title: Somatostatin receptor ligands and resistance to treatment in pituitary adenomas.
abstract: Somatostatin (SST), an inhibitory polypeptide with two biologically active forms SST14 and SST28, inhibits GH, prolactin (PRL), TSH, and ACTH secretion in the anterior pituitary gland. SST also has an antiproliferative effect inducing cell cycle arrest and apoptosis. Such actions are mediated through five G-protein-coupled somatostatin receptors (SSTR): SSTR1-SSTR5. In GH-secreting adenomas, SSTR2 expression predominates, and somatostatin receptor ligands (SRLs; octreotide and lanreotide) directed to SSTR2 are presently the mainstays of medical therapy. However, about half of patients show incomplete biochemical remission, but the definition of resistance per se remains controversial. We summarize here the determinants of SRL resistance in acromegaly patients, including clinical, imaging features as well as molecular (mutations, SSTR variants, and polymorphisms), and histopathological (granulation pattern, and proteins and receptor expression) predictors. The role of SSTR5 may explain the partial responsiveness to SRLs in patients with adequate SSTR2 density in the cell membrane. In patients with ACTH-secreting pituitary adenomas, i.e. Cushing's disease (CD), SSTR5 is the most abundant receptor expressed and tumors show low SSTR2 density due to hypercortisolism-induced SSTR2 down-regulation. Clinical studies with pasireotide, a multireceptor-targeted SRL with increased SSTR5 activity, lead to approval of pasireotide for treatment of patients with CD. Other SRL delivery modes (oral octreotide), multireceptor-targeted SRL (somatoprim) or chimeric compounds targeting dopamine D2 receptors and SSTR2 (dopastatin), are briefly discussed.
authors.affiliation: Department of MedicinePituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USANorthwest Pituitary Center and Departments of Medicine and Neurological SurgeryOregon Health and Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cuevas-Ramos
authors.affiliation: Department of MedicinePituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USANorthwest Pituitary Center and Departments of Medicine and Neurological SurgeryOregon Health and Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA fleseriu@ohsu.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Fleseriu
mesh_terms: D000236:Adenoma / Q000188:drug therapy*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000502:physiology; D004298:Dopamine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006728:Hormones / Q000627:therapeutic use*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010911:Pituitary Neoplasms / Q000188:drug therapy*; D011388:Prolactin / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013004:Somatostatin / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000627:therapeutic use; D013972:Thyrotropin / Q000378:metabolism
chemical_list: D006728:Hormones; D008024:Ligands; C420459:PTR 3173; D017481:Receptors, Somatostatin; D019382:Human Growth Hormone; D013004:Somatostatin; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013972:Thyrotropin; C517782:pasireotide; C531242:TBR-760; D004298:Dopamine