Figure 1 - uploaded by Oļesja Rogoza
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Structure of somatostatin-14 (A) and somatostatin-28 (B).
Source publication
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group...
Citations
... The emitted β-emission from the 177 Lu Lutathera preferentially binds to SSTR2, which is overexpressed in tumor cells and subsequently undergoes internalization. The emitted β-emission from the 177 Lu radionuclide induces cell damage by forming free radicals in the vicinity of SSTR2 and the adjacent cells [47,[56][57][58]. ...
Simple Summary
The extraordinary growth in the global pharmaceutical industry has extended to include peptides, which are amino acids linked together with an amide bond. Due to their well-tolerable safety profile and specificity, therapeutic peptides offer a means to address unmet medical challenges. A well-known example of a commonly administered peptide is insulin. Peptides are considered excellent complements and, in some cases, preferable alternatives to both small molecules such as paracetamol and very large antibodies. At present, around 100 peptide drugs are available on the global market, with ongoing research yielding over 150 peptides in clinical development and an additional 400–600 peptides undergoing preclinical studies. Peptides play a crucial role in cancer research and treatment, and they can be involved in various aspects of cancer development, detection, and treatment. These medicines demonstrate exceptional efficacy in combating cancer, contributing to improved survival rates for cancer patients.
Abstract
The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody–drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects.
... More than two-thirds of SST in the circulation is produced by gastrointestinal and pancreatic δ-cells, while the rest originates from the central nervous system (Ampofo et al., 2020). SST is released into the circulation through the portal venous system to exert its inhibitory effects on various endocrine effectors including GH, prolactin, thyrotropin, cholecystokinin, gastric inhibitory peptide, neurotensin, motilin, gastrin, secretin, glucagon, insulin, pancreatic polypeptide, and cytokines in immune cells (Ampofo et al., 2020;Rogoza et al., 2022). ...
Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.
... 45 receptor agonist, pasireotide, are available. SSAs have been shown to decrease growth hormone and insulin-like growth factor-I (IGF-I) levels in patients with acromegaly, 47 and contribute to progression-free survival in patients with NETs. 48 SSAs also inhibit the secretion of prolactin, thyrotropin, cholecystokinin, glucose-dependent insulinotropic polypeptide (GIP), gastrin, motilin, neurotensin, secretin, glucagon, insulin, and pancreatic polypeptide. ...
Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient’s treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients’ overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, ‘diabeto-oncology’, and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, ‘diabeto-oncology’ could represent a new specialized field that combines specific expertise, skills, and training.
... Highlighted in Table 1 are some of the peptides with receptors highly expressed on tumours. The best example is somatostatin (SST) receptor overexpression in neuroendocrine tumours (NETs), which are currently being targeted effectively with SST analogues, 111 In-DTPA-octreotide ( 111 In-OctreoScan) (Rogoza et al. 2022). ...
Targeted alpha therapy (TAT) has emerged as a viable therapeutic option for cancer management, due to its high target specificity and superlative ability to effectively disrupt the genetic make-up of the cancerous cells, thereby impeding their aggressive growth. TAT belongs to the category of radioligand therapies in oncology wherein alpha-emitting radionuclides are delivered directly to tumours and the tumour microenvironment with little impact on surrounding healthy cells. This approach is facilitated by chelating the radionuclides with ligands or conjugating them to targeting vehicles which facilitate their biodistribution, localization, and accumulation in the target sites. Currently, TAT continues to exhibit promising therapeutic outcomes in both preclinical and clinical evaluations, with more exciting prospects for the future. Accordingly, this timely review focuses on the pertinent, appealing merits of TAT, elaborating on the favourable chemical properties of potent alpha-emitting radionuclides and their enhancement. The current review also delves into the radiobiology and dosimetry of alpha-particles, and their application to TAT. Recent preclinical and clinical reports have further supported the viability of TAT as a promising therapeutic intervention. More so, this review sheds light on the promising therapeutic possibilities that nuclear medicine, particularly TAT, can offer in oncology.
... Similarly, METTL7B is critical for cell cycle progression and tumorigenesis in non-small cell lung cancer [67]. SSTR2 is a receptor that is often dysregulated in different types of tumors, including neuroendocrine tumors, breast cancer, lung cancer, and prostate cancer [68][69][70][71][72][73][74]. The activation of SSTR2 inhibits the proliferation of tumor cells primarily through growth arrests [75]. ...
Cuprotosis, an emerging mode of cell death, has recently caught the attention of researchers worldwide. However, its impact on low-grade glioma (LGG) patients has not been fully explored. To gain a deeper insight into the relationship between cuprotosis and LGG patients’ prognosis, we conducted this study in which LGG patients were divided into two clusters based on the expression of 18 cuprotosis-related genes. We found that LGG patients in cluster A had better prognosis than those in cluster B. The two clusters also differed in terms of immune cell infiltration and biological functions. Moreover, we identified differentially expressed genes (DEGs) between the two clusters and developed a cuprotosis-related prognostic signature through the least absolute shrinkage and selection operator (LASSO) analysis in the TCGA training cohort. This signature divided LGG patients into high- and low-risk groups, with the high-risk group having significantly shorter overall survival (OS) time than the low-risk group. Its predictive reliability for prognosis in LGG patients was confirmed by the TCGA internal validation cohort, CGGA325 cohort and CGGA693 cohort. Additionally, a nomogram was used to predict the 1-, 3-, and 5-year OS rates of each patient. The analysis of immune checkpoints and tumor mutation burden (TMB) has revealed that individuals belonging to high-risk groups have a greater chance of benefiting from immunotherapy. Functional experiments confirmed that interfering with the signature gene TNFRSF11B inhibited LGG cell proliferation and migration. Overall, this study shed light on the importance of cuprotosis in LGG patient prognosis. The cuprotosis-related prognostic signature is a reliable predictor for patient outcomes and immunotherapeutic response and can help to develop new therapies for LGG.
... For controlling tumor growth, several classes of therapeutics have been clinically utilized. Somatostatin receptors (SSTRs) are found upregulated in a variety of pNENs, making both imaging and therapeutic targeting technologies a promising therapeutic avenue [24]. Targeted therapy using somatostatin class mimics for SSTR2 to control hormone production is a first-line medicine treatment for most subtypes, with insulinomas excepted [25,26]. ...
Simple Summary
Pancreatic neuroendocrine neoplasms (pNENs) are a rare and understudied cancer. Some of this low knowledge base is due to a historical lack of study models. Study models have tremendous implications for validating data for a range of cancer research topics, including treatment development. Therefore, correctly choosing a model is imperative and needs to consider a range of factors pertinent to the research question. In this review, we summarized the current field of models in pNENs. We considered factors, including complexity, accuracy, and cost, in models ranging from cell line cultures, 3D cultures, and whole organismal models, including mice and zebrafish. Improving the number and quality of models available will lead to new breakthroughs in treating pNENs and may lead to findings beneficial for other cancers.
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors derived from multiple neuroendocrine origin cell subtypes. Incidence rates for pNENs have steadily risen over the last decade, and outcomes continue to vary widely due to inability to properly screen. These tumors encompass a wide range of functional and non-functional subtypes, with their rarity and slow growth making therapeutic development difficult as most clinically used therapeutics are derived from retrospective analyses. Improved molecular understanding of these cancers has increased our knowledge of the tumor biology for pNENs. Despite these advances in our understanding of pNENs, there remains a dearth of models for further investigation. In this review, we will cover the current field of pNEN models, which include established cell lines, animal models such as mice and zebrafish, and three-dimensional (3D) cell models, and compare their uses in modeling various disease aspects. While no study model is a complete representation of pNEN biology, each has advantages which allow for new scientific understanding of these rare tumors. Future efforts and advancements in technology will continue to create new options in modeling these cancers.
... In addition to being regarded as the mediators of glucose effects on glucagon secretion, insulin and somatostatin have been implicated in the regulation of mTORC1 [36,37]; hence, increased mTORC1 activity in alpha cells in diabetes may result from impaired paracrine inhibition by insulin and/or somatostatin. Therefore, we studied the effects of insulin and somatostatin on alpha cell mTORC1 activity and glucagon secretion. ...
... In contrast to beta cells, in which acute exposure to high glucose enhanced mTORC1 activity in the presence of AAs [39], in alpha cells the response to AAs was attenuated. This effect is probably mediated by somatostatin, which inhibits mTORC1 [37]. It is possible that somatostatin is an effective inhibitor of mTORC1 in alpha cells but not in beta cells. ...
Aim/hypothesis
Hyperglycaemia is associated with alpha cell dysfunction, leading to dysregulated glucagon secretion in type 1 and type 2 diabetes; however, the mechanisms involved are still elusive. The nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) plays a major role in the maintenance of alpha cell mass and function. We studied the regulation of alpha cell mTORC1 by nutrients and its role in the development of hyperglucagonaemia in diabetes.
Methods
Alpha cell mTORC1 activity was assessed by immunostaining for phosphorylation of its downstream target, the ribosomal protein S6, and glucagon, followed by confocal microscopy on pancreatic sections and flow cytometry on dispersed human and mouse islets and the alpha cell line, αTC1-6. Metabolomics and metabolic flux were studied by ¹³C glucose labelling in 2.8 or 16.7 mmol/l glucose followed by LC-MS analysis. To study the role of mTORC1 in mediating hyperglucagonaemia in diabetes, we generated an inducible alpha cell-specific Rptor knockout in the Akita mouse model of diabetes and tested the effects on glucose tolerance by IPGTT and on glucagon secretion.
Results
mTORC1 activity was increased in alpha cells from diabetic Akita mice in parallel to the development of hyperglycaemia and hyperglucagonaemia (two- to eightfold increase). Acute exposure of mouse and human islets to amino acids stimulated alpha cell mTORC1 (3.5-fold increase), whereas high glucose concentrations inhibited mTORC1 (1.4-fold decrease). The mTORC1 response to glucose was abolished in human and mouse diabetic alpha cells following prolonged islet exposure to high glucose levels, resulting in sustained activation of mTORC1, along with increased glucagon secretion. Metabolomics and metabolic flux analysis showed that exposure to high glucose levels enhanced glycolysis, glucose oxidation and the synthesis of glucose-derived amino acids. In addition, chronic exposure to high glucose levels increased the expression of Slc7a2 and Slc38a4, which encode amino acid transporters, as well as the levels of branched-chain amino acids and methionine cycle metabolites (~1.3-fold increase for both). Finally, conditional Rptor knockout in alpha cells from adult diabetic mice inhibited mTORC1, thereby inhibiting glucagon secretion (~sixfold decrease) and improving diabetes, despite persistent insulin deficiency.
Conclusions/interpretation
Alpha cell exposure to hyperglycaemia enhances amino acid synthesis and transport, resulting in sustained activation of mTORC1, thereby increasing glucagon secretion. mTORC1 therefore plays a major role in mediating alpha cell dysfunction in diabetes.
Data availability
All sequencing data are available from the Gene Expression Omnibus (GEO) repository (accession no. GSE154126; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154126)
Graphical Abstract
... Somatostatin (SST; Fig. 5a) is a naturally occurring neuropeptide composed of 14 amino acid residues (AGCKNFFWKTFTSC) with an intramolecular disulfide bond between Cys3 and Cys14. 155 SST plays a vital role in nervous systems despite its short half-life (around 3 min), inhibiting the secretion of growth hormone (GH) mediated by the growth hormone-releasing hormone (GHRH) from anterior pituitary somatotrophs. 156 In obese patients, GH secretion may be affected, with the subsequent responsivity of SST for suppressing insulin and glucagon. ...
Neurodegeneration is characterized by a disturbance in neurotransmitter-mediated signaling pathways. Recent studies have highlighted the significant role of transition metal ions, including Cu(i/ii), Zn(ii), and Fe(ii/iii), in neurotransmission, thereby making the coordination chemistry of neurotransmitters a growing field of interest in understanding signal dysfunction. This review outlines the physiological functions of transition metal ions and neurotransmitters, with the metal-binding properties of small molecule-based neurotransmitters and neuropeptides. Additionally, we discuss the structural and conformational changes of neurotransmitters induced by redox-active metal ions, such as Cu(i/ii) and Fe(ii/iii), and briefly describe the outcomes arising from their oxidation, polymerization, and aggregation. These observations have important implications for neurodegeneration and emphasize the need for further research to develop potential therapeutic strategies.
... Somatostatin receptors (SSTRs) are a common target for the treatment of neuroendocrine tumors (NETs) [112]. Octreotate is a peptide capable of SSTRs binding, which is used worldwide for the targeted delivery of radioactive isotopes to NETs [113,114]. ...
Copper-64 (T1/2 = 12.7 h) is a positron and beta-emitting isotope, with decay characteristics suitable for both positron emission tomography (PET) imaging and radiotherapy of cancer. Copper-67 (T1/2 = 61.8 h) is a beta and gamma emitter, appropriate for radiotherapy β-energy and with a half-life suitable for single-photon emission computed tomography (SPECT) imaging. The chemical identities of 64Cu and 67Cu isotopes allow for convenient use of the same chelating molecules for sequential PET imaging and radiotherapy. A recent breakthrough in 67Cu production opened previously unavailable opportunities for a reliable source of 67Cu with high specific activity and purity. These new opportunities have reignited interest in the use of copper-containing radiopharmaceuticals for the therapy, diagnosis, and theranostics of various diseases. Herein, we summarize recent (2018–2023) advances in the use of copper-based radiopharmaceuticals for PET, SPECT imaging, radiotherapy, and radioimmunotherapy.
... A different subtype may occupy tumour regions devoid of the expression of a given subtype. Furthermore, in advanced illness stages, the deletion or downregulation of SST2 is linked to a poorer prognosis, less sensitive imaging, and unsuccessful therapy with SST2-specific analogues due to poor tumour targeting [150]. For this reason, somatostatin analogues with an affinity for several receptor subtypes are of considerable interest since they can tackle the problems of receptor subtype co-expression and heterogeneous expression patterns. ...
Radiopharmaceutical therapy, which can detect and treat tumours simultaneously, was introduced more than 80 years ago, and it has changed medical strategies with respect to cancer. Many radioactive radionuclides have been developed, and functional, molecularly modified radiolabelled peptides have been used to produce biomolecules and therapeutics that are vastly utilised in the field of radio medicine. Since the 1990s, they have smoothly transitioned into clinical application, and as of today, a wide variety of radiolabelled radionuclide derivatives have been examined and evaluated in various studies. Advanced technologies, such as conjugation of functional peptides or incorporation of radionuclides into chelating ligands, have been developed for advanced radiopharmaceutical cancer therapy. New radiolabelled conjugates for targeted radiotherapy have been designed to deliver radiation directly to cancer cells with improved specificity and minimal damage to the surrounding normal tissue. The development of new theragnostic radionuclides, which can be used for both imaging and therapy purposes, allows for more precise targeting and monitoring of the treatment response. The increased use of peptide receptor radionuclide therapy (PRRT) is also important in the targeting of specific receptors which are overexpressed in cancer cells. In this review, we provide insights into the development of radionuclides and functional radiolabelled peptides, give a brief background, and describe their transition into clinical application.
