Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

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Relevance of somatostatin receptor expression in pancreatic neuroendocrine tumors for treatment with somatostatin analogues

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0034-1372310 ◽

2014 ◽

Vol 122 (03) ◽

Author(s):

S Brede ◽

G Brabant ◽

N Begum ◽

H Lehnert ◽

C Thorns

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Somatostatin Analogues ◽

Receptor Expression ◽

Pancreatic Neuroendocrine Tumors

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Filamin-A is involved in stabilisation, signal transduction, and angiogenesis regulation mediated by somatostatin receptor 2 in pancreatic neuroendocrine tumors

Endocrine Abstracts ◽

10.1530/endoabs.37.gp.28.05 ◽

2015 ◽

Author(s):

Eleonora Vitali ◽

Valeria Cambiaghi ◽

Federica Loiarro ◽

Alessandro Zerbi ◽

Piergiuseppe Colombo ◽

...

Keyword(s):

Signal Transduction ◽

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Pancreatic Neuroendocrine Tumors ◽

Filamin A

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Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors

Endocrine Related Cancer ◽

10.1677/erc-09-0078 ◽

2010 ◽

Vol 17 (1) ◽

pp. R53-R73 ◽

Cited By ~ 257

Author(s):

Dik J Kwekkeboom ◽

Boen L Kam ◽

Martijn van Essen ◽

Jaap J M Teunissen ◽

Casper H J van Eijck ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Pet Imaging ◽

Tumor Regression ◽

Somatostatin Receptor ◽

Somatostatin Analogs ◽

Receptor Subtype ◽

Receptor Imaging ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Pet Tracer ◽

First Choice

Somatostatin receptor imaging (SRI) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Newer radiolabeled somatostatin analogs which can be used in positron emission tomography (PET) imaging, and which have a higher affinity for the somatostatin receptor, especially receptor subtype-2, have been developed. It would be desirable, however, if one radiolabeled analog became the new standard for PET imaging, because the current application of a multitude of analogs implies a fragmented knowledge on the interpretation of the images that are obtained in clinical practice. In our view, the most likely candidates for such a universal PET tracer for SRI are [68Ga-DOTA0,Tyr3]octreotate or [68Ga-DOTA0,Tyr3]octreotide. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all 111In-, 90Y-, or 177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy (PRRT). The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with [177Lu-DOTA0,Tyr3]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable GEPNETs.

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Internalized Somatostatin Receptor Subtype 2 in Neuroendocrine Tumors of Octreotide-Treated Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2487 ◽

2010 ◽

Vol 95 (5) ◽

pp. 2343-2350 ◽

Cited By ~ 40

Author(s):

Jean Claude Reubi ◽

Beatrice Waser ◽

Renzo Cescato ◽

Beat Gloor ◽

Christoph Stettler ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Receptor Autoradiography ◽

Receptor Expression ◽

Receptor Subtype ◽

High Dose ◽

Somatostatin Receptor Subtype 2 ◽

In Vitro Receptor Autoradiography

Abstract Context: Somatostatin receptor subtype 2 (sst2) is widely expressed in neuroendocrine tumors and can be visualized immunohistochemically at the cell membrane for diagnostic purposes. Recently, it has been demonstrated in animal sst2 tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst2. Patients and Methods: In the present study, we evaluated whether sst2 expressed in neuroendocrine tumors of patients treated with octreotide are also internalized. Tumor samples were assessed in patients that were treated with various octreotide modalities before and during surgery and compared with tumor samples from untreated patients. Sst2 immunohistochemistry was performed in all samples with three different sst2 antibodies (R2-88, UMB-1, and SS-800). Sst2 receptor expression was confirmed by immunoblotting and in vitro receptor autoradiography. Results: Patients receiving a high dose of octreotide showed predominantly internalized sst2, and patients with a low dose of octreotide had a variable ratio of internalized vs. membranous sst2, whereas untreated patients had exclusively membranous sst2. The internalized sst2 receptor corresponded to a single sst2 band in immunoblots and to sst2 receptors in in vitro receptor autoradiography. Although generally found in endosome-like structures, internalized sst2 receptors were also identified to a small extent in lysosomes, as seen in colocalization experiments. Conclusion: It is the first evidence showing that sst2 receptors can be internalized in sst2-expressing neuroendocrine tumors in patients under octreotide therapy, providing clues about sst2 receptor biology and trafficking dynamics in patients.

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