Skip to main content

Advertisement

SpringerLink
Log in

Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Introduction

Somatostatin (SST) receptor ligands (SRL), in particular those of first generation (Octreotide and Lanreotide), are widely used in medical treatment of acromegaly, but they assure biochemical control of disease (and the possibility of an improvement of clinical symptoms and tumor shrinkage), only in a subset of patients.

Discussion

The mechanisms underlying the so called “SRL resistance” are various and involve in particular SST receptor expression and molecular pathways of signal transduction. Different predictors of SRL response have been reported, including clinical and biochemical features (gender, age, growth hormone and insulin-like growth factor-I levels at diagnosis), and tumor characteristic (both at preoperative magnetic resonance imaging study and histopathology) as well as expression of SST receptors. In some cases, only a “partial resistance” to SST can be detected, probably due to the presence of other impaired molecular mechanisms involved in signal transduction, which compromise specific pathways and not others. This may explain some cases of dissociated response between biochemical control and tumor shrinkage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Colao A, Auriemma RS, Pivonello R, Kasuki L, Gadelha MR (2016) Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly. Pituitary 19(3):235–247

    Article  CAS  PubMed  Google Scholar 

  2. Colao A, Bronstein MD, Freda P, Gu F, Shen CC, Gadelha M, Fleseriu M, van der Lely AJ, Farrall AJ, Hermosillo Reséndiz K, Ruffin M, Chen Y, Sheppard M, Pasireotide C2305 Study Group (2014) Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab 99(3):791–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hoyer D, Bell GI, Berelowitz M, Epelbaum J, Feniuk W, Humphrey PP, O’Carroll AM, Patel YC, Schonbrunn A, Taylor JE, Reisine T (1995) Classification and nomenclature of somatostatin receptors. Trends Pharmacol Sci 16(3):86–88

    Article  CAS  PubMed  Google Scholar 

  4. Reisine T, Kong H, Raynor K, Yano H, Takeda J, Yasuda K, Bell GI (1993) Splice variant of the somatostatin receptor 2 subtype, somatostatin receptor 2B, couples to adenylyl cyclase. Mol Pharmacol 44(5):1016–1020

    CAS  PubMed  Google Scholar 

  5. Krantic S, Goddard I, Saveanu A, Giannetti N, Fombonne J, Cardoso A, Jaquet P, Enjalbert A (2004) Novel modalities of somatostatin actions. Eur J Endocrinol 151(6):643–655

    Article  CAS  PubMed  Google Scholar 

  6. Patel YC (1997) Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest 20(6):348–367

    Article  CAS  PubMed  Google Scholar 

  7. Maurer R, Reubi JC (1985) Somatostatin receptors. JAMA 253(18):2741

    Article  CAS  PubMed  Google Scholar 

  8. Ben-Shlomo A, Melmed S (2010) Pituitary somatostatin receptor signaling. Trends Endocrinol Metab 21(3):123–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cordelier P, Estève JP, Bousquet C, Delesque N, O’Carroll AM, Schally AV, Vaysse N, Susini C, Buscail L (1997) Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. Proc Natl Acad Sci USA 94(17):9343–9348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ferrante E, Pellegrini C, Bondioni S, Peverelli E, Locatelli M, Gelmini P, Luciani P, Peri A, Mantovani G, Bosari S, Beck-Peccoz P, Spada A, Lania A (2006) Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocr Relat Cancer 13(3):955–962

    Article  CAS  PubMed  Google Scholar 

  11. Sharma K, Patel YC, Srikant CB (1996) Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Mol Endocrinol 10(12):1688–1696

    CAS  PubMed  Google Scholar 

  12. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G (2002) SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol 146(5):707–716

    Article  CAS  PubMed  Google Scholar 

  13. Cuevas-Ramos D, Fleseriu M (2016) Pasireotide: a novel treatment for patients with acromegaly. Drug Des Dev Ther 11(10):227–239

    Google Scholar 

  14. Lesche S, Lehmann D, Nagel F, Schmid HA, Schulz S (2009) Differential effects of Octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J Clin Endocrinol Metab 94(2):654–661

    Article  CAS  PubMed  Google Scholar 

  15. Reubi JC, Schaer JC, Waser B, Mengod G (1994) Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Cancer Res 54(13):3455–3459

    CAS  PubMed  Google Scholar 

  16. Murray RD, Kim K, Ren S-G, Chelly M, Umehara Y, Melmed S (2004) Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest 114(3):349–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fleseriu M (2011) Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: a literature review. Pituitary 14(2):184–193

    Article  CAS  PubMed  Google Scholar 

  18. Roelfsema F, Biermasz NR, Pereira AM, Romijn JA (2008) Therapeutic options in the management of acromegaly: focus on Lanreotide Autogel. Biologics 2(3):463–479

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mazziotti G, Giustina A (2010) Effects of Lanreotide SR and Autogel on tumor mass in patients with acromegaly: a systematic review. Pituitary 13(1):60–67

    Article  CAS  PubMed  Google Scholar 

  20. Giustina A, Mazziotti G, Torri V, Spinello M, Floriani I, Melmed S (2012) Meta-analysis on the effects of Octreotide on tumor mass in acromegaly. PLoS ONE 7(5):e36411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cuevas-Ramos D, Fleseriu M (2014) Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 52(3):R223–R240

    Article  CAS  PubMed  Google Scholar 

  22. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA, Endocrine Society (2014) Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99(11):3933–3951

    Article  CAS  PubMed  Google Scholar 

  23. Arafat AM, Mohlig M, Weickert MO, Perschel FH, Purschwitz J, Spranger J, Strasburger CJ, Schöfl C, Pfeiffer AF (2008) Growth hormone response during OGTT: the impact of assay method on the estimation of reference values in patients with acromegaly and in healthy controls and the role of gender, age and BMI. J Clin Endocrinol Metab 93(4):1254–1262

    Article  CAS  PubMed  Google Scholar 

  24. Clemmons DR (2007) IGF-I assays: current assay methodologies and their limitations. Pituitary 10(2):121–128

    Article  CAS  PubMed  Google Scholar 

  25. Colao A, Auriemma RS, Lombardi G, Pivonello R (2011) Resistance to somatostatin analogs in acromegaly. Endocr Rev 32(2):247–271

    Article  CAS  PubMed  Google Scholar 

  26. Besser GM, Burman P, Daly AF (2005) Predictors and rates of treatment-resistant tumor growth in acromegaly. Eur J Endocrinol 153(2):187–193

    Article  CAS  PubMed  Google Scholar 

  27. Casarini AP, Pinto EM, Jallad RS, Giorgi RR, Giannella Neto D, Bronstein MD (2006) Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3. J Endocrinol Invest 29(9):826–830

    Article  CAS  PubMed  Google Scholar 

  28. Colao A, Pivonello R, Auriemma RS, Briganti F, Galdiero M, Tortora F, Caranci F, Cirillo S, Lombardi G (2006) Predictors of tumor shrinkage after primary therapy with somatostatin analogues in acromegaly: a prospective study in 99 patients. J Clin Endocrinol Metab 91(6):2112–2118

    Article  CAS  PubMed  Google Scholar 

  29. Colao A, Pivonello R, Auriemma RS, Galdiero M, Savastano S, Grasso LF, Lombardi G (2008) Growth hormone-secreting tumor shrinkage after 3 months of Octreotide-long-acting release therapy predicts the response at 12 months. J Clin Endocrinol Metab 93(9):3436–3442

    Article  PubMed  Google Scholar 

  30. Melmed S (2006) Medical progress: acromegaly. N Engl J Med 355(24):2558–2573

    Article  CAS  PubMed  Google Scholar 

  31. Sherlock M, Fernandez-Rodriguez E, Alonso AA, Reulen RC, Ayuk J, Clayton RN, Holder G, Sheppard MC, Bates A, Stewart PM (2009) Medical therapy in patients with acromegaly: predictors of response and comparison of efficacy of dopamine agonists and somatostatin analogues. J Clin Endocrinol Metab 94(4):1255–1263

    Article  CAS  PubMed  Google Scholar 

  32. Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M (2013) Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary 16(4):490–498

    Article  CAS  PubMed  Google Scholar 

  33. Heck A, Ringstad G, Fougner SL, Casar-Borota O, Nome T, Ramm-Pettersen J, Bollerslev J (2012) Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf) 77(1):72–78

    Article  CAS  Google Scholar 

  34. Plöckinger U, Bäder M, Hopfenmüller W, Saeger W, Quabbe HJ (1997) Results of somatostatin receptor scintigraphy do not predict pituitary tumor volume- and hormone-response to octreotide therapy and do not correlate with tumor histology. Eur J Endocrinol 136(4):369–376

    Article  PubMed  Google Scholar 

  35. Reubi JC, Landolt AM (1989) The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab 68(4):844–850

    Article  CAS  PubMed  Google Scholar 

  36. Plöckinger U, Albrecht S, Mawrin C, Saeger W, Buchfelder M, Petersenn S, Schulz S (2008) Selective loss of somatostatin receptor 2 in octreotide-resistant growth hormone-secreting adenomas. J Clin Endocrinol Metab 93(4):1203–1210

    Article  PubMed  Google Scholar 

  37. Bertherat J, Chanson P, Dewailly D, Dupuy M, Jaquet P, Peillon F, Epelbaum J (1993) Somatostatin receptors, adenylate cyclase activity, and growth hormone (GH) response to octreotide in GH-secreting adenomas. J Clin Endocrinol Metab 77(6):1577–1583

    CAS  PubMed  Google Scholar 

  38. Gatto F, Biermasz NR, Feelders RA, Kros JM, Dogan F, van der Lely AJ, Neggers SJ, Lamberts SW, Pereira AM, Ferone D, Hofland LJ (2016) Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly. Eur J Endocrinol 174(5):651–662

    Article  PubMed  Google Scholar 

  39. Peverelli E, Treppiedi D, Giardino E, Vitali E, Lania AG, Mantovani G (2015) Dopamine and somatostatin analogues resistance of pituitary tumors: focus on cytoskeleton involvement. Front Endocrinol (Lausanne) 6:187

    Google Scholar 

  40. Rocheville M, Lange DC, Kumar U, Sasi R, Patel RC, Patel YC (2000) Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem 275(11):7862–7869

    Article  CAS  PubMed  Google Scholar 

  41. Taboada GF, Luque RM, Neto LV, Machado Ede O, Sbaffi BC, Domingues RC, Marcondes JB, Chimelli LM, Fontes R, Niemeyer P, de Carvalho DP, Kineman RD, Gadelha MR (2008) Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur J Endocrinol 158(3):295–303

    Article  CAS  PubMed  Google Scholar 

  42. Jaquet P, Gunz G, Saveanu A, Dufour H, Taylor J, Dong J, Kim S, Moreau JP, Enjalbert A, Culler MD (2005) Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy. Eur J Endocrinol 153(1):135–141

    Article  CAS  PubMed  Google Scholar 

  43. Zatelli MC, Piccin D, Tagliati F, Ambrosio MR, Margutti A, Padovani R, Scanarini M, Culler MD, degli Uberti EC (2003) Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH, and PRL secretion. J Clin Endocrinol Metab 88(6):2797–2802

    Article  CAS  PubMed  Google Scholar 

  44. Ballarè E, Persani L, Lania AG, Filopanti M, Giammona E, Corbetta S, Mantovani S, Arosio M, Beck-Peccoz P, Faglia G, Spada A (2001) Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. J Clin Endocrinol Metab 86(8):3809–3814

    Article  PubMed  Google Scholar 

  45. Ciganoka D, Balcere I, Kapa I, Peculis R, Valtere A, Nikitina-Zake L, Lase I, Schiöth HB, Pirags V, Klovins J (2011) Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly. Eur J Endocrinol 165(4):517–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Filopanti M, Ballarè E, Lania AG, Bondioni S, Verga U, Locatelli M, Zavanone LM, Losa M, Gelmini S, Peri A, Orlando C, Beck-Peccoz P (2004) Spada A (2004) Loss of heterozygosity at the SS receptor type 5 locus in human GH- and TSH-secreting pituitary tumors. J Endocrinol Invest 27(10):937–942

    Article  CAS  PubMed  Google Scholar 

  47. Marina D, Burman P, Klose M, Casar-Borota O, Luque RM, Castaño JP, Feldt-Rasmussen U (2015) Truncated somatostatin receptor 5 may modulate therapy response to somatostatin analogues—observations in two patients with acromegaly and severe headache. Growth Horm IGF Res 25(5):262–267

    Article  CAS  PubMed  Google Scholar 

  48. Spada A, Arosio M, Bochicchio D, Bazzoni N, Vallar L, Bassetti M (1990) Faglia G (1990) Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab 71(6):1421–1426

    Article  CAS  PubMed  Google Scholar 

  49. Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O (2013) Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. Eur J Endocrinol 168(4):491–499

    Article  CAS  PubMed  Google Scholar 

  50. Ballarè E, Mantovani S, Bassetti M, Lania AG, Spada A (1997) Immunodetection of G proteins in human pituitary adenomas: evidence for a low expression of proteins of the Gi subfamily. Eur J Endocrinol 137(5):482–489

    Article  PubMed  Google Scholar 

  51. Daly AF, Tichomirowa MA, Petrossians P, Heliövaara E, Jaffrain-Rea ML, Barlier A, Naves LA, Ebeling T, Karhu A, Raappana A, Cazabat L, De Menis E, Montañana CF, Raverot G, Weil RJ, Sane T, Maiter D, Neggers S, Yaneva M, Tabarin A, Verrua E, Eloranta E, Murat A, Vierimaa O, Salmela PI, Emy P, Toledo RA, Sabaté MI, Villa C, Popelier M, Salvatori R, Jennings J, Longás AF, Labarta Aizpún JI, Georgitsi M, Paschke R, Ronchi C, Valimaki M, Saloranta C, De Herder W, Cozzi R, Guitelman M, Magri F, Lagonigro MS, Halaby G, Corman V, Hagelstein MT, Vanbellinghen JF, Barra GB, Gimenez-Roqueplo AP, Cameron FJ, Borson-Chazot F, Holdaway I, Toledo SP, Stalla GK, Spada A, Zacharieva S, Bertherat J, Brue T, Bours V, Chanson P, Aaltonen LA, Beckers A (2010) Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab 95(11):E373–E383

    Article  PubMed  Google Scholar 

  52. Dénes J, Kasuki L, Trivellin G, Colli LM, Takiya CM, Stiles CE, Barry S, de Castro M, Gadelha MR, Korbonits M (2015) Regulation of aryl hydrocarbon receptor interacting protein (AIP) protein expression by MiR-34a in sporadic somatotropinomas. PLoS ONE 10(2):e0117107

    Article  PubMed  PubMed Central  Google Scholar 

  53. Gadelha MR, Kasuki L, Korbonits M (2013) Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol Metab 24(5):238–246

    Article  CAS  PubMed  Google Scholar 

  54. Tuominen I, Heliövaara E, Raitila A, Rautiainen MR, Mehine M, Katainen R, Donner I, Aittomäki V, Lehtonen HJ, Ahlsten M, Kivipelto L, Schalin-Jäntti C, Arola J, Hautaniemi S, Karhu A (2014) AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling. Oncogene 34(9):1174–1184

    Article  PubMed  Google Scholar 

  55. Iacovazzo D, Carlsen E, Lugli F, Chiloiro S, Piacentini S, Bianchi A, Giampietro A, Mormando M, Clear AJ, Doglietto F, Anile C, Maira G, Lauriola L, Rindi G, Roncaroli F, Pontecorvi A, Korbonits M, De Marinis L (2016) Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study. Eur J Endocrinol 174(2):241–250

    Article  CAS  PubMed  Google Scholar 

  56. Theodoropoulou M, Stalla GK, Spengler D (2010) ZAC1 target genes and pituitary tumorigenesis. Mol Cell Endocrinol 326(1–2):60–65

    Article  CAS  PubMed  Google Scholar 

  57. Fougner SL, Lekva T, Borota OC, Hald JK, Bollerslev J, Berg JP (2010) The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. J Clin Endocrinol Metab 95(5):2334–2342

    Article  CAS  PubMed  Google Scholar 

  58. Fougner SL, Bollerslev J, Latif F, Hald JK, Lund T, Ramm-Pettersen J, Berg JP (2008) Low levels of raf kinase inhibitory protein in growth hormone-secreting pituitary adenomas correlate with poor response to octreotide treatment. J Clin Endocrinol Metab 93(4):1211–1216

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unit of Endocrinology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy

    Rosa Maria Paragliola & Salvatore Maria Corsello

  2. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Pituitary Center, Johns Hopkins University School of Medicine, 1830 East Monument Street Suite #333, Baltimore, MD, 21287, USA

    Roberto Salvatori

Authors
  1. Rosa Maria Paragliola
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salvatore Maria Corsello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberto Salvatori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Salvatori.

Ethics declarations

Conflict of interest

Rosa Maria Paragliola and Salvatore Maria Corsello have declares that they have no conflict of interest. Roberto Salvatori serves in advisory board for Pfizer, Novo Nordisk, and Ionis Pharmaceutical, receives research support from Novartis, Pfizer, and Chiasma, and has received in the past research support from Ipsen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paragliola, R.M., Corsello, S.M. & Salvatori, R. Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance. Pituitary 20, 109–115 (2017). https://doi.org/10.1007/s11102-016-0768-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-016-0768-4

Keywords

Search

Navigation