Prognostic Implications, Modifications & Therapeutic Strategies Targeting Somatostatin Receptor-2 Expression in Gastroenteropancreatic Neuroendocrine Tumors
Main Article Content
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are a diverse group of tumors often characterized by somatostatin receptor type 2 (SSTR2) positivity. The objective of this article is to review basic information on GEP NETs and somatostatin receptors (SSTR) with a focus on SSTR2. The prognostic implications of the receptor, how epigenetic modifications play a role, and the diagnostic and therapeutic strategies available that rely on the somatostatin receptor including somatostatin analogs (SSAs), SSTR-based imaging, and peptide receptor radionuclide therapy (PRRT) are explored. While surgery is the only curative option, current therapy for SSTR2 positive GEP NETs is based on the use of SSAs which have been shown to both control symptoms and exert antiproliferative effects in SSTR2 positive GEP NETs. SSTR-based imaging offers numerous benefits over standard imaging techniques including revealing additional metastases, assessing response to therapy, and by demonstrating sufficient SSTR expression in tumors to render patients eligible for PRRT. PRRT has been shown to be an effective treatment in low grade, SSTR2 positive GEP NETs. Adjuncts are being investigated to synergize with PRRT and improve patient outcomes. Complete responses to SSA and PRRT are rare and SSTR2 negative tumors have limited treatment options. Given that GEP NETs have a low frequency of mutations and no mutations in SSTR2 have been identified, efforts are being made to investigate epigenetic regulations influencing SSTR2 expression as a future therapeutic option.
Keywords:
Somatostatin receptor, somatostatin analog, neuroendocrine tumor, epigenetics
Article Details
How to Cite
REMER, Lindsay F. et al.
Prognostic Implications, Modifications & Therapeutic Strategies Targeting Somatostatin Receptor-2 Expression in Gastroenteropancreatic Neuroendocrine Tumors.
Medical Research Archives, [S.l.], v. 13, n. 2, feb. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6309>. Date accessed: 16 mar. 2025.
doi: https://doi.org/10.18103/mra.v13i2.6309.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Das S, Dasari A. Epidemiology, Incidence, and Prevalence of Neuroendocrine Neoplasms: Are There Global Differences? Curr Oncol Rep. Mar 14 2021;23(4):43. doi:10.1007/s11912-021-01029-7
2. Kos-Kudla B, Cwikla J, Ruchala M, et al. Current treatment options for gastroenteropancreatic neuroendocrine tumors with a focus on the role of lanreotide. Contemp Oncol (Pozn). 2017;21(2):115-122. doi:10.5114/wo.2017.68619
3. Forsythe SD, Pu T, Andrews SG, Madigan JP, Sadowski SM. Models in Pancreatic Neuroendocrine Neoplasms: Current Perspectives and Future Directions. Cancers (Basel). Jul 25 2023;15(15)doi:10.3390/cancers15153756
4. Diez M, Teule A, Salazar R. Gastroenteropancreatic neuroendocrine tumors: diagnosis and treatment. Ann Gastroenterol. 2013;26(1):29-36.
5. Refardt J, Zandee WT, Brabander T, et al. Inferior outcome of neuroendocrine tumor patients negative on somatostatin receptor imaging. Endocr-Relat Cancer. Nov 2020;27(11):615-624. doi:10.1530/Erc-20-0340
6. Klomp MJ, Dalm SU, de Jong M, Feelders RA, Hofland J, Hofland LJ. Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer. Rev Endocr Metab Disord. Sep 2021;22(3):495-510. doi:10.1007/s11154-020-09607-z
7. Rogoza O, Megnis K, Kudrjavceva M, Gerina-Berzina A, Rovite V. Role of Somatostatin Signalling in Neuroendocrine Tumours. Int J Mol Sci. Jan 27 2022;23(3)doi:10.3390/ijms23031447
8. Zamora V, Cabanne A, Salanova R, et al. Immunohistochemical expression of somatostatin receptors in digestive endocrine tumours. Dig Liver Dis. Mar 2010;42(3):220-5. doi:10.1016/j.dld.2009.07.018
9. Kulaksiz H, Eissele R, Rossler D, et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut. Jan 2002;50(1):52-60. doi:10.1136/gut.50.1.52
10. Qian ZR, Li T, Ter-Minassian M, et al. Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors. Pancreas. Nov 2016;45(10):1386-1393. doi:10.1097/MPA.0000000000000700
11. Hu HF, Hu YH, Xu XW, et al. Role of Somatostatin Receptor 2 in Nonfunctional Pancreatic Neuroendocrine Tumors: Clinicopathological Analysis of 223 Cases and Whole Exome Sequencing of a Multifocal Case. Pancreas. Nov-Dec 01 2022;51(10):1404-1410. doi:10.1097/MPA.0000000000002199
12. Stueven AK, Kayser A, Wetz C, et al. Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future. Int J Mol Sci. Jun 22 2019;20(12)doi:10.3390/ijms20123049
13. Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. Jan 5 1973;179(4068):77-9. doi:10.1126/science.179.4068.77
14. Pradayrol L, Jornvall H, Mutt V, Ribet A. N-terminally extended somatostatin: the primary structure of somatostatin-28. FEBS Lett. Jan 1 1980;109(1):55-8. doi:10.1016/0014-5793(80)81310-x
15. Warren TG, Shields D. Expression of preprosomatostatin in heterologous cells: biosynthesis, posttranslational processing, and secretion of mature somatostatin. Cell. Dec 1984;39(3 Pt 2):547-55. doi:10.1016/0092-8674(84)90461-6
16. Francis BH, Baskin DG, Saunders DR, Ensinck JW. Distribution of somatostatin-14 and somatostatin-28 gastrointestinal-pancreatic cells of rats and humans. Gastroenterology. Nov 1990;99(5):1283-91. doi:10.1016/0016-5085(90)91151-u
17. Patel YC, Greenwood MT, Warszynska A, Panetta R, Srikant CB. All five cloned human somatostatin receptors (hSSTR1-5) are functionally coupled to adenylyl cyclase. Biochem Biophys Res Commun. Jan 28 1994;198(2):605-12. doi:10.1006/bbrc.1994.1088
18. Bell GI, Yasuda K, Kong H, Law SF, Raynor K, Reisine T. Molecular biology of somatostatin receptors. Ciba Found Symp. 1995;190:65-79; discussion 80-8. doi:10.1002/9780470514733.ch5
19. Costanzi E, Simioni C, Conti I, et al. Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives. J Cell Physiol. Apr 2021;236(4):2505-2518. doi:10.1002/jcp.30062
20. Chaudhary PK, Kim S. An Insight into GPCR and G-Proteins as Cancer Drivers. Cells. Nov 24 2021;10(12)doi:10.3390/cells10123288
21. Alexander SP, Christopoulos A, Davenport AP, et al. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein-coupled receptors. Br J Pharmacol. Dec 2017;174 Suppl 1(Suppl Suppl 1):S17-S129. doi:10.1111/bph.13878
22. Li YG, Meng XY, Yang X, et al. Structural insights into somatostatin receptor 5 bound with cyclic peptides. Acta Pharmacol Sin. Jun 26 2024;doi:10.1038/s41401-024-01314-8
23. Gunther T, Tulipano G, Dournaud P, et al. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol Rev. Oct 2018;70(4):763-835. doi:10.1124/pr.117.015388
24. Yamada Y, Stoffel M, Espinosa R, 3rd, et al. Human somatostatin receptor genes: localization to human chromosomes 14, 17, and 22 and identification of simple tandem repeat polymorphisms. Genomics. Feb 1993;15(2):449-52. doi:10.1006/geno.1993.1088
25. Papotti M, Bongiovanni M, Volante M, et al. Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. May 2002;440(5):461-75. doi:10.1007/s00428-002-0609-x
26. Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W. Regulation and function of somatostatin receptors. J Neurochem. Jun 2004;89(5):1057-91. doi:10.1111/j.1471-4159.2004.02402.x
27. Piwko C, Thoss VS, Schupbach E, et al. Pharmacological characterisation of human cerebral cortex somatostatin SRIF1 and SRIF2 receptors. Naunyn Schmiedebergs Arch Pharmacol. Feb 1997;355(2):161-7. doi:10.1007/pl00004927
28. Bocci G, Culler MD, Fioravanti A, et al. In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists. Eur J Clin Invest. Sep 2007;37(9):700-8. doi:10.1111/j.1365-2362.2007.01848.x
29. Thermos K. Functional mapping of somatostatin receptors in the retina: a review. Vision Res. Aug 2003;43(17):1805-15. doi:10.1016/s0042-6989(03)00169-x
30. Atkinson H, England JA, Rafferty A, et al. Somatostatin receptor expression in thyroid disease. Int J Exp Pathol. Jun 2013;94(3):226-9. doi:10.1111/iep.12024
31. Kumar U, Sasi R, Suresh S, et al. Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes. Jan 1999;48(1):77-85. doi:10.2337/diabetes.48.1.77
32. Voros I, Saghy E, Pohoczky K, et al. Somatostatin and Its Receptors in Myocardial Ischemia/Reperfusion Injury and Cardioprotection. Front Pharmacol. 2021;12:663655. doi:10.3389/fphar.2021.663655
33. Watanabe N, Nakanishi Y, Kinukawa N, et al. Expressions of Somatostatin Receptor Subtypes (SSTR-1, 2, 3, 4 and 5) in Neuroblastic Tumors; Special Reference to Clinicopathological Correlations with International Neuroblastoma Pathology Classification and Outcomes. Acta Histochem Cytochem. 2014;47(5):219-29. doi:10.1267/ahc.14024
34. Kaemmerer D, Trager T, Hoffmeister M, et al. Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget. Sep 29 2015;6(29):27566-79. doi:10.18632/oncotarget.4491
35. Cives M, Kunz PL, Morse B, et al. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr Relat Cancer. Feb 2015;22(1):1-9. doi:10.1530/ERC-14-0360
36. Kumar U, Singh S. Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity. Int J Mol Sci. Apr 7 2020;21(7)doi:10.3390/ijms21072568
37. Somvanshi RK, Jhajj A, Heer M, Kumar U. Characterization of somatostatin receptors and associated signaling pathways in pancreas of R6/2 transgenic mice. Biochim Biophys Acta Mol Basis Dis. Feb 2018;1864(2):359-373. doi:10.1016/j.bbadis.2017.11.002
38. Di Muro G, Catalano R, Treppiedi D, et al. The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells. Int J Mol Sci. Mar 23 2024;25(7)doi:10.3390/ijms25073606
39. Yao Q, Liu Q, Xu H, et al. Upregulated Expression of SSTR3 is Involved in Neuronal Apoptosis After Intracerebral Hemorrhage in Adult Rats. Cell Mol Neurobiol. Nov 2017;37(8):1407-1416. doi:10.1007/s10571-017-0471-7
40. War SA, Kim B, Kumar U. Human somatostatin receptor-3 distinctively induces apoptosis in MCF-7 and cell cycle arrest in MDA-MB-231 breast cancer cells. Mol Cell Endocrinol. Sep 15 2015;413:129-44. doi:10.1016/j.mce.2015.06.019
41. Lee M, Lupp A, Mendoza N, et al. SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary. Endocr Relat Cancer. Feb 2015;22(1):111-9. doi:10.1530/ERC-14-0472
42. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. Jul 1999;20(3):157-98. doi:10.1006/frne.1999.0183
43. Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging. May 2003;30(5):781-93. doi:10.1007/s00259-003-1184-3
44. Borzsei R, Zsido BZ, Balint M, Helyes Z, Pinter E, Hetenyi C. Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4. Int J Mol Sci. Jun 21 2022;23(13)doi:10.3390/ijms23136878
45. Van Op den Bosch J, Torfs P, De Winter BY, et al. Effect of genetic SSTR4 ablation on inflammatory peptide and receptor expression in the non-inflamed and inflamed murine intestine. J Cell Mol Med. Sep 2009;13(9B):3283-95. doi:10.1111/j.1582-4934.2009.00760.x
46. Van Op den Bosch J, van Nassauw L, Lantermann K, van Marck E, Timmermans JP. Effect of intestinal inflammation on the cell-specific expression of somatostatin receptor subtypes in the murine ileum. Neurogastroenterol Motil. Jul 2007;19(7):596-606. doi:10.1111/j.1365-2982.2007.00931.x
47. Sandoval KE, Farr SA, Banks WA, et al. Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice. Eur J Pharmacol. Mar 1 2011;654(1):53-9. doi:10.1016/j.ejphar.2010.12.013
48. Kecskes A, Pohoczky K, Kecskes M, et al. Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains. Int J Mol Sci. Oct 21 2020;21(20)doi:10.3390/ijms21207788
49. Patel YC. Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest. Jun 1997;20(6):348-67. doi:10.1007/BF03350317
50. Corleto VD, Falconi M, Panzuto F, et al. Somatostatin receptor subtypes 2 and 5 are associated with better survival in well-differentiated endocrine carcinomas. Neuroendocrinology. 2009;89(2):223-30. doi:10.1159/000167796
51. Taboada GF, Luque RM, Bastos W, et al. Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol. Jan 2007;156(1):65-74. doi:10.1530/eje.1.02313
52. Srirajaskanthan R, Watkins J, Marelli L, Khan K, Caplin ME. Expression of somatostatin and dopamine 2 receptors in neuroendocrine tumours and the potential role for new biotherapies. Neuroendocrinology. 2009;89(3):308-14. doi:10.1159/000179899
53. Wang YH, Wang W, Jin KZ, et al. Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors. Oncol Lett. Mar 2017;13(3):1165-1174. doi:10.3892/ol.2017.5591
54. Mehta S, de Reuver PR, Gill P, et al. Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors. Medicine (Baltimore). Oct 2015;94(40):e1281. doi:10.1097/MD.0000000000001281
55. Childs A, Vesely C, Ensell L, et al. Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours. Br J Cancer. Dec 6 2016;115(12):1540-1547. doi:10.1038/bjc.2016.377
56. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. Oct 1 2009;27(28):4656-63. doi:10.1200/JCO.2009.22.8510
57. Caplin ME, Pavel M, Ruszniewski P. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. Oct 16 2014;371(16):1556-7. doi:10.1056/NEJMc1409757
58. Khan MS, El-Khouly F, Davies P, Toumpanakis C, Caplin ME. Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel). Aliment Pharmacol Ther. Jul 2011;34(2):235-42. doi:10.1111/j.1365-2036.2011.04693.x
59. Pedraza-Arevalo S, Ibanez-Costa A, Blazquez-Encinas R, et al. Epigenetic and post-transcriptional regulation of somatostatin receptor subtype 5 (SST(5) ) in pituitary and pancreatic neuroendocrine tumors. Mol Oncol. Feb 2022;16(3):764-779. doi:10.1002/1878-0261.13107
60. Fuentes-Fayos AC, ME GG, Perez-Gomez JM, et al. Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival, Increased Aggressiveness Features, and Somatostatin Analogs Resistance. Int J Mol Sci. Jan 20 2022;23(3)doi:10.3390/ijms23031143
61. Gahete MD, Rincon-Fernandez D, Duran-Prado M, et al. The truncated somatostatin receptor sst5TMD4 stimulates the angiogenic process and is associated to lymphatic metastasis and disease-free survival in breast cancer patients. Oncotarget. Sep 13 2016;7(37):60110-60122. doi:10.18632/oncotarget.11076
62. Hormaechea-Agulla D, Jimenez-Vacas JM, Gomez-Gomez E, et al. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer. FASEB J. Nov 2017;31(11):4682-4696. doi:10.1096/fj.201601264RRR
63. Lehman JM, Hoeksema MD, Staub J, et al. Somatostatin receptor 2 signaling promotes growth and tumor survival in small-cell lung cancer. Int J Cancer. Mar 1 2019;144(5):1104-1114. doi:10.1002/ijc.31771
64. Sagie N, Romanov E, Kezerle Y, Meirovitz A, Sheva K. Expression Analysis of SSTR 1, 2 and 3 in Small-cell Lung Cancer Patients as Targets for Future Peptide Receptor Radionuclide Therapy. Anticancer Res. Sep 2024;44(9):3807-3812. doi:10.21873/anticanres.17206
65. Tsuta K, Wistuba, II, Moran CA. Differential expression of somatostatin receptors 1-5 in neuroendocrine carcinoma of the lung. Pathol Res Pract. Aug 15 2012;208(8):470-4. doi:10.1016/j.prp.2012.05.014
66. Lapa C, Hanscheid H, Wild V, et al. Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. Oncotarget. Apr 12 2016;7(15):20033-40. doi:10.18632/oncotarget.7706
67. Sen F, Sheikh GT, von Hinten J, et al. In-Vivo Somatostatin-Receptor Expression in Small Cell Lung Cancer as a Prognostic Image Biomarker and Therapeutic Target. Cancers (Basel). Jul 13 2023;15(14)doi:10.3390/cancers15143595
68. Rauch H, Kitzberger C, Janghu K, et al. Combining [(177)Lu]Lu-DOTA-TOC PRRT with PARP inhibitors to enhance treatment efficacy in small cell lung cancer. Eur J Nucl Med Mol Imaging. Jul 18 2024;doi:10.1007/s00259-024-06844-1
69. Menke JR, Raleigh DR, Gown AM, Thomas S, Perry A, Tihan T. Somatostatin receptor 2a is a more sensitive diagnostic marker of meningioma than epithelial membrane antigen. Acta Neuropathol. Sep 2015;130(3):441-3. doi:10.1007/s00401-015-1459-3
70. Anis SE, Lotfalla M, Zain M, Kamel NN, Soliman AA. Value of SSTR2A and Claudin - 1 in Differentiating Meningioma from Schwannoma and Hemangiopericytoma. Open Access Maced J Med Sci. Feb 15 2018;6(2):248-253. doi:10.3889/oamjms.2018.062
71. Durand A, Champier J, Jouvet A, et al. Expression of c-Myc, neurofibromatosis Type 2, somatostatin receptor 2 and erb-B2 in human meningiomas: relation to grades or histotypes. Clin Neuropathol. Sep-Oct 2008;27(5):334-45. doi:10.5414/npp27334
72. Rachinger W, Stoecklein VM, Terpolilli NA, et al. Increased 68Ga-DOTATATE uptake in PET imaging discriminates meningioma and tumor-free tissue. J Nucl Med. Mar 2015;56(3):347-53. doi:10.2967/jnumed.114.149120
73. Ivanidze J, Roytman M, Lin E, et al. Gallium-68 DOTATATE PET in the Evaluation of Intracranial Meningiomas. J Neuroimaging. Sep 2019;29(5):650-656. doi:10.1111/jon.12632
74. Wu W, Zhou Y, Wang Y, et al. Clinical Significance of Somatostatin Receptor (SSTR) 2 in Meningioma. Front Oncol. 2020;10:1633. doi:10.3389/fonc.2020.01633
75. Mawrin C, Schulz S, Pauli SU, et al. Differential expression of sst1, sst2A, and sst3 somatostatin receptor proteins in low-grade and high-grade astrocytomas. J Neuropathol Exp Neurol. Jan 2004;63(1):13-9. doi:10.1093/jnen/63.1.13
76. He JH, Wang J, Yang YZ, et al. SSTR2 is a prognostic factor and a promising therapeutic target in glioma. Am J Transl Res. 2021;13(10):11223-11234.
77. Ostrom QT, Bauchet L, Davis FG, et al. The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. Jul 2014;16(7):896-913. doi:10.1093/neuonc/nou087
78. Reubi JC, Lang W, Maurer R, Koper JW, Lamberts SW. Distribution and biochemical characterization of somatostatin receptors in tumors of the human central nervous system. Cancer Res. Nov 1 1987;47(21):5758-64.
79. Tarkin JM, Calcagno C, Dweck MR, et al. (68)Ga-DOTATATE PET Identifies Residual Myocardial Inflammation and Bone Marrow Activation After Myocardial Infarction. J Am Coll Cardiol. May 21 2019;73(19):2489-2491. doi:10.1016/j.jacc.2019.02.052
80. Bhanat E, Koch CA, Parmar R, Garla V, Vijayakumar V. Somatostatin receptor expression in non-classical locations - clinical relevance? Rev Endocr Metab Disord. Jun 2018;19(2):123-132. doi:10.1007/s11154-018-9470-3
81. Li L, Tian Y, He Y. Late Pseudoprogression: A Potential Pitfall in 68Ga-DOTATATE PET/CT for Glioma. Clin Nucl Med. Apr 1 2023;48(4):e207-e208. doi:10.1097/RLU.0000000000004511
82. Sampedro-Nunez M, Luque RM, Ramos-Levi AM, et al. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors. Oncotarget. Feb 9 2016;7(6):6593-608. doi:10.18632/oncotarget.6565
83. Fan S, Zheng H, Zhan Y, et al. Somatostatin receptor2 (SSTR2) expression, prognostic implications, modifications and potential therapeutic strategies associates with head and neck squamous cell carcinomas. Crit Rev Oncol Hematol. Jan 2024;193:104223. doi:10.1016/j.critrevonc.2023.104223
84. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. Nov 26 2020;6(1):92. doi:10.1038/s41572-020-00224-3
85. Lechner M, Schartinger VH, Steele CD, et al. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. Nat Commun. Jan 5 2021;12(1):117. doi:10.1038/s41467-020-20308-8
86. Viswanathan K, Sadow PM. Somatostatin receptor 2 is highly sensitive and specific for Epstein-Barr virus-associated nasopharyngeal carcinoma. Hum Pathol. Nov 2021;117:88-100. doi:10.1016/j.humpath.2021.08.004
87. Patel R, Marano G, Joseph J, Chung J, Plata A, Vos JA. (18) F-fludeoxyglucose positron emission computed tomography ((18) F-FDG-PET/CT) versus (68) Ga-DOTATATE-PET/CT in patients with head and neck cancer: Comparisons and implications for treatment. Head Neck. Feb 2023;45(2):347-354. doi:10.1002/hed.27243
88. Juntikka T, Vaittinen S, Vahlberg T, Jyrkkio S, Minn H. Somatostatin Receptors and Chemokine Receptor CXCR4 in Lymphomas: A Histopathological Review of Six Lymphoma Subtypes. Front Oncol. 2021;11:710900. doi:10.3389/fonc.2021.710900
89. Dalm VA, Hofland LJ, Mooy CM, et al. Somatostatin receptors in malignant lymphomas: targets for radiotherapy? J Nucl Med. Jan 2004;45(1):8-16.
90. Ferone D, Semino C, Boschetti M, Cascini GL, Minuto F, Lastoria S. Initial staging of lymphoma with octreotide and other receptor imaging agents. Semin Nucl Med. Jul 2005;35(3):176-85. doi:10.1053/j.semnuclmed.2005.03.001
91. Priyadarshini S, Allison DB, Chauhan A. Comprehensive Assessment of Somatostatin Receptors in Various Neoplasms: A Systematic Review. Pharmaceutics. Jul 1 2022;14(7)doi:10.3390/pharmaceutics14071394
92. Gatto F, Hofland LJ. The role of somatostatin and dopamine D
receptors in endocrine tumors. Endocr-Relat Cancer. Dec 2011;18(6):R233-R251. doi:10.1530/Erc-10-0334
93. Okuwaki K, Kida M, Mikami T, et al. Clinicopathologic Characteristics of Pancreatic Neuroendocrine Tumors and Relation of Somatostatin Receptor Type 2A to Outcomes. Cancer-Am Cancer Soc. Dec 1 2013;119(23):4094-4102. doi:10.1002/cncr.28341
94. van Adrichem RC, Kamp K, van Deurzen CH, et al. Is There an Additional Value of Using Somatostatin Receptor Subtype 2a Immunohistochemistry Compared to Somatostatin Receptor Scintigraphy Uptake in Predicting Gastroenteropancreatic Neuroendocrine Tumor Response? Neuroendocrinology. 2016;103(5):560-6. doi:10.1159/000441604
95. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. Jul 17 2014;371(3):224-33. doi:10.1056/NEJMoa1316158
96. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. Jan 12 2017;376(2):125-135. doi:10.1056/NEJMoa1607427
97. Di Domenico A, Wiedmer T, Marinoni I, Perren A. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer. Sep 2017;24(9):R315-R334. doi:10.1530/ERC-17-0012
98. Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet. Aug 2016;17(8):487-500. doi:10.1038/nrg.2016.59
99. Sharma R, Earla B, Baidoo KE, et al. Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model. Mol Cancer Ther. Sep 5 2023;22(9):1052-1062. doi:10.1158/1535-7163.MCT-22-0798
100. Mensah IK, Norvil AB, AlAbdi L, et al. Misregulation of the expression and activity of DNA methyltransferases in cancer. NAR Cancer. Dec 2021;3(4):zcab045. doi:10.1093/narcan/zcab045
101. Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet. Nov 2021;37(11):1012-1027. doi:10.1016/j.tig.2021.05.002
102. Angeloni A, Bogdanovic O. Sequence determinants, function, and evolution of CpG islands. Biochem Soc Trans. Jun 30 2021;49(3):1109-1119. doi:10.1042/BST20200695
103. Torrisani J, Hanoun N, Laurell H, et al. Identification of an upstream promoter of the human somatostatin receptor, hSSTR2, which is controlled by epigenetic modifications. Endocrinology. Jun 2008;149(6):3137-47. doi:10.1210/en.2007-1525
104. Klomp MJ, Refardt J, van Koetsveld PM, et al. Epigenetic regulation of SST(2) expression in small intestinal neuroendocrine tumors. Front Endocrinol (Lausanne). 2023;14:1184436. doi:10.3389/fendo.2023.1184436
105. Marmorstein R, Zhou MM. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol. Jul 1 2014;6(7):a018762. doi:10.1101/cshperspect.a018762
106. Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. Apr 1 2014;6(4):a018713. doi:10.1101/cshperspect.a018713
107. Taelman VF, Radojewski P, Marincek N, et al. Upregulation of Key Molecules for Targeted Imaging and Therapy. J Nucl Med. Nov 2016;57(11):1805-1810. doi:10.2967/jnumed.115.165092
108. Guenter RE, Aweda T, Carmona Matos DM, et al. Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors. Cancers (Basel). Jun 3 2019;11(6)doi:10.3390/cancers11060767
109. Klomp MJ, Dalm SU, van Koetsveld PM, Dogan F, de Jong M, Hofland LJ. Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [(111)In]In-DOTATATE Uptake in NET Cells. Cancers (Basel). Sep 29 2021;13(19)doi:10.3390/cancers13194905
110. Veenstra MJ, van Koetsveld PM, Dogan F, et al. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. Oncotarget. Mar 13 2018;9(19):14791-14802. doi:10.18632/oncotarget.9462
111. Del Olmo-Garcia MI, Prado-Wohlwend S, Andres A, Soriano JM, Bello P, Merino-Torres JF. Somatostatin and Somatostatin Receptors: From Signaling to Clinical Applications in Neuroendocrine Neoplasms. Biomedicines. Dec 1 2021;9(12)doi:10.3390/biomedicines9121810
112. Hofland J, Herrera-Martinez AD, Zandee WT, de Herder WW. Management of carcinoid syndrome: a systematic review and meta-analysis. Endocr Relat Cancer. Mar 2019;26(3):R145-R156. doi:10.1530/ERC-18-0495
113. Caplin ME, Pavel M, Cwikla JB, et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. Mar 2016;23(3):191-9. doi:10.1530/ERC-15-0490
114. Pavel M, Cwikla JB, Lombard-Bohas C, et al. Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results. Eur J Cancer. Nov 2021;157:403-414. doi:10.1016/j.ejca.2021.06.056
115. Wolin EM, Jarzab B, Eriksson B, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015;9:5075-86. doi:10.2147/DDDT.S84177
116. Sundin A, Arnold R, Baudin E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine & Hybrid Imaging. Neuroendocrinology. 2017;105(3):212-244. doi:10.1159/000471879
117. Wong KK, Waterfield RT, Marzola MC, et al. Contemporary nuclear medicine imaging of neuroendocrine tumours. Clin Radiol. Nov 2012;67(11):1035-50. doi:10.1016/j.crad.2012.03.019
118. Malan N, Vangu MD. Normal Variants, Pitfalls and Artifacts in Ga-68 DOTATATE PET/CT Imaging. Front Nucl Med. 2022;2:825486. doi:10.3389/fnume.2022.825486
119. Xu C, Zhang H. Somatostatin receptor based imaging and radionuclide therapy. Biomed Res Int. 2015;2015:917968. doi:10.1155/2015/917968
120. Etchebehere EC, de Oliveira Santos A, Gumz B, et al. 68Ga-DOTATATE PET/CT, 99mTc-HYNIC-octreotide SPECT/CT, and whole-body MR imaging in detection of neuroendocrine tumors: a prospective trial. J Nucl Med. Oct 2014;55(10):1598-604. doi:10.2967/jnumed.114.144543
121. Gabriel M, Decristoforo C, Kendler D, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. Apr 2007;48(4):508-18. doi:10.2967/jnumed.106.035667
122. Sharma P, Arora S, Mukherjee A, et al. Predictive value of 68Ga-DOTANOC PET/CT in patients with suspicion of neuroendocrine tumors: is its routine use justified? Clin Nucl Med. Jan 2014;39(1):37-43. doi:10.1097/RLU.0000000000000257
123. Sadowski SM, Neychev V, Millo C, et al. Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. J Clin Oncol. Feb 20 2016;34(6):588-96. doi:10.1200/JCO.2015.64.0987
124. Hofman MS, Lau WF, Hicks RJ. Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation. Radiographics. Mar-Apr 2015;35(2):500-16. doi:10.1148/rg.352140164
125. Haug AR, Rominger A, Mustafa M, et al. Treatment with octreotide does not reduce tumor uptake of (68)Ga-DOTATATE as measured by PET/CT in patients with neuroendocrine tumors. J Nucl Med. Nov 2011;52(11):1679-83. doi:10.2967/jnumed.111.089276
126. Ayati N, Lee ST, Zakavi R, et al. Long-Acting Somatostatin Analog Therapy Differentially Alters (68)Ga-DOTATATE Uptake in Normal Tissues Compared with Primary Tumors and Metastatic Lesions. J Nucl Med. Feb 2018;59(2):223-227. doi:10.2967/jnumed.117.192203
127. Paluri RK, Killeen RB. Neuroendocrine Tumor Lu-177-Dotatate Therapy. StatPearls. 2024.
128. Strosberg J, Wolin E, Chasen B, et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With (177)Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. Sep 1 2018;36(25):2578-2584. doi:10.1200/JCO.2018.78.5865
129. Strosberg JR, Caplin ME, Kunz PL, et al. (177)Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. Dec 2021;22(12):1752-1763. doi:10.1016/S1470-2045(21)00572-6
130. Singh S, Halperin D, Myrehaug S, et al. [(177)Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. Jun 29 2024;403(10446):2807-2817. doi:10.1016/S0140-6736(24)00701-3
131. Arnold R, Wilke A, Rinke A, et al. Plasma chromogranin A as marker for survival in patients with metastatic endocrine gastroenteropancreatic tumors. Clin Gastroenterol Hepatol. Jul 2008;6(7):820-7. doi:10.1016/j.cgh.2008.02.052
132. Becx MN, Minczeles NS, Brabander T, de Herder WW, Nonnekens J, Hofland J. A Clinical Guide to Peptide Receptor Radionuclide Therapy with (177)Lu-DOTATATE in Neuroendocrine Tumor Patients. Cancers (Basel). Nov 24 2022;14(23)doi:10.3390/cancers14235792
133. Hicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology. 2017;105(3):295-309. doi:10.1159/000475526
134. Nonnekens J, van Kranenburg M, Beerens CE, et al. Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib. Theranostics. 2016;6(11):1821-32. doi:10.7150/thno.15311
135. Hofving T, Sandblom V, Arvidsson Y, et al. 177Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition. Endocr Relat Cancer. Apr 1 2019;26(4):437-449. doi:10.1530/ERC-18-0509
136. Guenter R, Aweda T, Carmona Matos DM, et al. Overexpression of somatostatin receptor type 2 in neuroendocrine tumors for improved Ga68-DOTATATE imaging and treatment. Surgery. Jan 2020;167(1):189-196. doi:10.1016/j.surg.2019.05.092
137. Sun L, Qian Q, Sun G, et al. Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide-drug conjugate via activating somatostatin receptor type II. J Drug Target. 2016;24(2):169-77. doi:10.3109/1061186X.2015.1066794
138. Evans JS, Beaumont J, Braga M, et al. Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy. Eur J Cancer. Nov 2022;176:110-120. doi:10.1016/j.ejca.2022.09.009
139. Klomp MJ, Hofland LJ, van den Brink L, et al. The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo. Pharmaceutics. Jan 12 2022;14(1)doi:10.3390/pharmaceutics14010173
140. Klomp MJ, van den Brink L, van Koetsveld PM, et al. Applying HDACis to increase SSTR2 expression and radiolabeled DOTA-TATE uptake: from cells to mice. Life Sci. Dec 1 2023;334:122173. doi:10.1016/j.lfs.2023.122173
141. Refardt J, Klomp MJ, van Koetsveld PM, et al. Effect of epigenetic treatment on SST(2) expression in neuroendocrine tumour patients. Clin Transl Med. Jul 2022;12(7):e957. doi:10.1002/ctm2.957
142. Pollard JH, Menda Y, Zamba KD, et al. Potential for Increasing Uptake of Radiolabeled (68)Ga-DOTATOC and (123)I-MIBG in Patients with Midgut Neuroendocrine Tumors Using a Histone Deacetylase Inhibitor Vorinostat. Cancer Biother Radiopharm. Oct 2021;36(8):632-641. doi:10.1089/cbr.2020.4633
143. Sharma R. Lutathera and ASTX727 in Neuroendocrine Tumours (LANTana). Updated 03/20/2024. Accessed 10/30/2024, 2024. https://www.clinicaltrials.gov/study/NCT05178693
2. Kos-Kudla B, Cwikla J, Ruchala M, et al. Current treatment options for gastroenteropancreatic neuroendocrine tumors with a focus on the role of lanreotide. Contemp Oncol (Pozn). 2017;21(2):115-122. doi:10.5114/wo.2017.68619
3. Forsythe SD, Pu T, Andrews SG, Madigan JP, Sadowski SM. Models in Pancreatic Neuroendocrine Neoplasms: Current Perspectives and Future Directions. Cancers (Basel). Jul 25 2023;15(15)doi:10.3390/cancers15153756
4. Diez M, Teule A, Salazar R. Gastroenteropancreatic neuroendocrine tumors: diagnosis and treatment. Ann Gastroenterol. 2013;26(1):29-36.
5. Refardt J, Zandee WT, Brabander T, et al. Inferior outcome of neuroendocrine tumor patients negative on somatostatin receptor imaging. Endocr-Relat Cancer. Nov 2020;27(11):615-624. doi:10.1530/Erc-20-0340
6. Klomp MJ, Dalm SU, de Jong M, Feelders RA, Hofland J, Hofland LJ. Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer. Rev Endocr Metab Disord. Sep 2021;22(3):495-510. doi:10.1007/s11154-020-09607-z
7. Rogoza O, Megnis K, Kudrjavceva M, Gerina-Berzina A, Rovite V. Role of Somatostatin Signalling in Neuroendocrine Tumours. Int J Mol Sci. Jan 27 2022;23(3)doi:10.3390/ijms23031447
8. Zamora V, Cabanne A, Salanova R, et al. Immunohistochemical expression of somatostatin receptors in digestive endocrine tumours. Dig Liver Dis. Mar 2010;42(3):220-5. doi:10.1016/j.dld.2009.07.018
9. Kulaksiz H, Eissele R, Rossler D, et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut. Jan 2002;50(1):52-60. doi:10.1136/gut.50.1.52
10. Qian ZR, Li T, Ter-Minassian M, et al. Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors. Pancreas. Nov 2016;45(10):1386-1393. doi:10.1097/MPA.0000000000000700
11. Hu HF, Hu YH, Xu XW, et al. Role of Somatostatin Receptor 2 in Nonfunctional Pancreatic Neuroendocrine Tumors: Clinicopathological Analysis of 223 Cases and Whole Exome Sequencing of a Multifocal Case. Pancreas. Nov-Dec 01 2022;51(10):1404-1410. doi:10.1097/MPA.0000000000002199
12. Stueven AK, Kayser A, Wetz C, et al. Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future. Int J Mol Sci. Jun 22 2019;20(12)doi:10.3390/ijms20123049
13. Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. Jan 5 1973;179(4068):77-9. doi:10.1126/science.179.4068.77
14. Pradayrol L, Jornvall H, Mutt V, Ribet A. N-terminally extended somatostatin: the primary structure of somatostatin-28. FEBS Lett. Jan 1 1980;109(1):55-8. doi:10.1016/0014-5793(80)81310-x
15. Warren TG, Shields D. Expression of preprosomatostatin in heterologous cells: biosynthesis, posttranslational processing, and secretion of mature somatostatin. Cell. Dec 1984;39(3 Pt 2):547-55. doi:10.1016/0092-8674(84)90461-6
16. Francis BH, Baskin DG, Saunders DR, Ensinck JW. Distribution of somatostatin-14 and somatostatin-28 gastrointestinal-pancreatic cells of rats and humans. Gastroenterology. Nov 1990;99(5):1283-91. doi:10.1016/0016-5085(90)91151-u
17. Patel YC, Greenwood MT, Warszynska A, Panetta R, Srikant CB. All five cloned human somatostatin receptors (hSSTR1-5) are functionally coupled to adenylyl cyclase. Biochem Biophys Res Commun. Jan 28 1994;198(2):605-12. doi:10.1006/bbrc.1994.1088
18. Bell GI, Yasuda K, Kong H, Law SF, Raynor K, Reisine T. Molecular biology of somatostatin receptors. Ciba Found Symp. 1995;190:65-79; discussion 80-8. doi:10.1002/9780470514733.ch5
19. Costanzi E, Simioni C, Conti I, et al. Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives. J Cell Physiol. Apr 2021;236(4):2505-2518. doi:10.1002/jcp.30062
20. Chaudhary PK, Kim S. An Insight into GPCR and G-Proteins as Cancer Drivers. Cells. Nov 24 2021;10(12)doi:10.3390/cells10123288
21. Alexander SP, Christopoulos A, Davenport AP, et al. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein-coupled receptors. Br J Pharmacol. Dec 2017;174 Suppl 1(Suppl Suppl 1):S17-S129. doi:10.1111/bph.13878
22. Li YG, Meng XY, Yang X, et al. Structural insights into somatostatin receptor 5 bound with cyclic peptides. Acta Pharmacol Sin. Jun 26 2024;doi:10.1038/s41401-024-01314-8
23. Gunther T, Tulipano G, Dournaud P, et al. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol Rev. Oct 2018;70(4):763-835. doi:10.1124/pr.117.015388
24. Yamada Y, Stoffel M, Espinosa R, 3rd, et al. Human somatostatin receptor genes: localization to human chromosomes 14, 17, and 22 and identification of simple tandem repeat polymorphisms. Genomics. Feb 1993;15(2):449-52. doi:10.1006/geno.1993.1088
25. Papotti M, Bongiovanni M, Volante M, et al. Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. May 2002;440(5):461-75. doi:10.1007/s00428-002-0609-x
26. Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W. Regulation and function of somatostatin receptors. J Neurochem. Jun 2004;89(5):1057-91. doi:10.1111/j.1471-4159.2004.02402.x
27. Piwko C, Thoss VS, Schupbach E, et al. Pharmacological characterisation of human cerebral cortex somatostatin SRIF1 and SRIF2 receptors. Naunyn Schmiedebergs Arch Pharmacol. Feb 1997;355(2):161-7. doi:10.1007/pl00004927
28. Bocci G, Culler MD, Fioravanti A, et al. In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists. Eur J Clin Invest. Sep 2007;37(9):700-8. doi:10.1111/j.1365-2362.2007.01848.x
29. Thermos K. Functional mapping of somatostatin receptors in the retina: a review. Vision Res. Aug 2003;43(17):1805-15. doi:10.1016/s0042-6989(03)00169-x
30. Atkinson H, England JA, Rafferty A, et al. Somatostatin receptor expression in thyroid disease. Int J Exp Pathol. Jun 2013;94(3):226-9. doi:10.1111/iep.12024
31. Kumar U, Sasi R, Suresh S, et al. Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes. Jan 1999;48(1):77-85. doi:10.2337/diabetes.48.1.77
32. Voros I, Saghy E, Pohoczky K, et al. Somatostatin and Its Receptors in Myocardial Ischemia/Reperfusion Injury and Cardioprotection. Front Pharmacol. 2021;12:663655. doi:10.3389/fphar.2021.663655
33. Watanabe N, Nakanishi Y, Kinukawa N, et al. Expressions of Somatostatin Receptor Subtypes (SSTR-1, 2, 3, 4 and 5) in Neuroblastic Tumors; Special Reference to Clinicopathological Correlations with International Neuroblastoma Pathology Classification and Outcomes. Acta Histochem Cytochem. 2014;47(5):219-29. doi:10.1267/ahc.14024
34. Kaemmerer D, Trager T, Hoffmeister M, et al. Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget. Sep 29 2015;6(29):27566-79. doi:10.18632/oncotarget.4491
35. Cives M, Kunz PL, Morse B, et al. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr Relat Cancer. Feb 2015;22(1):1-9. doi:10.1530/ERC-14-0360
36. Kumar U, Singh S. Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity. Int J Mol Sci. Apr 7 2020;21(7)doi:10.3390/ijms21072568
37. Somvanshi RK, Jhajj A, Heer M, Kumar U. Characterization of somatostatin receptors and associated signaling pathways in pancreas of R6/2 transgenic mice. Biochim Biophys Acta Mol Basis Dis. Feb 2018;1864(2):359-373. doi:10.1016/j.bbadis.2017.11.002
38. Di Muro G, Catalano R, Treppiedi D, et al. The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells. Int J Mol Sci. Mar 23 2024;25(7)doi:10.3390/ijms25073606
39. Yao Q, Liu Q, Xu H, et al. Upregulated Expression of SSTR3 is Involved in Neuronal Apoptosis After Intracerebral Hemorrhage in Adult Rats. Cell Mol Neurobiol. Nov 2017;37(8):1407-1416. doi:10.1007/s10571-017-0471-7
40. War SA, Kim B, Kumar U. Human somatostatin receptor-3 distinctively induces apoptosis in MCF-7 and cell cycle arrest in MDA-MB-231 breast cancer cells. Mol Cell Endocrinol. Sep 15 2015;413:129-44. doi:10.1016/j.mce.2015.06.019
41. Lee M, Lupp A, Mendoza N, et al. SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary. Endocr Relat Cancer. Feb 2015;22(1):111-9. doi:10.1530/ERC-14-0472
42. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. Jul 1999;20(3):157-98. doi:10.1006/frne.1999.0183
43. Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging. May 2003;30(5):781-93. doi:10.1007/s00259-003-1184-3
44. Borzsei R, Zsido BZ, Balint M, Helyes Z, Pinter E, Hetenyi C. Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4. Int J Mol Sci. Jun 21 2022;23(13)doi:10.3390/ijms23136878
45. Van Op den Bosch J, Torfs P, De Winter BY, et al. Effect of genetic SSTR4 ablation on inflammatory peptide and receptor expression in the non-inflamed and inflamed murine intestine. J Cell Mol Med. Sep 2009;13(9B):3283-95. doi:10.1111/j.1582-4934.2009.00760.x
46. Van Op den Bosch J, van Nassauw L, Lantermann K, van Marck E, Timmermans JP. Effect of intestinal inflammation on the cell-specific expression of somatostatin receptor subtypes in the murine ileum. Neurogastroenterol Motil. Jul 2007;19(7):596-606. doi:10.1111/j.1365-2982.2007.00931.x
47. Sandoval KE, Farr SA, Banks WA, et al. Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice. Eur J Pharmacol. Mar 1 2011;654(1):53-9. doi:10.1016/j.ejphar.2010.12.013
48. Kecskes A, Pohoczky K, Kecskes M, et al. Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains. Int J Mol Sci. Oct 21 2020;21(20)doi:10.3390/ijms21207788
49. Patel YC. Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest. Jun 1997;20(6):348-67. doi:10.1007/BF03350317
50. Corleto VD, Falconi M, Panzuto F, et al. Somatostatin receptor subtypes 2 and 5 are associated with better survival in well-differentiated endocrine carcinomas. Neuroendocrinology. 2009;89(2):223-30. doi:10.1159/000167796
51. Taboada GF, Luque RM, Bastos W, et al. Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol. Jan 2007;156(1):65-74. doi:10.1530/eje.1.02313
52. Srirajaskanthan R, Watkins J, Marelli L, Khan K, Caplin ME. Expression of somatostatin and dopamine 2 receptors in neuroendocrine tumours and the potential role for new biotherapies. Neuroendocrinology. 2009;89(3):308-14. doi:10.1159/000179899
53. Wang YH, Wang W, Jin KZ, et al. Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors. Oncol Lett. Mar 2017;13(3):1165-1174. doi:10.3892/ol.2017.5591
54. Mehta S, de Reuver PR, Gill P, et al. Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors. Medicine (Baltimore). Oct 2015;94(40):e1281. doi:10.1097/MD.0000000000001281
55. Childs A, Vesely C, Ensell L, et al. Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours. Br J Cancer. Dec 6 2016;115(12):1540-1547. doi:10.1038/bjc.2016.377
56. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. Oct 1 2009;27(28):4656-63. doi:10.1200/JCO.2009.22.8510
57. Caplin ME, Pavel M, Ruszniewski P. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. Oct 16 2014;371(16):1556-7. doi:10.1056/NEJMc1409757
58. Khan MS, El-Khouly F, Davies P, Toumpanakis C, Caplin ME. Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel). Aliment Pharmacol Ther. Jul 2011;34(2):235-42. doi:10.1111/j.1365-2036.2011.04693.x
59. Pedraza-Arevalo S, Ibanez-Costa A, Blazquez-Encinas R, et al. Epigenetic and post-transcriptional regulation of somatostatin receptor subtype 5 (SST(5) ) in pituitary and pancreatic neuroendocrine tumors. Mol Oncol. Feb 2022;16(3):764-779. doi:10.1002/1878-0261.13107
60. Fuentes-Fayos AC, ME GG, Perez-Gomez JM, et al. Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival, Increased Aggressiveness Features, and Somatostatin Analogs Resistance. Int J Mol Sci. Jan 20 2022;23(3)doi:10.3390/ijms23031143
61. Gahete MD, Rincon-Fernandez D, Duran-Prado M, et al. The truncated somatostatin receptor sst5TMD4 stimulates the angiogenic process and is associated to lymphatic metastasis and disease-free survival in breast cancer patients. Oncotarget. Sep 13 2016;7(37):60110-60122. doi:10.18632/oncotarget.11076
62. Hormaechea-Agulla D, Jimenez-Vacas JM, Gomez-Gomez E, et al. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer. FASEB J. Nov 2017;31(11):4682-4696. doi:10.1096/fj.201601264RRR
63. Lehman JM, Hoeksema MD, Staub J, et al. Somatostatin receptor 2 signaling promotes growth and tumor survival in small-cell lung cancer. Int J Cancer. Mar 1 2019;144(5):1104-1114. doi:10.1002/ijc.31771
64. Sagie N, Romanov E, Kezerle Y, Meirovitz A, Sheva K. Expression Analysis of SSTR 1, 2 and 3 in Small-cell Lung Cancer Patients as Targets for Future Peptide Receptor Radionuclide Therapy. Anticancer Res. Sep 2024;44(9):3807-3812. doi:10.21873/anticanres.17206
65. Tsuta K, Wistuba, II, Moran CA. Differential expression of somatostatin receptors 1-5 in neuroendocrine carcinoma of the lung. Pathol Res Pract. Aug 15 2012;208(8):470-4. doi:10.1016/j.prp.2012.05.014
66. Lapa C, Hanscheid H, Wild V, et al. Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. Oncotarget. Apr 12 2016;7(15):20033-40. doi:10.18632/oncotarget.7706
67. Sen F, Sheikh GT, von Hinten J, et al. In-Vivo Somatostatin-Receptor Expression in Small Cell Lung Cancer as a Prognostic Image Biomarker and Therapeutic Target. Cancers (Basel). Jul 13 2023;15(14)doi:10.3390/cancers15143595
68. Rauch H, Kitzberger C, Janghu K, et al. Combining [(177)Lu]Lu-DOTA-TOC PRRT with PARP inhibitors to enhance treatment efficacy in small cell lung cancer. Eur J Nucl Med Mol Imaging. Jul 18 2024;doi:10.1007/s00259-024-06844-1
69. Menke JR, Raleigh DR, Gown AM, Thomas S, Perry A, Tihan T. Somatostatin receptor 2a is a more sensitive diagnostic marker of meningioma than epithelial membrane antigen. Acta Neuropathol. Sep 2015;130(3):441-3. doi:10.1007/s00401-015-1459-3
70. Anis SE, Lotfalla M, Zain M, Kamel NN, Soliman AA. Value of SSTR2A and Claudin - 1 in Differentiating Meningioma from Schwannoma and Hemangiopericytoma. Open Access Maced J Med Sci. Feb 15 2018;6(2):248-253. doi:10.3889/oamjms.2018.062
71. Durand A, Champier J, Jouvet A, et al. Expression of c-Myc, neurofibromatosis Type 2, somatostatin receptor 2 and erb-B2 in human meningiomas: relation to grades or histotypes. Clin Neuropathol. Sep-Oct 2008;27(5):334-45. doi:10.5414/npp27334
72. Rachinger W, Stoecklein VM, Terpolilli NA, et al. Increased 68Ga-DOTATATE uptake in PET imaging discriminates meningioma and tumor-free tissue. J Nucl Med. Mar 2015;56(3):347-53. doi:10.2967/jnumed.114.149120
73. Ivanidze J, Roytman M, Lin E, et al. Gallium-68 DOTATATE PET in the Evaluation of Intracranial Meningiomas. J Neuroimaging. Sep 2019;29(5):650-656. doi:10.1111/jon.12632
74. Wu W, Zhou Y, Wang Y, et al. Clinical Significance of Somatostatin Receptor (SSTR) 2 in Meningioma. Front Oncol. 2020;10:1633. doi:10.3389/fonc.2020.01633
75. Mawrin C, Schulz S, Pauli SU, et al. Differential expression of sst1, sst2A, and sst3 somatostatin receptor proteins in low-grade and high-grade astrocytomas. J Neuropathol Exp Neurol. Jan 2004;63(1):13-9. doi:10.1093/jnen/63.1.13
76. He JH, Wang J, Yang YZ, et al. SSTR2 is a prognostic factor and a promising therapeutic target in glioma. Am J Transl Res. 2021;13(10):11223-11234.
77. Ostrom QT, Bauchet L, Davis FG, et al. The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. Jul 2014;16(7):896-913. doi:10.1093/neuonc/nou087
78. Reubi JC, Lang W, Maurer R, Koper JW, Lamberts SW. Distribution and biochemical characterization of somatostatin receptors in tumors of the human central nervous system. Cancer Res. Nov 1 1987;47(21):5758-64.
79. Tarkin JM, Calcagno C, Dweck MR, et al. (68)Ga-DOTATATE PET Identifies Residual Myocardial Inflammation and Bone Marrow Activation After Myocardial Infarction. J Am Coll Cardiol. May 21 2019;73(19):2489-2491. doi:10.1016/j.jacc.2019.02.052
80. Bhanat E, Koch CA, Parmar R, Garla V, Vijayakumar V. Somatostatin receptor expression in non-classical locations - clinical relevance? Rev Endocr Metab Disord. Jun 2018;19(2):123-132. doi:10.1007/s11154-018-9470-3
81. Li L, Tian Y, He Y. Late Pseudoprogression: A Potential Pitfall in 68Ga-DOTATATE PET/CT for Glioma. Clin Nucl Med. Apr 1 2023;48(4):e207-e208. doi:10.1097/RLU.0000000000004511
82. Sampedro-Nunez M, Luque RM, Ramos-Levi AM, et al. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors. Oncotarget. Feb 9 2016;7(6):6593-608. doi:10.18632/oncotarget.6565
83. Fan S, Zheng H, Zhan Y, et al. Somatostatin receptor2 (SSTR2) expression, prognostic implications, modifications and potential therapeutic strategies associates with head and neck squamous cell carcinomas. Crit Rev Oncol Hematol. Jan 2024;193:104223. doi:10.1016/j.critrevonc.2023.104223
84. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. Nov 26 2020;6(1):92. doi:10.1038/s41572-020-00224-3
85. Lechner M, Schartinger VH, Steele CD, et al. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. Nat Commun. Jan 5 2021;12(1):117. doi:10.1038/s41467-020-20308-8
86. Viswanathan K, Sadow PM. Somatostatin receptor 2 is highly sensitive and specific for Epstein-Barr virus-associated nasopharyngeal carcinoma. Hum Pathol. Nov 2021;117:88-100. doi:10.1016/j.humpath.2021.08.004
87. Patel R, Marano G, Joseph J, Chung J, Plata A, Vos JA. (18) F-fludeoxyglucose positron emission computed tomography ((18) F-FDG-PET/CT) versus (68) Ga-DOTATATE-PET/CT in patients with head and neck cancer: Comparisons and implications for treatment. Head Neck. Feb 2023;45(2):347-354. doi:10.1002/hed.27243
88. Juntikka T, Vaittinen S, Vahlberg T, Jyrkkio S, Minn H. Somatostatin Receptors and Chemokine Receptor CXCR4 in Lymphomas: A Histopathological Review of Six Lymphoma Subtypes. Front Oncol. 2021;11:710900. doi:10.3389/fonc.2021.710900
89. Dalm VA, Hofland LJ, Mooy CM, et al. Somatostatin receptors in malignant lymphomas: targets for radiotherapy? J Nucl Med. Jan 2004;45(1):8-16.
90. Ferone D, Semino C, Boschetti M, Cascini GL, Minuto F, Lastoria S. Initial staging of lymphoma with octreotide and other receptor imaging agents. Semin Nucl Med. Jul 2005;35(3):176-85. doi:10.1053/j.semnuclmed.2005.03.001
91. Priyadarshini S, Allison DB, Chauhan A. Comprehensive Assessment of Somatostatin Receptors in Various Neoplasms: A Systematic Review. Pharmaceutics. Jul 1 2022;14(7)doi:10.3390/pharmaceutics14071394
92. Gatto F, Hofland LJ. The role of somatostatin and dopamine D
receptors in endocrine tumors. Endocr-Relat Cancer. Dec 2011;18(6):R233-R251. doi:10.1530/Erc-10-0334
93. Okuwaki K, Kida M, Mikami T, et al. Clinicopathologic Characteristics of Pancreatic Neuroendocrine Tumors and Relation of Somatostatin Receptor Type 2A to Outcomes. Cancer-Am Cancer Soc. Dec 1 2013;119(23):4094-4102. doi:10.1002/cncr.28341
94. van Adrichem RC, Kamp K, van Deurzen CH, et al. Is There an Additional Value of Using Somatostatin Receptor Subtype 2a Immunohistochemistry Compared to Somatostatin Receptor Scintigraphy Uptake in Predicting Gastroenteropancreatic Neuroendocrine Tumor Response? Neuroendocrinology. 2016;103(5):560-6. doi:10.1159/000441604
95. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. Jul 17 2014;371(3):224-33. doi:10.1056/NEJMoa1316158
96. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. Jan 12 2017;376(2):125-135. doi:10.1056/NEJMoa1607427
97. Di Domenico A, Wiedmer T, Marinoni I, Perren A. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer. Sep 2017;24(9):R315-R334. doi:10.1530/ERC-17-0012
98. Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet. Aug 2016;17(8):487-500. doi:10.1038/nrg.2016.59
99. Sharma R, Earla B, Baidoo KE, et al. Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model. Mol Cancer Ther. Sep 5 2023;22(9):1052-1062. doi:10.1158/1535-7163.MCT-22-0798
100. Mensah IK, Norvil AB, AlAbdi L, et al. Misregulation of the expression and activity of DNA methyltransferases in cancer. NAR Cancer. Dec 2021;3(4):zcab045. doi:10.1093/narcan/zcab045
101. Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet. Nov 2021;37(11):1012-1027. doi:10.1016/j.tig.2021.05.002
102. Angeloni A, Bogdanovic O. Sequence determinants, function, and evolution of CpG islands. Biochem Soc Trans. Jun 30 2021;49(3):1109-1119. doi:10.1042/BST20200695
103. Torrisani J, Hanoun N, Laurell H, et al. Identification of an upstream promoter of the human somatostatin receptor, hSSTR2, which is controlled by epigenetic modifications. Endocrinology. Jun 2008;149(6):3137-47. doi:10.1210/en.2007-1525
104. Klomp MJ, Refardt J, van Koetsveld PM, et al. Epigenetic regulation of SST(2) expression in small intestinal neuroendocrine tumors. Front Endocrinol (Lausanne). 2023;14:1184436. doi:10.3389/fendo.2023.1184436
105. Marmorstein R, Zhou MM. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol. Jul 1 2014;6(7):a018762. doi:10.1101/cshperspect.a018762
106. Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. Apr 1 2014;6(4):a018713. doi:10.1101/cshperspect.a018713
107. Taelman VF, Radojewski P, Marincek N, et al. Upregulation of Key Molecules for Targeted Imaging and Therapy. J Nucl Med. Nov 2016;57(11):1805-1810. doi:10.2967/jnumed.115.165092
108. Guenter RE, Aweda T, Carmona Matos DM, et al. Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors. Cancers (Basel). Jun 3 2019;11(6)doi:10.3390/cancers11060767
109. Klomp MJ, Dalm SU, van Koetsveld PM, Dogan F, de Jong M, Hofland LJ. Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [(111)In]In-DOTATATE Uptake in NET Cells. Cancers (Basel). Sep 29 2021;13(19)doi:10.3390/cancers13194905
110. Veenstra MJ, van Koetsveld PM, Dogan F, et al. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. Oncotarget. Mar 13 2018;9(19):14791-14802. doi:10.18632/oncotarget.9462
111. Del Olmo-Garcia MI, Prado-Wohlwend S, Andres A, Soriano JM, Bello P, Merino-Torres JF. Somatostatin and Somatostatin Receptors: From Signaling to Clinical Applications in Neuroendocrine Neoplasms. Biomedicines. Dec 1 2021;9(12)doi:10.3390/biomedicines9121810
112. Hofland J, Herrera-Martinez AD, Zandee WT, de Herder WW. Management of carcinoid syndrome: a systematic review and meta-analysis. Endocr Relat Cancer. Mar 2019;26(3):R145-R156. doi:10.1530/ERC-18-0495
113. Caplin ME, Pavel M, Cwikla JB, et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. Mar 2016;23(3):191-9. doi:10.1530/ERC-15-0490
114. Pavel M, Cwikla JB, Lombard-Bohas C, et al. Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results. Eur J Cancer. Nov 2021;157:403-414. doi:10.1016/j.ejca.2021.06.056
115. Wolin EM, Jarzab B, Eriksson B, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015;9:5075-86. doi:10.2147/DDDT.S84177
116. Sundin A, Arnold R, Baudin E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine & Hybrid Imaging. Neuroendocrinology. 2017;105(3):212-244. doi:10.1159/000471879
117. Wong KK, Waterfield RT, Marzola MC, et al. Contemporary nuclear medicine imaging of neuroendocrine tumours. Clin Radiol. Nov 2012;67(11):1035-50. doi:10.1016/j.crad.2012.03.019
118. Malan N, Vangu MD. Normal Variants, Pitfalls and Artifacts in Ga-68 DOTATATE PET/CT Imaging. Front Nucl Med. 2022;2:825486. doi:10.3389/fnume.2022.825486
119. Xu C, Zhang H. Somatostatin receptor based imaging and radionuclide therapy. Biomed Res Int. 2015;2015:917968. doi:10.1155/2015/917968
120. Etchebehere EC, de Oliveira Santos A, Gumz B, et al. 68Ga-DOTATATE PET/CT, 99mTc-HYNIC-octreotide SPECT/CT, and whole-body MR imaging in detection of neuroendocrine tumors: a prospective trial. J Nucl Med. Oct 2014;55(10):1598-604. doi:10.2967/jnumed.114.144543
121. Gabriel M, Decristoforo C, Kendler D, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. Apr 2007;48(4):508-18. doi:10.2967/jnumed.106.035667
122. Sharma P, Arora S, Mukherjee A, et al. Predictive value of 68Ga-DOTANOC PET/CT in patients with suspicion of neuroendocrine tumors: is its routine use justified? Clin Nucl Med. Jan 2014;39(1):37-43. doi:10.1097/RLU.0000000000000257
123. Sadowski SM, Neychev V, Millo C, et al. Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. J Clin Oncol. Feb 20 2016;34(6):588-96. doi:10.1200/JCO.2015.64.0987
124. Hofman MS, Lau WF, Hicks RJ. Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation. Radiographics. Mar-Apr 2015;35(2):500-16. doi:10.1148/rg.352140164
125. Haug AR, Rominger A, Mustafa M, et al. Treatment with octreotide does not reduce tumor uptake of (68)Ga-DOTATATE as measured by PET/CT in patients with neuroendocrine tumors. J Nucl Med. Nov 2011;52(11):1679-83. doi:10.2967/jnumed.111.089276
126. Ayati N, Lee ST, Zakavi R, et al. Long-Acting Somatostatin Analog Therapy Differentially Alters (68)Ga-DOTATATE Uptake in Normal Tissues Compared with Primary Tumors and Metastatic Lesions. J Nucl Med. Feb 2018;59(2):223-227. doi:10.2967/jnumed.117.192203
127. Paluri RK, Killeen RB. Neuroendocrine Tumor Lu-177-Dotatate Therapy. StatPearls. 2024.
128. Strosberg J, Wolin E, Chasen B, et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With (177)Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. Sep 1 2018;36(25):2578-2584. doi:10.1200/JCO.2018.78.5865
129. Strosberg JR, Caplin ME, Kunz PL, et al. (177)Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. Dec 2021;22(12):1752-1763. doi:10.1016/S1470-2045(21)00572-6
130. Singh S, Halperin D, Myrehaug S, et al. [(177)Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. Jun 29 2024;403(10446):2807-2817. doi:10.1016/S0140-6736(24)00701-3
131. Arnold R, Wilke A, Rinke A, et al. Plasma chromogranin A as marker for survival in patients with metastatic endocrine gastroenteropancreatic tumors. Clin Gastroenterol Hepatol. Jul 2008;6(7):820-7. doi:10.1016/j.cgh.2008.02.052
132. Becx MN, Minczeles NS, Brabander T, de Herder WW, Nonnekens J, Hofland J. A Clinical Guide to Peptide Receptor Radionuclide Therapy with (177)Lu-DOTATATE in Neuroendocrine Tumor Patients. Cancers (Basel). Nov 24 2022;14(23)doi:10.3390/cancers14235792
133. Hicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology. 2017;105(3):295-309. doi:10.1159/000475526
134. Nonnekens J, van Kranenburg M, Beerens CE, et al. Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib. Theranostics. 2016;6(11):1821-32. doi:10.7150/thno.15311
135. Hofving T, Sandblom V, Arvidsson Y, et al. 177Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition. Endocr Relat Cancer. Apr 1 2019;26(4):437-449. doi:10.1530/ERC-18-0509
136. Guenter R, Aweda T, Carmona Matos DM, et al. Overexpression of somatostatin receptor type 2 in neuroendocrine tumors for improved Ga68-DOTATATE imaging and treatment. Surgery. Jan 2020;167(1):189-196. doi:10.1016/j.surg.2019.05.092
137. Sun L, Qian Q, Sun G, et al. Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide-drug conjugate via activating somatostatin receptor type II. J Drug Target. 2016;24(2):169-77. doi:10.3109/1061186X.2015.1066794
138. Evans JS, Beaumont J, Braga M, et al. Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy. Eur J Cancer. Nov 2022;176:110-120. doi:10.1016/j.ejca.2022.09.009
139. Klomp MJ, Hofland LJ, van den Brink L, et al. The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo. Pharmaceutics. Jan 12 2022;14(1)doi:10.3390/pharmaceutics14010173
140. Klomp MJ, van den Brink L, van Koetsveld PM, et al. Applying HDACis to increase SSTR2 expression and radiolabeled DOTA-TATE uptake: from cells to mice. Life Sci. Dec 1 2023;334:122173. doi:10.1016/j.lfs.2023.122173
141. Refardt J, Klomp MJ, van Koetsveld PM, et al. Effect of epigenetic treatment on SST(2) expression in neuroendocrine tumour patients. Clin Transl Med. Jul 2022;12(7):e957. doi:10.1002/ctm2.957
142. Pollard JH, Menda Y, Zamba KD, et al. Potential for Increasing Uptake of Radiolabeled (68)Ga-DOTATOC and (123)I-MIBG in Patients with Midgut Neuroendocrine Tumors Using a Histone Deacetylase Inhibitor Vorinostat. Cancer Biother Radiopharm. Oct 2021;36(8):632-641. doi:10.1089/cbr.2020.4633
143. Sharma R. Lutathera and ASTX727 in Neuroendocrine Tumours (LANTana). Updated 03/20/2024. Accessed 10/30/2024, 2024. https://www.clinicaltrials.gov/study/NCT05178693