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Neuroendocrine tumours
Published in Anju Sahdev, Sarah J. Vinnicombe, Husband & Reznek's Imaging in Oncology, 2020
Sairah R Khan, Kathryn L Wallitt, Adil Al-Nahhas, Tara D Barwick
Functional receptor imaging of NETs relies on the fact that many tumours express high levels of somatostatin receptors on their cell membranes, which can then be targeted with radiolabelled receptor ligands, both for diagnosis as well as for peptide receptor radionuclide therapy (PRRT). Of the five human somatostatin receptors (SSTR1–5), SSTR2 is the most commonly expressed on NET cell membranes (24).
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
Somatostatin (SST) is a cyclic peptide hormone that is expressed in the central and peripheral nervous systems and is present in two forms: SST-14 consisting of 14 amino acids and SST-28 consisting of 28 amino acids. SST inhibits the release of hormones such as growth hormone, glucagon, and insulin by binding to five different G-coupled SST cell membrane receptors (sstr1–5), which recognize the ligand and generate a transmembrane signal. The resulting hormone–receptor complexes have the ability to be internalized. Neuroendocrine tumors frequently express a high density of sstr, with the sstr2 subtype generally showing the highest density (Weckbecker et al. 2003).
Radionuclide imaging of carcinoid tumors, neurendocrine tumors of the pancreas and adrenals
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
There are five well-characterized SSTR subtypes expressed on the tumor cell surface: SSTR1 to SSTR5. The expression and the density of the SSTR subtypes vary among tumors [7], but SSTR2 is the predominantly expressed SSTR subtype on well-differentiated NETs, and it binds to various synthetic analogs of somatostatin (e.g., octreotide and lanreotide) with high affinity [8–10]. After a diagnosis of NET based on elevated biomarkers and clinical symptoms and confirmatory findings by CT or MRI, the goals for the initial SRI are the determination of disease extent and the identification of the primary tumor site to help formulate treatment planning. In the post-therapy setting, follow-up SRI studies are performed for surveillance, even without elevated biomarkers, to confirm the presence of recurrence. SRI can also be performed after surgery to ensure the completeness of resection and to confirm the presence or absence of recurrence after treatment.
Current strategies for the discovery and bioconjugation of smaller, targetable drug conjugates tailored for solid tumor therapy
Published in Expert Opinion on Drug Discovery, 2021
Mahendra P. Deonarain, Gokhan Yahioglu
The pentarin (which stands for penetrate, target) system developed by Tarveda, consists of small peptides that can be made into pentarin-drug conjugates (PDC). Their lead compound, is PEN-221, a somatostatin receptor-2 (SSTR2, which is expressed on neuroendocrine tumors) targeted DM1-maytansine payload. This conjugated to the disulfide-cyclized Tyr3-octreotate moiety and demonstrated picomolar affinity and rapid internalization. Doses of 1–2 mg/kg PEN221 were able to cure HCC33 (liver) and H524MD (lung) cancer tumor models in vivo given in 4 cycles on a weekly schedule with payload uptake achieved peaking within 2 hours [78]. Results presented at ASCO (2018) demonstrated that PEN221 was well-tolerated at doses up to 18 mg every 3 weeks with evidence of efficacy in the Phase 1 trial [79]. This product is now in a Phase 2 clinical study for SSTR2-expressing neuroendocrine and lung tumors. Another advanced compound, PEN866, is a PDC carrying the validated SN38 payload aimed at the heat-shock protein chaperone, HSP90. This is currently in a phase 1/2a clinical trial for solid cancers that are sensitive to topoisomerase I inhibitors and recent updates at the European Society for Medical Oncology (ESMO) and American Association for Cancer Research (AACR) conferences indicated good tolerability, clinical efficacy signals [80], measurable clinical uptake and good pharmacokinetic profile [81].
Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1
Published in Islets, 2021
Scott A. Campbell, Janyne Johnson, Peter E. Light
Alpha cell-derived peptides potentiate insulin release from beta cells and somatostatin release from delta cells. This occurs primarily via GLP-1 and glucagon signaling at the GLP-1R, and the relevance of beta cell GCGR activation by GLP-1 is unclear due to GLP-1’s relative potency at this receptor. GLP-1 has a bidirectional effect on alpha cells, whereby receptor activation in hyperglycemia inhibits alpha cell hormone release, and GLP-1 potentiates hormone release in hypoglycemia. So far, the GLP-1R has only been identified in a subpopulation of alpha cells. Insulin released from beta cells inhibits alpha cell hormone release and potentiates somatostatin release from delta cells. SSTR2 activation on both alpha and beta cells inhibits further hormone secretion by hyperpolarizing cells into a less-excitable state.
New insights into targeting hepatic cystogenesis in autosomal dominant polycystic liver and kidney disease
Published in Expert Opinion on Therapeutic Targets, 2020
Thijs R. M. Barten, Lucas H. P. Bernts, Joost P. H. Drenth, Tom J. G. Gevers
One way to reduce cAMP in cholangiocytes is by using somatostatin, a naturally occurring hormone that targets somatostatin receptors (SSTR) 1–5. Since natural somatostatin has a half-life of approximately 3 min, somatostatin analogues (SAs) with longer half-lives have been developed (e.g. octreotide with a high affinity for SSTR2 and SSTR5 and lanreotide with a high affinity for SSTR2 and minor affinity for SSTR5). Octreotide long-acting release (LAR) showed a reduction of both hepatic and renal cystic growth at 1 year and 3 years of administration in several studies with ADPKD patients [3,26,27]. These studies did not observe any beneficial effect on the estimated glomerular filtration rate (eGFR) decline, but one trial documented that fewer patients progressed from chronic kidney disease stage 4 to stage 5 [27]. Similarly, lanreotide reduced both hepatic and renal cyst growth in ADPLD and ADPKD patients in several large studies [3,28–30]. As total kidney volume (TKV) predicts disease progression in ADPKD, it was assumed that preventing renal cyst growth would also prevent eGFR decline [31]. This was refuted when a randomized trial showed that lanreotide did not affect eGFR decline but did reduce kidney and liver volume [28]. However, since only small changes in total liver volume (TLV) and TKV were observed over prolonged periods of time, alternative treatment options are needed.