• breast cancer
• igf-1r
• lanreotide
• sstr2
• trastuzumab deruxtecan therapy
• tsh-pitnet

• 1,4-disubstituted 1,2,3-triazole
• Entresto®
• amide-to-triazole substitution
• bioisosteres
• metabolic stability
• neprilysin
• pansomatostatin
• peptide-based radiotracer
• somatostatin
• triazolo-peptidomimetic

• P 31477 Austrian Science Fund FWF
• Open Access Funding University of Vienna
• P 31477-B28 FWF Austrian Science Fund

• SST/SSAs in cancer therapy
• colorectal cancer (CRC)
• mechanisms of antitumor activity
• neuroendocrine and non-endocrine tumors
• somatostatin (SST, SRIF)
• somatostatin analogues (SSAs)

• Cholesterol
• Fat
• Rat
• Somatostatin
• Stomach

Somatostatin, a growth hormone-release inhibiting peptide, exerts antiproliferative and antiangiogenic effects on tumor cells. However, the short half-life of somatostatin limits its application in human therapy, and long-acting somatostatin fusion protein is also limited by its severe terminal degradation. Therefore, oncolytic virus delivery system was introduced to express somatostatin fusion protein and the anti-tumor effects of both somatostatin and oncolytic virus were combined to destroy tumor tissues. Here, a vaccinia VG9/(SST-14)₂-HSA recombinant was constructed by replacing somatostatin fusion gene into TK locus of attenuated VG9 strain via homologous recombination. Results showed that vaccinia VG9/(SST-14)₂-HSA possessed a combined anti-tumor effect on sstr-positive tumor cells in vitro. In the tumor burden models, BALB/c mice with complete immunity are most suitable for evaluating tumor regression and immune activation. Complete tumor regression was observed in 3 out of 10 mice treated with vaccinia VG9/TK⁻ or VG9/(SST-14)₂-HSA, and the survival of all mice in both groups was significantly prolonged. Besides, vaccinia VG9/(SST-14)₂-HSA is more effective in prolonging survival than VG9/TK⁻. Vaccinia VG9/(SST-14)₂-HSA exerts a combined anti-tumor efficacy including the oncolytic ability provided by the virus and the anti-tumor effect contributed by (SST-14)₂-HSA, which is expected to become a potent therapeutic agent for cancer treatment.

Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists.

• 68Ga PET
• LU-DOTA-TATE
• neuroendocrine neoplasms
• peptide receptor radionuclide therapy
• somatostatin analogues
• somatostatin antagonists
• somatostatin receptors

• GRK2
• MAPK
• PDZ domain
• SYNJ2BP
• somatostatin receptor 2

• Extracellular Signal-Regulated MAP Kinases/metabolism
• G-Protein-Coupled Receptor Kinase 2/metabolism
• HEK293 Cells
• Humans
• MAP Kinase Signaling System
• Membrane Proteins/metabolism
• PDZ Domains
• Phosphorylation
• Receptors, Somatostatin/metabolism

• R01 DK106357 NIDDK NIH HHS
• National Institute of Diabetes and Digestive and Kidney Diseases
• Cancer Prevention and Research Institute of Texas

• CXCL14
• chemokine
• dorsal horn
• rat
• spinal cord

Primary hepatic neuroendocrine tumors (PHNETs), a group of neuroendocrine neoplasms, are extremely rare. There are only few case reports about PHNETs in the literature. The lack of large samples and multicenter research results in poor diagnostic and therapeutic approaches.

To discuss the clinical characteristics, diagnosis, and treatment of PHNETs and risk factors related to survival.

We retrospectively analyzed the clinical data, imaging features, immunohistochemistry data, and treatment efficacy of 40 patients who were pathologically diagnosed with PHNETs and admitted to The First Affiliated Hospital of Zhengzhou University from January 1, 2014 to November 15, 2019. Finally, survival analysis was performed to identify the risk factors for survival.

The main symptoms and signs included intermittent abdominal pain (19 patients, 47.5%) and bloating (8 patients, 20.0%). The positive rates of tested tumor markers were recorded as follows: Carbohydrate antigen 19-9 (CA19-9) (6 patients, 15.0%), CA72-4 (3 patients, 7.5%), carcinoembryonic antigen (7 patients, 17.5%), and alpha-fetoprotein (6 patients, 15.0%). Immunohistochemical staining results showed positivity for Syn in 38 (97.4%) of 39 patients, for chromogranin A in 17 (65.4%) of 26 patients, for CD56 in 35 (94.6%) of 37 patients, for AE1/AE3 in 28 (87.5%) of 32 patients, and for Ki-67 in all 40 (100.0%) patients. The overall survival rate was significantly related to the tumor grade, AE1/AE3, and Ki-67. No significant correlation was found between other parameters (age, gender, tumor number, tumor size, metastasis, and treatment) and overall survival.

Higher grade, negative AE1/AE3, and higher Ki-67 are associated with a worse survival rate. Kinds of treatment and other parameters have no significant influence on overall survival.

• Neuroendocrine tumors
• Primary hepatic neuroendocrine tumors
• Diagnosis
• Survival analysis
• Tumor grade
• Treatment

• imaging
• radiolabeling
• radionuclide therapy
• radiopharmaceuticals
• somatostatin analogs

• Amino Acid Sequence
• Animals
• Humans
• Neoplasms/diagnostic imaging
• Neoplasms/therapy
• Peptides/chemistry
• Radiopharmaceuticals/chemistry
• Receptors, Somatostatin/metabolism
• Somatostatin/agonists
• Somatostatin/analogs & derivatives
• Somatostatin/antagonists & inhibitors
• Somatostatin/therapeutic use
• Tissue Distribution

• N/A Ligue Contre le Cancer
• ANR-11-LABX-0018 Laboratoire d'Excellence IRON

Cancer became recently the leading cause of death in industrialized countries. Even though standard treatments achieve significant effects in growth inhibition and tumor elimination, they cause severe side effects as most of the applied drugs exhibit only minor selectivity for the malignant tissue. Hence, specific addressing of tumor cells without affecting healthy tissue is currently a major desire in cancer therapy. Cell surface receptors, which bind peptides are frequently overexpressed on cancer cells and can therefore be considered as promising targets for selective tumor therapy. In this review, the benefits of peptides as tumor homing agents are presented and an overview of the most commonly addressed peptide receptors is given. A special focus was set on the bombesin receptor family and the neuropeptide Y receptor family. In the second part, the specific requirements of peptide-drug conjugates (PDC) and intelligent linker structures as an essential component of PDC are outlined. Furthermore, different drug cargos are presented including classical and recent toxic agents as well as radionuclides for diagnostic and therapeutic approaches. In the last part, boron neutron capture therapy as advanced targeted cancer therapy is introduced and past and recent developments are reviewed.

• GPCR
• boron neutron capture therapy
• cancer
• peptide
• peptide-drug conjugate

Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves’ orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula).

• Somatostatin analog
• cancer
• carcinoid
• lanreotide
• neuroendocrine tumor
• octreotide
• pasireotide
• pituitary adenoma

• Antineoplastic Agents, Hormonal/therapeutic use
• Diabetic Retinopathy/drug therapy
• Diabetic Retinopathy/pathology
• Graves Ophthalmopathy/drug therapy
• Graves Ophthalmopathy/pathology
• Growth Hormone-Secreting Pituitary Adenoma/drug therapy
• Growth Hormone-Secreting Pituitary Adenoma/genetics
• Growth Hormone-Secreting Pituitary Adenoma/pathology
• Humans
• Intestinal Neoplasms/drug therapy
• Intestinal Neoplasms/genetics
• Intestinal Neoplasms/pathology
• Macular Edema/drug therapy
• Macular Edema/pathology
• Neuroendocrine Tumors/drug therapy
• Neuroendocrine Tumors/genetics
• Neuroendocrine Tumors/pathology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Pituitary Neoplasms/drug therapy
• Pituitary Neoplasms/pathology
• Somatostatin/analogs & derivatives
• Somatostatin/genetics
• Somatostatin/therapeutic use
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology

• Lanreotide depot
• Neuroendocrine tumors
• Octreotide LAR
• Real‐world
• Somatostatin analogs

• Cohort Studies
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Neuroendocrine Tumors/secondary
• Neuroendocrine Tumors/therapy
• Retrospective Studies

• Ipsen Biopharmaceuticals

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST₅ > SST₂ > SST₃ > SST₁). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands.

• neuroendocrine tumors
• pituitary adenomas
• somatostatin receptor ligands
• somatostatin receptors

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.

• GLP-1
• GnRH
• LHRH
• cancer
• chemical linker
• diabetes
• drug discovery
• mixed-mode pharmacology
• obesity
• peptide
• peptide-drug conjugate

• Evans blue
• TATE
• neuroendocrine tumor (NET)
• peptide receptor radionuclide therapy (PRRT)
• somatostatin receptor (SSTR)

• Adult
• Coordination Complexes/adverse effects
• Coordination Complexes/pharmacokinetics
• Coordination Complexes/therapeutic use
• Evans Blue
• Female
• Humans
• Kidney/radiation effects
• Lutetium/adverse effects
• Lutetium/pharmacokinetics
• Lutetium/therapeutic use
• Male
• Middle Aged
• Neuroendocrine Tumors/metabolism
• Neuroendocrine Tumors/radiotherapy
• Neuroendocrine Tumors/secondary
• Octreotide/adverse effects
• Octreotide/analogs & derivatives
• Octreotide/pharmacokinetics
• Octreotide/therapeutic use
• Organometallic Compounds
• Positron Emission Tomography Computed Tomography
• Radioisotopes/adverse effects
• Radioisotopes/pharmacokinetics
• Radioisotopes/therapeutic use
• Radiopharmaceuticals/adverse effects
• Radiopharmaceuticals/pharmacokinetics
• Radiopharmaceuticals/therapeutic use
• Radiotherapy Dosage
• Single Photon Emission Computed Tomography Computed Tomography
• Somatostatin/adverse effects
• Somatostatin/analogs & derivatives
• Somatostatin/metabolism
• Somatostatin/pharmacokinetics
• Somatostatin/therapeutic use
• Tissue Distribution
• Whole Body Imaging

• bombesin
• cancer GPCR
• cancer RTK
• cancer signal transduction
• neurotensin
• pituitary adenylate cyclase activating polypeptide (PACAP)
• somatostatin
• vasoactive intestinal peptide

Cancer is the second leading cause of death affecting nearly one in two people, and the appearance of new cases is projected to rise by >70% by 2030. To effectively combat the menace of cancer, a variety of strategies have been exploited. Among them, the development of peptide–drug conjugates (PDCs) is considered as an inextricable part of this armamentarium and is continuously explored as a viable approach to target malignant tumors. The general architecture of PDCs consists of three building blocks: the tumor-homing peptide, the cytotoxic agent and the biodegradable connecting linker. The aim of the current review is to provide a spherical perspective on the basic principles governing PDCs, as also the methodology to construct them. We aim to offer basic and integral knowledge on the rational design towards the construction of PDCs through analyzing each building block, as also to highlight the overall progress of this rapidly growing field. Therefore, we focus on several intriguing examples from the recent literature, including important PDCs that have progressed to phase III clinical trials. Last, we address possible difficulties that may emerge during the synthesis of PDCs, as also report ways to overcome them.

• PDC
• bioconjugates
• cancer
• drug delivery
• peptide
• peptide–drug conjugate
• side-products in PDCs

Purpose: Radionuclide therapy directed against tumors that express somatostatin receptors (SSTRs) has proven effective for the treatment of advanced, low- to intermediate-grade neuroendocrine tumors in the clinic. In clinical usage, somatostatin peptide-based analogs, labeled with therapeutic radionuclides, provide an overall response rate of about 30%, despite the high cumulative activity injected per patient. We set out to improve the effectiveness of somatostatin radiotherapy by preparing a chemical analog that would clear more slowly through the urinary tract and, concomitantly, have increased blood circulation half-life and higher targeted accumulation in the tumors. Experimental Design: We conjugated a common, clinically-used SST peptide derivative, DOTA-octreotate, to an Evans blue analog (EB), which reversibly binds to circulating serum albumin. The resulting molecule was used to chelate ⁸⁶Y and ⁹⁰Y, a diagnostic and a therapeutic radionuclide, respectively. The imaging capabilities and the radiotherapeutic efficacy of the resulting radioligand was evaluated in HCT116/SSTR2, HCT116, and AR42J cell lines that express differing levels of SST2 receptors. Results: The synthesized radiopharmaceutical retained affinity and specificity to SSTR2. The new molecule also retained the high internalization rate of DOTA-octreotate, and therefore, showed significantly higher accumulation in SSTR2-positive tumors. Labeling of our novel EB-octreotate derivative with the therapeutic, pure beta emitter, ⁹⁰Y, resulted in improved tumor response and survival rates of mice bearing SSTR2 xenografts and had long term efficacy when compared to DOTA-octreotate itself. Conclusions: The coupling of a targeted peptide, a therapeutic radionuclide, and the EB‑based albumin binding provides for effective treatment of SSTR2-containing tumors.

• Evans blue
• PET
• SSTR2
• albumin.
• peptide radiotherapy

• CXCL14
• chemokine
• gut
• mouse
• somatostatin

Gastrinomas are functionally active pancreatic neuroendocrine tumors (NETs) secreting gastrin and are associated with local or regional metastases in 60% of the cases. Somatostatin analogs (SSAs) are currently recommended as a first-line treatment for the symptomatic treatment of NETs. Although antiproliferative activity of SSAs has been demonstrated in various cancer types in several in vivo and in vitro studies, clinical benefits with SSAs have been only achieved in a small proportion of patients. We report a disease control on a long-acting SSA lanreotide in a patient with metastatic gastrinoma. A 60-year-old man, who had previously undergone a surgical resection of metastatic pancreatic gastrinoma, presented with abdominal bloating, edema in the lower limbs, fatigue, and weight loss. The gastrinoma relapse with additional metastases in the pancreas, duodenum, and liver was confirmed by positron emission tomography-computed tomography (PET-CT) scan; the patient's blood gastrin level was >5,000 ng/L. Treatment with the SSA octreotide long-acting release was initiated to treat the gastrinoma relapse. On the CT scan done in September 2011, the liver metastases were still identifiable. In December 2011, the treatment was switched to lanreotide Autogel® (120 mg every 2 weeks). Following the treatment, the gastrin levels were reduced to <1,200 ng/L in September 2013, and 812 ng/L in July 2016. Since November 2012, the gastrinoma lesions were no longer visible in abdominal CT. At the time of this report, the patient's gastrinoma was under control with lanreotide Autogel®. This case report supports the use of lanreotide Autogel® as effective treatment for metastatic gastrinoma.

• Case report
• Gastrinoma
• Gastroenteropancreatic neuroendocrine tumors
• Lanreotide
• Liver metastasis
• Somatostatin analogs

• consensus
• diagnosis
• guideline
• neuroendocrine tumor
• treatment

• SCLC
• V2r
• antitumor
• neuroendocrine tumors
• prostate cancer
• vasopressin analogs

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs.

We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines.

sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies.

sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs.

• angiogenesis
• gastroenteropancreatic neuroendocrine tumors
• neuroendocrine tumors
• sst5TMD4
• sst5TMD5

• castration-resistant
• docetaxel
• neuroendocrine transdifferentiation
• octreotide
• prostate cancer
• somatostatin analogues
• somatostatin receptor scintigraphy