chi Liu, Huijun Liu, Lang Pan, Xiangping Qu
In our recent studies, we have found the homologous protein of bombesin receptor-activated protein (BRAP) might be involved in the development of mood disorders in mice. BRAP, encoded by C6orf89 in human, is a protein of 354 amino acids, and contains a transmembrane sequence within its N terminus. It was found by our group in a bacteria two-hybrid search as a potential partner that interacts with bombesin receptor subtype-3 (BRS-3), an orphan receptor belonging to mammalian bombesin receptor family (H. J. Liu et al., 2011；Qu et al., 2013) . BRAP shares about 83% identity to its homologous protein in mice, which is encoded by bc004004 gene. In our previous studies, we found that overexpression of BRAP could inhibit the transcriptional activity of NF-κB in cultured human bronchial epithelial cells and suppress the antigen uptake ability of those cells (Y. Liu et al., 2016). In order to further elucidate the mechanisms underlying its biological role, we constructed a gene knockout mouse bc004004−/− in which bc004004 was disrupted by CRISPR/Cas9-mediated genome engineering (Wang et al., 2022). When maintaining and handling those mice we observed reduced aggressive behaviors in the knockout mice. Further behavioral tests suggested that the male bc004004−/− mice exhibited mild anxiety-like behaviors. And western blot analysis of brain tissues revealed that the homologous protein of BRAP was also expressed in mouse brain, indicating a potential role of this protein in nervous system. Therefore, we treated bc004004−/− mice with chronic unpredictable mild stress (CUMS) to examine the possible role of BRAP homologous protein in mood disorders. By using this model we found that mice deficient in BRAP homologous protein exhibited vulnerability to stress-related disorders. Furthermore, lack of BRAP homologous protein led to changes in synapses of hippocampus in mice, which might contribute to behavioral changes in those mice induced by stressful events. Our findings of the current study provide evidence that BRAP homologous protein plays a role in brain function.
Gastrin-releasing peptide receptor agonists and antagonists for molecular imaging of breast and prostate cancer: from pre-clinical studies to translational perspectives
Published in Expert Review of Molecular Diagnostics, 2022
Joana Gorica, Maria Silvia De Feo, Luca Filippi, Viviana Frantellizzi, Orazio Schillaci, Giuseppe De Vincentis
The management of patients with prostate cancer might be improved by the use of GRPR molecular imaging. The pre-clinical study of Rinne et al. has demonstrated the high-affinity binding and excellent uptake of the antagonist RM26 in GRPR-expressing tumors. The quick clearance from the circulation of 68Ga-, 55/57Co- and 111In-labeled RM26 variants allowed to clearly visualize GRPR expression in pre-clinical models. Rinne et al. have also undergone a clinical study on 28 healthy volunteers, patients with newly diagnosed prostate cancer, and post-therapy patients showing the safety and feasibility of 68Ga-RM26 for imaging of GRPR-expressing primary tumors, as well as lymph node and bone metastases [30]. PET and SPECT images are important for diagnosing small lesions. The use of 55/57Co and 111In-labeled RM26 demonstrated a greater contrast and better tumor detection in the later image acquisitions due to the clearance of the tracer from healthy tissue. PET imaging has a higher sensitivity than SPECT, but there is a shortage of long-life positron-emitting radionuclides suitable to allow image acquisition after multiple hours and at late time points. In this regard, gallium-66 (66Ga) has a half-life of 9.5 h making it a suitable candidate, but its high energy, 4,15 MeV could unfavorably impact on spatial resolution [30]. Fassbender et al. compared [68Ga]Ga-RM2-PET to histopathology, showing a good accuracy for patients with prostate cancer. They included in their study 15 patients before undergoing radical prostatectomy [31]. Gesche et al. used 68Ga-RM2-PET/CT in a selected population of patients with biochemically recurrent prostate cancer and a negative or inconclusive [18F]fluoroethylcholine (18FECH)-PET/CT scans. 68Ga-RM2-PET/CT managed to find prostate cancer relapse in the majority of the cases [32]. Nock et al. have introduced GRPR-antagonist [68Ga]SB3 ([68Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), showing precise tumor localizing in animal models and in patients. NeoBOMB1 was radiolabeled with the GRPR-antagonist radioligands [67Ga/111In/177Lu], and their behavior in prostate cancer models showed promising theranostic use in GRPR-positive cancer patients [33]. Kähkönen et al. used [(68)Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) to detect primary and metastatic prostate cancer using PET/CT. BAY86-7548 has a high affinity to bombesin receptor subtype II; therefore, it was synthesized and evaluated for prostate cancer, and it showed promising results in detecting intraprostatic prostate cancer [34].