Medical Radiology and Radiation Safety. 2017. Vol. 62. No. 3. P. 42-49

DOI: 10.12737/article_5927f627a5c123.67647794

Labeled Somatostatin Analogues in Theranostics of Neuroendocrine Tumors

V.I. Chernov^1,2, O.D. Bragina^1,2, R.V. Zelchan^1,2, A.A. Medvedeva^1,2, I.G. Sinilkin^1,2, M.S. Larkina³, E.S. Stasyuk², E.A. Nesterov², V.S. Skuridin²

1. Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, Tomsk, Russia, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. ; 2. National Research Tomsk Polytechnic University, Tomsk, Russia; 3. Siberian State Medical University, Tomsk, Russia

V.I. Chernov – Head of the Department of Cancer Research Institute, Cancer Research Institute, Deputy Director of Tomsk National Research Medical Center Russian Academy of Sciences, Dr. Sc. Med., Prof.; O.D. Bragina – Junior Researcher, PhD Med.; R.V. Zel’chan – Radiologist, PhD Med.; A.A. Medvedeva – Senior Researcher, PhD Med.; I.G. Sinilkin – Senior researcher, PhD Med.; M.S. Larkina – Associate Prof., PhD Pharm; E.S. Stasyuk – Researcher, PhD Tech.; E.A. Nesterov – Researcher, PhD Tech.; V.S. Skuridin – Head of Lab., Dr. Sc. Tech., Prof.

Abstract

The article discusses the problems of diagnosis and treatment of neuroendocrine tumors, which represent a heterogeneous group of oncological diseases with a variety of clinical manifestations and biological features, depending both on the localization, the tumor process and hormonal secretion. Despite the fact that neuroendocrine tumors are quite rare, there is a continuous increase in the incidence.

In this work particular attention is paid to the study of the role of high-affinity somatostatin receptors (sstr), considered as the main targets in the theranostics of this group of oncological pathology. In connection with the inability to use native somatostatin, its non-natural synthetic analogues are now actively used. Unlike native somatostatin, which binds to all sstr (1–5) with high affinity and specificity, somatostatin analogues interact with sstr2, sstr3 and sstr5.

Diagnosis of neuroendocrine tumors is usually made on the basis of clinical symptoms, histological data and immunohistochemical studies with evaluation of hormonal expression. Unfortunately, the use of traditional diagnostic methods does not always fully assess the prevalence of the tumor process, which necessitates the creation of new visualizing agents. The application of nuclear medicine methods, especially the implementation of PET studies, in this case demonstrates high sensitivity and specificity.

The rapid development of personalized medicine makes it possible to use effective molecular targets in the same way for the therapy of oncological diseases. More recently, this principle has been applied to neuroendocrine tumors using ⁶⁸Ga-DOTATATE / ¹⁷⁷Lu-DOTA-octreotide pairs, which are successfully used in many nuclear medical centers.

Thus, currently labeled somatostatin analogues are widely used both for radionuclide diagnostics of neuroendocrine tumors, and for radionuclide therapy of these tumors. Multicentre studies with respect to radionuclide therapy of neuroendocrine tumors demonstrated high efficacy and proved the safety of its use. At the same time, only one pharmaceutical for imaging neuroendocrine tumors, ¹¹¹In-octreotide, has been registered in the Russian Federation, which necessitates research on the development of new domestic diagnostic and therapeutic radiopharmaceuticals.

Key words: neuroendocrine tumors, somatostatin receptors, radiopharmaceuticals, theranostics

REFERENCES

1. Sundin A., Rockall A. Therapeutic monitoring of gastroenteropancreatic neuroendocrine tumors: the challenges ahead. Neuroendocrinology. 2012. Vol. 96. P. 261–271.
2. Eads J.R., Meropol N.J. A new era for the systemic therapy of neuroendocrine tumors. Oncologist. 2012. Vol. 17. P. 326–338.
3. Tan E.H., Tan C.H. Imaging of gastroenteropancreatic neuroendocrine tumors. World J. Clin. Oncol. 2011. Vol. 2. P. 28–43.
4. Oberg K.E., Reubi J.C., Kwekkeboom D.J. et al. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology. 2010. Vol. 139. 742–753.
5. Ambrosini V., Campana D., Tomassetti P. et al. PET/CT with ⁶⁸Gallium-DOTA-peptides in NET: an overview. Eur. J. Radiol. 2011. Vol. 80. P. 116–119.
6. Lindholm D.P., Oberg K. Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors. Hormone and Metabol. Res. 2011. Vol. 43. P. 832–837.
7. Pfeifer A., Knigge U., Mortensen J. et al. Clinical PET of neuroendocrine tumors using ⁶⁴Cu-DOTATATE: first-in-humans study. J. Nucl. Med. 2012. Vol. 53. P. 1207–1215.
8. Kulke M.H., Siu L.L., Tepper J.E. et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute neuroendocrine tumor clinical trials planning meeting. J. Clin. Oncol. 2011. Vol. 29. P. 934–943.
9. Herder W.W., Hofland L.J., Lely A.J. et al. Somatostatin receptors in gastroenteropancreatic neuroendocrine tumours. Endocrine-Related Cancer. 2003. Vol. 10. P. 451–458.
10. Wang L., Tang K., Zhang Q. et al. Somatostatin receptor-based molecular imaging and therapy for neuroendocrine tumors. BioMed Res. Internat. 2013. Vol. 2013. 102819.
11. Maecke H.R., Reubi J.C. Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment. J. Nucl. Med. 2011. Vol. 52. P. 841–844.
12. Zhang H., Moroz A.M., Serganova I. et al. Imaging expression of the human somatostatin receptor subtype-2 reporter gene with ⁶⁸Ga-DOTATOC. J. Nucl. Med. 2011. Vol. 52. P. 123–131.
13. Kam B.L., Teunissen J.J., Krenning E.P. et al. Lutetiumlabelled peptides for therapy of neuroendocrine tumours. Eur. J. Nucl. Med. Molec. Imaging. 2012. Vol. 39. P. 103–112.
14. Wong K.K., Waterfield R.T., Marzola M.C. et al. Contemporary nuclear medicine imaging of neuroendocrine tumours. Clin. Radiol. 2012. Vol. 67. P. 1035–1050.
15. Naswa N., Bal C.S. Divergent role of ⁶⁸Ga-labeled Somatostatin analogs in the workup of patients with NETs: AIIMS Experience. Recent Results in Cancer Res. 2012. Vol. 194. P. 321–351.
16. Srirajaskanthan R., Kayani I., Quigley A.M. et al. The role of ⁶⁸Ga-DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on ¹¹¹In-DTPA-octreotide scintigraphy. J. Nucl. Med. 2010. Vol. 51. P. 875–882.
17. Poeppel T.D., Binse I., Petersenn S. et al. ⁶⁸Ga-DOTATOC versus ⁶⁸Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. J. Nucl. Med. 2010. Vol. 52. P. 1864–1870.
18. Desai K., Watkins J., Woodward N. et al. Use of molecular imaging to differentiate liver metastasis of colorectal cancer metastasis from neuroendocrine tumor origin. J. Clin. Gastroenterol. 2011. Vol. 45. P. 8–11.
19. Treglia G., Castaldi P., Rindi G. et al. Diagnostic performance of Gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis. Endocrine. 2012. Vol. 59. P. 80–87.
20. Ezziddin S., Lohmar J., Yong-Hing C.J. et al. Does the pretherapeutic tumor SUV in ⁶⁸Ga DOTATOC PET predict the absorbed dose of ¹⁷⁷Lu octreotate?. Clin. Nucl. Med. 2012. Vol. 37. P. 141–147.
21. Kwekkeboom D.J., Boen L.K., Martijn E. et al. Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr. Relat. Cancer. 2010. Vol. 10. P. 53–73.
22. Garske U., Sandstrom M., Johansson S. et al. Lessons on tumour response: imaging during therapy with ¹⁷⁷Lu-DOTAoctreotate a case report on a patient with a large volume of poorly differentiated neuroendocrine carcinoma. Theranostics. 2012. Vol. 2. P. 459–471.
23. Strosberg J.R., Fine R.L., Choi J. et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011. Vol. 117. P. 268–275.
24. Shiryaev S.V., Odzharova A.A., Orel N.F. et al. Scintigraphy with ¹¹¹In-octreotide in diagnosis of carcinoid tumors of different localization and well-differentiated neuroendocrine pancreatic cancer. Meditsinskaia Radiologogiia i Radiatsionnaia Bezopasnost. 2008. Vol. 53. 1. P. 53–62. (In Russian).
25. Lishmanov Yu. B., Chernov V.I. National guide on radionuclide diagnostics. 2010. Vol. 1. Tomsk. STT. (In Russian).
26. Kayani I., Bomanji J.B., Groves A. et al. Functional imaging of neuroendocrine tumors with combined PET/CT using ⁶⁸Ga-DOTATATE (Dota-DPhe1, Tyr3-octreotate) and ¹⁸F-FDG. Cancer. 2008. Vol. 112. P. 2447–2455.
27. Gabriel M., Decristoforo C., Kendler D. et al. ⁶⁸Ga-DOTATE 3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J. Nucl. Med. 2007. Vol. 48. P. 508–518.
28. Poeppel T.D., Binse I., Petersenn S. et al. ⁶⁸Ga-DOTATOC versus ⁶⁸Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. J. Nucl. Med. 2011. Vol. 52. P. 1864–1870.
29. Wild D., Mäcke H.R., Waser B. et al. ⁶⁸Ga-DOTANOC: a first compound for PET imaging with high affinity for somatostatin receptor subtypes 2 and 5. Eur. J. Nucl. Med. Molec. Imaging. 2005. Vol. 32, P. 724.
30. Pfeifer A., Knigge U., Mortensen J. et al. Clinical PET of neuroendocrine tumors using 64Cu-DOTATATE: first-in-humans study. J. Nucl. Med. 2012. Vol. 53. P. 1207–1215.
31. Meisetschläger G., Poethko T., Stah A. et al. Gluc-Lys([¹⁸F]FP)-TOCA PET in patients with SSTR-positive tumors: biodistribution and diagnostic evaluation compared with [¹¹¹In] DTPA-octreotide. J. Nucl. Med. 2006. Vol. 47. P. 566–573.
32. Ambrosini V., Campana D., Bodei L. et al. ⁶⁸Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors. J. Nucl. Med. 2010. Vol. 51. P. 669-673.
33. Burstein H.J., Sun Y., Dirix L.Y. et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB positive breast cancer. J. Clin. Oncol. 2010. Vol. 28. P. 1301-1307.
34. Idée J.M., Louguet S., Ballet S. et al. Theranostics and contrast-agents for medical imaging: a pharmaceutical company viewpoint. Imaging Med. Surg. 2013. Vol. 3. Suppl. 6. P. 292-297.
35. Kelkar S.S., Reineke T.M. Theranostics: combining imaging and therapy. Bioconjug. Chem. 2011. Vol. 22. P. 1879-1903.
36. Chernov V.I., Bragina O.D., Sinilkin I.G. et al. Radioimmunotherapy in the treatment of malignancies. Siber. J. Oncol. 2016. Vol. 15 (2). P. 101-106. (In Russian).
37. Chernov V.I.,Bragina O.D., Sinilkin I.G. et al. Radionuclide teranostic of malignancies. Vestnik Rentgenologii i Radiologii. 2016. Vol. 97 (5). P. 306-313. (In Russian).
38. Chernov V.I.,Bragina O.D., Sinilkin I.G., et al. Radioimmunotherapy: current state of the problem. Voprosi Oncologii. 2016. Vol. 62 (1). P. 24-30. (In Russian).
39. Denoye D., Pouliot N. Radionuclide theranostics in cancer. J. Mol. Imaging Dynam. 2013. Vol. 4. Suppl. 1. P. 1-2.
40. Jandl T., Revskaya E., Jiang Z. et al. Complement dependent cytotoxicity of an antibody to melanin in radioimmunotherapy of metastatic melanoma. Immunotherapy. 2013. Vol. 5. P. 357-364.
41. Hicks R.J. Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy. Cancer Imaging. 2010. Vol.10. P. 83-91.
42. Baum R.P., Kulkarni H.R. Theranostics: From molecular imaging using Ga-68 labeled tracers and PET/CT to personalized radionuclide therapy - the bad BERKA experience. Theranostics. 2012. Vol. 2. P. 437-447.
43. Oh S., Prasad V., Lee D.S. et al. Effect of peptide receptor radionuclide therapy on somatostatin receptor status and glucose metabolism in neuroendocrine tumors: intraindividual comparison of ⁶⁸Ga-DOTANOC PET/CT and ¹⁸F-FDG PET/CT. Internat. J. Molec. Imaging. Vol. 2011. Article ID 524130.
44. Savelli G., Bertagna F., Franco F. et al. Final results of a phase 2A study for the treatment of metastatic neuroendocrine tumors with a fixed activity of ⁹⁰Y-DOTA-D-Phe1-Tyr3 octreotide. Cancer. 2012. Vol. 118. P. 2915-2924.
45. Valkema R., Pauwels S., Kvols L.K. et al. Survival and response after peptide receptor radionuclide therapy with [⁹⁰Y-DOTA, Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Sem. Nucl. Med. 2006. Vol. 36. P. 147-156.
46. Forrer F., Waldherr C., Maecke H.R. et.al Targeted radionuclide therapy with ⁹⁰Y-DOTATOC in patients with neuroendocrine tumors. Anticancer Res. 2006. Vol. 26. P. 703-707.
47. Kwekkeboom D. J., De Herder W.W., Kam B.L. et al. Treatment with the radiolabeled somatostatin analog [¹⁷⁷Lu-DOTA, Tyr3]octreotate: toxicity, efficacy, and survival. J. Clin. Oncol. 2008. Vol. 26. 13. P. 2124-2130.
48. Kam B.L., Teunissen J.J., Krenning E.P. et al. Lutetiumlabelled peptides for therapy of neuroendocrine tumours. Eur. J. Nucl. Med. Molec. Imaging. 2012. Vol. 39. Supplement 1. P. 103-112.
49. Kwekkeboom D.J., de Herder W.W., van Eijck C.H. J. et al. Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Sem. Nucl. Med. 2010. Vol. 40, P. 78-88.
50. Kunikowska J., Królicki L., Hubalewska-Dydejczyk A. et al. Clinical results of radionuclide therapy of neuroendocrine tumours with ⁹⁰Y-DOTATATE and tandem ⁹⁰Y/¹⁷⁷Lu-DOTATATE: which is a better therapy option?. Eur. J. Nucl. Med. Molec. Imaging. 2011. Vol. 38. P. 1788-1797.
51. Chernov V.I., Medvedeva A.A., Sinilkin I.G. et al. Experience of the development of innovative radiopharmaceuticals in Tomsk Research Institute of Oncology. Siber. Oncol. 2015. Vol.2. P. 45-47. (In Russian).

For citation: Chernov VI, Bragina OD, Zelchan RV, Medvedeva AA, Sinilkin IG, Larkina MS, Stasyuk ES, Nesterov EA, Skuridin VS. Labeled Somatostatin Analogues in Theranostics of Neuroendocrine Tumors. Medical Radiology and Radiation Safety. 2017;62(3):42-9. Russian. DOI: 10.12737/article_5927f627a5c123.67647794

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