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S W J Lamberts and Octreotide 181:5 R173–R183 Review L J Hofland

ANNIVERSARY REVIEW Octreotide, 40 years later Correspondence should be addressed Steven W J Lamberts and Leo J Hofland to S W J Lamberts Division of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands Email [email protected]

Abstract

Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide.

European Journal of Endocrinology (2019) 181, R173–R183

Introduction

A peptide inhibiting the release of growth hormone initial enthusiasm for its clinical use. From 1978 on, a (GH) was accidentally detected in the hypothalamus of number of drug companies started programs to synthesize rats during studies of the distribution of GH-releasing long-acting somatostatin analogs. factor (1). This peptide, called somatostatin, is a peptide Octreotide (SMS 201-995) was one of the first hormone that plays an inhibitory role in the regulation biologically stable somatostatin analogs to be synthesized of multiple physiological functions, including pituitary, (8): it has a much longer half-life in the human circulation

European Journal of Endocrinology pancreatic and gastrointestinal hormone secretion (2, 3). than somatostatin and binds with a high affinity to Somatostatin exerts its biological effects by interaction SST2 (9). The structure of natural somatostatin and with specific somatostatin receptors (SSTs) expressed on octreotide is shown in Fig. 1. In patients with acromegaly target tissues. Five human receptor subtypes have been subcutaneously administered octreotide suppressed detected (SST 1-5), each mediating a distinct signaling GH secretion without a rebound hypersecretion (10). pathway (4, 5). In clinical applications, only SST2 and A long-acting repeatable formulation (Octreotide-LAR) SST5 play an important role so far (6). was introduced for intramusculair administration later. Somatostatin acts in different organ systems as a neu- Lanreotide, another metabolically stable somatostatin rohormone, a neurotransmitter or as local factor acting analog with a similar high SST2 binding profile (11), was via autocrine or paracrine mechanisms. In his Nobel introduced shortly after octreotide. Lanreotide is now lecture, Guillemin summarized a number of potential available in a subcutaneously administered sustained- problems with regard to the clinical application of soma- release formulation (Lanreotide-Autogel). Octreotide and tostatin (7): in view of its ability to inhibit such a variety lanreotide have very similar characteristics both with of physiological processes, he predicted that somatosta- regard to tolerability and efficacy (vide infra). tin might be of therapeutic value in clinical conditions involving hyperfunction of the organ systems mentioned above. However, the multiple simultaneous effects of Adverse effects pharmacological concentrations of somatostatin in different organs, the need for intravenous administration, Common adverse effects of octreotide treatment include its short half-life in the circulation, and the post-infusion nausea, abdominal cramps, diarrhea, flatulence and fat hypersecretion of hormones considerably hampered the malabsorption (12). These symptoms start within hours

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-19-0074 European Journal of Endocrinology https://eje.bioscientifica.com However, after1weekadaptationdevelops, andduring administration reducedglucose toleranceisobserved. of carbohydrates.Inthe firstdaysofoctreotide in normalindividuals,while itdelaystheabsorption Octreotide inhibits GH,insulinand glucagon secretion occurs inonly1%ofpatientspertreatmentyear( sludge orgallstones,butsymptomaticgallbladderdisease one-third ofpatientswithacromegalydevelopbiliary composition andgallbladdercontractility( ( lipase diminishandsubsequentlydisappearcompletely and on thesecretionofgastricacid,amylase,trypsin effects volunteers theinitialdose-dependentinhibitory Indeed, after7daysofoctreotideadministrationinhealthy on thefunctionofgastrointestinaltractandpancreas. desensitization/tachyphylaxis oftheeffectsoctreotide resolution ofthesesymptomssuggestsrapidadaptation/ tract andexocrinepancreas ( actions ofsomatostatininthegastroenterological effects isreadilyunderstoodfromthephysiological continuous treatment. The occurrence of these adverse and theyresolvespontaneouslywithin7–14days,despite after injectionofthedrug,theirseverityisdosedependent, The structureofnaturalsomatostatin-14andoctreotide. Figure 1 13 Amino acidsessentialforreceptorbinding Ala Review Octreotide , 14 ). Octreotidetherapycanleadtochangesinbile Gly Human somatostatin Cys Cys S S Ser Ly s D-Phe Thr-ol Thr Asn 2 Cys Cys L JHofland S WJLambertsand Phe , Phe S S

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IGF-I normalizedin67%of patients. it becameevidentthatGH wascontrolledin57%,and elicited similar response rates ( Interestingly, Octreotide-LAR andLanreotide-Autogel subsequently causedasimilar orevenbettercontrol( ( octreotide reducedGHandIGF-Ilevelsinmostpatients therapy contributestothis. However, it remainsunknowntowhichextentmedical long-term therapywithoctreotidefailedordemonstrated nesidioblastosis andinthepreventionoftallstature, complications of diabetes, in (neonatal) hypoglycemia, the metaboliccontrolandpreventionofchronic diarrhea, intestinal fistulas, fistulas. Alsoin secretory orofpancreatic the outcomeofelectivepancreaticsurgery suppression turnedouttobetooshort-livedimprove transient suppression by octreotide of pancreatic enzyme gastrointestinal andpancreaticdiseasesdiabetes.The concerning itspotentialclinicaluseforanumberof organ systemseventuallyresultedindisappointment on anumberofphysiologicalfunctionsindifferent shown in effect ofoctreotideonnormalGHsecretioninratsis example oftherapidadaptationinitialsuppressive GH secretionandIGF-Ilevelsremainunchanged. An glucose homeostasis in normal individuals, while also long-term administration,octreotidedoesnotchange mortality riskassociatedwithacromegaly( normalization ofGH/IGF-Ilevelsimprovestheexcess improve duringlong-termtherapy. disorders(snoring,sleep apnea) cardiac andrespiratory 19 improve togetherwiththealloverqualityoflife( excessive perspiration,paresthesiasandcarpalsyndrome rapidly afterthestartoftherapy, forexampleheadaches, majority ofpatients:amarkedreliefsymptomsoccurs of acromegalyhasbeenparamountbenefitforthe The introductionofoctreotideinthemedicaltreatment Acromegaly of patients( the abdominalvessels,improvingoutcomeinasubset bleeding octreotidetransientlylowersbloodpressurein only short(days)transientbeneficialeffects( Octreotide 18 ). Alsodisease-associatedco-morbiditiesincluding , The rapidadaptationoftheseinitialeffectsoctreotide The initiallyavailable subcutaneous form of There isevidencethatanearlydiagnosisand Only intheinitialtreatmentofacutevariceal 19 , 22 Fig. 2 ), butthemonthlyOctreotide-LARpreparation 17 ). . Downloaded fromBioscientifica.com at09/23/202109:50:19AM 24 , 25 ). From these studies, 181 :5 12 , 16 20 12 R174 ). , , 23 21 18 via freeaccess ). ). ,

European Journal of Endocrinology mean last injection; in normalfemalerats.Bloodwas collected30 minafterthe (middle panel)or10days(right panel)oncirculatingGHlevels octreotide (SMS201-995)orplacebofor4(leftpanel),6 The effectoftwicedailysubcutaneousadministration Figure 2 Review plasma GH ( g/L) plasma GH ( g/L) plasma GH ( g/L) ± 40 20 30 50

20 30 50 10 10 40 10 20 40 30 50 s . e . m . AdaptedfromRef.( n = 8 animalspergroup;values represent placebo placebo placebo 2x2 2x2 after 10days after 6days after 4days 2x2 52 g g ). g SMS 201-99 SMS 201-99 L JHofland S WJLambertsand SMS 201-99 2x5 2x5 2x5 g g g2 2x10 5 5 2x10 5 x10 g g g from 17to37%. prior somatostatintherapy, responseratesareranging naive patientsnotpreselectedforresponsivenessto composite biochemicalendpointstoevaluatetreatment- IGF-I levels( of age-adjustednormalizationbothmeanGHand endpoints havebecomemorestrictintheirrequirement but mostimportantthatoverthepastyearsbiochemical standardization ofGHandIGF-Iassaysisoftenlacking, betweenstudies,thatthethat biochemicaltargetsvary therapy arepotentialconfounders.Anotherproblemis of treatmentrespondersandpretreatmentwithmedical populations withregardtotumorsize,age,inclusion contribute tothesevariations:differenceinpatient 86% forOctreotide-LAR.Amultitudeoffactorsmight ( considerable variationbetweenstudies.Colao shrinkage occursintwo-thirdofpatients( acromegaly arealsoofclinicalimportance:tumor beta-arrestin 1 and filamin-A, have been associated with treatment. Otherfactors,including cellularE-cadherin, not theonlydeterminantin theresponsetooctreotide poor response( octreotide ( related totheinvivoresponseofGHandIGF-Ilevels to adenoma cells areclosely the GH-secretingpituitary ( transsphenoidal surgery tumor tissueremoved from acromegalic patients during of octreotidecamemostlyfrom the disease. might havehappenedsomewhereinthecourse of Spontaneous hemorrhagewithinthetumortissue The mechanismofthisphenomenonremainsunclear. follow-up afterstoppingsomatostatinanalogtreatment. inthelong-termbiochemical ‘cure’hasbeenobserved take manymonths.Inalimitednumberofpatients symptomatology andtumorsize.Thisreversalcan results inmostinstancesaslowreversalofGHrelease, in thelong-termfollow-up.Stoppingoctreotidetherapy shrinkage onecanrelyonthemaintenanceofthiseffect responds withadecreaseinGHreleaseandtumor adenomainitiallyrare: oncetheGH-secretingpituitary functionremainsintact. and posteriorpituitary throughout therapy. Duringtreatment(remnant)anterior reaching itsmaximalafter6–12months,andlasts typically within 3 months, volume reduction is observed Octreotide 26 ) observed response rates varying between17and responseratesvarying ) observed Other effectsofsomatostatinanalogtherapyin However, thesebiochemicalresponseratesshowed Pathophysiological explanation of the effects Escapes fromoctreotidetherapyareextremely 29 27 , 30 Fig. 3 ). Inprospectivestudiesusingstringent ). LowSST2-expressingtumors exhibita ). SST2receptorexpression appears Downloaded fromBioscientifica.com at09/23/202109:50:19AM 9 , 28 ): the number of SST2 on https://eje.bioscientifica.com in vitro 181 :5 studieswith 27 ). Tumor R175 t al et via freeaccess .

European Journal of Endocrinology https://eje.bioscientifica.com target organs( processes, between the adenoma cell and SST2 on normal intracellular mechanisms involved indesensitization complex onthecellmembrane and/oradifferencein internalization andreappearance ofthepeptidereceptor tachyphylaxis couldinvolveadifferenceinthe tumor sizewithoutanescape/adaptation/desensitization/ long-term effectofoctreotideonGHsecretionand administration. Themechanismwhichascertainsthe and reversaloftumorsizeafterstoppingoctreotide anti-tumor effect,asreflectedinreboundGHsecretion shrinking effectdoesprobablynotincludeanimportant capacity and of related intracellular components. This results intoshrinkageoftheGH-synthesizingandstoring degradation ofstoredhormone( suggests thatoctreotideinducesincreasedlysosomal is associatedwithaccumulationoflysosomes,which of GHreleaseinsomatotrophadenomasbyoctreotide of octreotide-naïvepatients( patients treatedwithoctreotide,comparedtoadenomas levels are significantly lowerin adenomas of acromegalic adenomas( pituitary culturesofhumanGH-secreting expression inprimary effectonGHmRNA not seemtohaveaninhibitory hormone synthesismaydecrease.Somatostatindoes suppressive effectonGHsecretion,buteventually adenomasinvolvesnotonlyanacute these pituitary 32 response to treatment with octreotide and lanreotide ( normalized group( an immunoreactivityscore(IRS))comparedwiththenon- significantly higherSST2Aimmunoreactivity(asquantifiedby treatment with long-acting octreotide (Octreotide-LAR) showed Patients thatachievedIGF-1normalizationafteradjuvant Figure 3 Review , 33 ). The mechanism of action of octreotide on 9 ). P = 0.002; 34 ). On the otherhand,GHmRNA n = 18). AdaptedfromRef.( 35 L JHofland S WJLambertsand ). Moreover, inhibition 36 ). Altogether, this 29 ). 31 ,

hypersecretion. Their clinicalmanifestationsareoftenrelatedtohormonal malignant tumors,whichhavemetastasizedatdiagnosis. tumors expressSST2( from which they originate: more than 80% of these neuroendocrine cellsinthegutandendocrinepancreas (GEP-NETs) haveretainedmanycharacteristicsofthe Gastro-entero andpancreaticneuroendocrinetumors neuroendocrine tumors Gastro-entero andpancreatic improvement ( release andcontroloftumorgrowth,aswellclinical and respondtooctreotidewithsuppressionofhormone adenomasexpressSST2 Most TSH-secretingpituitary TSH-secreting pituitaryadenomas was notreported. measured, whilepotentialshrinkage inasubsetofpatients group. Inthesestudies,progression oftumorgrowthwas of65.1vs33.0%intheplacebo progression-free survival other study lanreotide induced after 2 years a median tumor progressionfrom6to14.3months,whileinthe in thefirststudyoctreotideadministrationdelayed with well-differentiatedmetastaticGEP-NETs ( and Lanreotide-Autogel(Clarinetstudy)inpatients anti-tumor effectofOctreotide-LAR(PROMIDstudy) analog administration( suggesting direct anti-tumor effects by somatostatin many experimentalstudies,mainlyfromSchally’s group hormonal hypersecretion.Ontheotherhand,therewere improvement inmanyofthesepatientsduringcontrol might beattributedontheonehandtoclinical ofpatientswithGEP-NETS.Suchaneffect survival suggestions thatthismedicaltreatmentmightprolong of octreotideinthemid-eightiestherehavebeen on qualityoflifeareinmostcasesstriking. immediate clinicaleffectsofsomatostatinanalogtherapy gastrin, insulin and glucagon, respectively ( tumors secretingvasoactiveintestinalpolypeptide, lesions in50–80%ofpatientswithendocrinepancreatic ulceration, hypoglycemicattacksandnecrolyticskin dehydration, hypokalemicalkalosis,diarrhea,peptic in 70–90%ofcarcinoid patients ( caused byanoverproductionofserotoninandtachykinins Octreotide Two largeclinicaltrialsindeeddemonstratedadirect From earlyonaftertheclinicalintroduction Octreotide controlsdiarrheaandflushingattacks 37 , 38 ). 43 39 Downloaded fromBioscientifica.com at09/23/202109:50:19AM , , 44 40 ). ). Mostareslow-growing 41 ), whileitameliorates 181 :5 12 , 42 45 R176 ). The , 46 via freeaccess ): European Journal of Endocrinology binds to octreotide, resultinginacompound whichefficiently spacer (DTPA (diethylenetriaminepentaacetic acid))to use of Because oflogisticaland practical drawbacksofthe and the tumors relationship betweenthepresenceofSST2onthese octreotide hadbeencarriedout.Therewasacloseparallel in vitro number ofthesepatientsweresubsequentlyinvestigated paragangliomas ( in 38of42patientswithcarcinoids, isletcelltumorsand tumorsand theirmetastases localization oftheprimary to after theadministrationofTyr3-octreotide coupled feasibility tovisualizesuchtumors on hormone secretion by thesetumors,suggestedthe ( in vitro human neuroendocrinetumors,asdemonstratedby The presence of a high density of SST2 receptors on In vivo cell clonesappearthatlackSST2( its intracellularmessengersystem,buteventuallytumor connection betweenthepeptidereceptorcomplexand loss ofsensitivityseemsinitiallyberelatedtoa sensitivity isnotrestoredafteradrugholiday( downregulation ofSST2onthetumorcells,because Escape fromtherapyseemsnotrelatedtotransient by increaseofthedoseoctreotide/lanreotide. growth develops( loss of the control of hormonal secretion and of tumor these patientsis,however, thateventuallyadecrease/ octreotide/lanreotide. treatmentwith infra), candidatesforlong-termprimary patients, if SST2 are presentonthese tumors (vide therapy inmetastatic, inoperable GEP-NETs makethese the proven anti-tumor effects of somatostatin analog angiogenesis ( indirectly influencecellcycling( to intracellularsignalingpathwaysthatdirectlyor interaction with SST2 on the tumor cells is coupled of octreotide/lanreotide in GEP-NETs suggeststhattheir 39 Review , 123 A majorproblemofsomatostatinanalogtherapyin The immediateclinicalimprovementtogetherwith The molecularbasisoftheanti-proliferativeeffect 40 I ( , whilealsopreoperativehormonalstudieswith ), as well as the inhibitory effect of octreotide ), as well as the inhibitory 123 in vitro visualizationofSST2receptors 53 autoradiographyusing 111 in vivo I, analternativewascreated bycouplinga ). [ Indium ( 49 123 , thehormonalresponsepre-operatively, ). I-Tyr 54 visualization of these tumors ( 50 ). Thesurgicallyremovedtumorsofa 56 3 , ]octreotide scanningrevealedthe ). 51 ). Itcaninitiallybereversed 47 L JHofland S WJLambertsand ), apoptosis( 9 ). 125 in vivo I-Tyr3-octreotide inpatients 48 52 ) and/or ) and/or ). This 55 ).

developed; thisnewcompoundallowsanevengreater imaging with Recently with the introduction of PET imaging molecular is acandidateforSST2-targetedradiotherapy(videinfra). densities. ApositiveSSTscanpredictswhetherthepatient frequently eitherdonotexpressSST2orsoinlow of differentiation,becausepoorlydifferentiatedtumors 50% ofcases,butresultsheavilydependonthedegree visualization ofGEP-NETlesionssmallerthan1 changes in25–50%ofcases.SSTscintigraphyallows detection ofdistantmetastasesresultedinmanagement of patients.Wholebodyimagingatonetimeforthe sensitivity thanconventionalimagingstudiesin60–90% previously unknown metastases. SST imaging has greater tumor,allowing thevisualizationofprimary aswell 58 diagnostic andtherapeuticapproach( in patientswithGEP-NETs hasrevolutionizedtheir meningioma, sarcoidosis orrheumatoidarthritis. GEP-NET, ratherthanforexampleapreviously unknown alert whetheraSST2-positive locationindeedrepresentsa NETS is not high: in a given patient one should remain should realizethatthespecificity ofSSTimagingforGEP- visualized tissueswasascertained all conditions mentioned above the presence of SST on the and specificityofSSTimagingisextremelyhigh:indeed in processes wasunexpected.Itproventhatthesensitivity concerning the pathophysiological role of SST2 expression. in vivo tuberculosis and rheumatoid arthritis) can bevisualized activated immune cells in granulomas (in sarcoidosis and as well.Finally, itwasdemonstratedthat clustersof lymphocytes (malignantlymphomas)canbevisualized (meningiomas), glia(well-differentiatedastrocytomas), tissues thatnormallyexpressSSTRliketheleptomeninx in vivo cells expressSST2atavariabledegree,allowingtheir other organs, which contain dispersed neuroendocrine originating fromthebreast,kidney, and colon,ovary small-cell lung cancers. A number of adenocarcinomas thyroidcancersand pheochromocytomas, medullary well astheirmetastases: these includeparagangliomas, location as SST to allow visualization of their primary NETS many other neuroendocrine tumors express enough in humandiseases( provided many new insights in the distribution of SSTR spatial resolutionthan Octreotide ): 80–100%ofGEP-NETs expressatdiagnosisSST2, The introductionof The visualizationofSSTonsuchavarietydisease The clinicalintroductionofSSTscintigraphy has ( visualization.Tumors originatingfromother 52 , 54 68 , Ga-labeled somatostatinanalogshasbeen 57 ). Today, thereislimited knowledge 52 111 , 111 Downloaded fromBioscientifica.com at09/23/202109:50:19AM 54 In-DTPA-octreotide ( In-DTPA-octreotide scintigraphy , 57 https://eje.bioscientifica.com ). ApartfrommostGEP- in vitro 181 :5 53 . However, one , 54 59 , ). 55 R177 cm in , 57 via freeaccess , European Journal of Endocrinology https://eje.bioscientifica.com patients receivedthesamedoseofOctreotide-LARoncea received Octreotide-LARalone(60 metastatic midgutneuroendocrinetumors113patients multicenter studyin229patientswithwell-differentiated range of2 gamma-emitting radionuclidewithamaximumparticle the highest affinity to SST2. Lutetium-177 isa beta- and Tyr3-octreotate wasfoundtobethecompoundwith and were subsequentlyfoundwith doses of Initially, high efficacyresultswerebasedontheuseofvery internalization. AdaptedfromRef. ( excess (1 [ uptake, expressedasthepercentage oftheaddeddose cells ofahumancarcinoid.Values representtheamountof Time-dependent increaseduptakeof[ Figure 4 has beendevelopedstepbyoverthepast25years( for thetherapyofadvancedwell-differentiatedGEP-NETs radioactivity inthebloodandtumortissue( via thekidneys:thisresultsinahighgradientbetween while theunboundsomatostatinligandisrapidlycleared that suchinternalizationandretentionoccurs bearing SST2 expressingtumors, it wasdemonstrated ( and retentionofradioactivitywithinthesetumorcells resulted in a dose- and time-dependent specific uptake SST2-positive humantumorcellsto[ Early studies demonstrated that exposure ofcultured SST-targeted radiotherapy 125 Fig. 4

125 3 Review I-Tyr

[ I-Tyr ]octreotide The useofradiolabeledsomatostatinanalogtherapy 177 ) ( 3 internalized (% dose) Lu-DOTA-Tyr3-octreotide. Eventually ]octreotide, intheabsenceand inthepresenceof 0. 0. 1. 1. 2. 2. μ 60 111 M) unlabeledoctreotide,todetermine non-specific mm, andahalf-lifeof160 0 5 0 5 0 5 , In-DTPA octreotide.Morepromisingresults 61 ). Also,inanimalstudiesinvolvingrats c 60 ont ro ti l me 90 60 (m L JHofland S WJLambertsand Y-DOTA Tyr3-octreotide ). 125 oc mg/month), and116 h. Inamultinational, in I-Tyr tr 125 .) eot I-Tyr 3 ]octreotide by 240 id 177 e 3 vs *p ]octreotide Lu-DOTA- (1 56 c <0 in vivo µM) ont ). .0 62 1 ro ). l ,

( adenomas in bothGH-and ACTH-secreting pituitary SST5 expressionisfoundtobeofclinicalimportance lining thegutandofpancreas.Inhumanpathology organs, includingtheanteriorpituitary, theendocrinecells SST5 is distributed throughout the human body inseveral Somatostatin receptorsubtype5(SST5) and FDAapproval. octreotate therapyforNETpatientsrecentlyreceivedEMA and adverseeffectswerelimited( (14vs26deaths).Toxicityan increasedoverallsurvival dose Octreotide-LARonlygroup,whiletherewasalso at20months65vs10.8%inthehigh free survival: with the octreotate (7.4 month togetherwithfourinfusionsof[ et al long-term follow-up ( body growth,whileIGF-Ilevels remainloweredduring pasireotide administrationin youngratscompletelystops were biochemicallycuredwithpasireotide( in acromegalicpatientsdemonstratedthatmore term treatmentofOctreotide-LARandpasireotide-LAR as expected, a comparison betweentheeffect of long- higher suppressionofGHbypasireotide( SST 5mRNAexpressionwasaccompaniedbyasignificantly in anumberofacromegalictumorshigherexpression of nanomolar concentrationsofoctreotideandpasireotide: compounds alone( SST2 and SST5 suppressed GH more than SST2-specific compounds whichboundwithhighaffinitytoboth tumor cellswere functional: several newchimeric demonstrated that SST5 expressed on GH-producing patients withCushing’s disease,respectively( freecortisolconcentrationsin15and25%of urinary (82 patients)or900 of cases( by pasireotide in nanomolarconcentrations in 60% cells obtainedattranssphenoidaloperationissuppressed SST5 ( SST5 ( affinity toSST2,butanearly40timeshigher analog withanincomparisontooctreotideslightlylower Octreotide 64 , From pre-clinicaldata,ithad becomeevidentthat Van derHoek In earlystudiesfromMelmed’s laboratory, itwas Pasireotide isamultireceptor-targeted somatostatin . ( 65 75 67 ), whiletheirpresenceislowinGEP-NETS( 66 ) inpatientswithCushing’s disease,IGF-Ilevels 177 , 69 ). Corticotropinomaspredominantlyexpress 68 Lu compoundresultedinalongerprogression- ). Inamulticenterstudypasireotide(600 ) andACTHsecretionbyculturedtumor GBq with intervals of8weeks).TreatmentGBq withintervals μ 6 t al et g (80 patients) twice daily) normalized g (80patients)twicedaily)normalized , 71 74 ). Downloaded fromBioscientifica.com at09/23/202109:50:19AM . ( ). Also in a study by Feelders 72 ) comparedtheeffectsof 63 ). [ 181 177 177 :5 Lu-DOTA, Tyr Fig. 5 Lu-DOTA-Tyr 73 70 ). ). Indeed, ). 65 R178 ). via freeaccess μ 3 3 g ] ]

European Journal of Endocrinology and GEP-NETs. Very little innovation that competes which iscommonlyusedin thetreatmentofacromegaly Octreotide remains40years afteritsdevelopmentadrug, Octreotide after40years alone orincombinationwithaGHreceptorantagonist. of thisdrugisincomparisonwithoctreotide/lanreotide guidelines sofarconcerningthequestionwhatplace in abouthalfofacromegalicpatients;thereareno ( response tothecontrolofACTH/cortisolhypersecretion despite theexpectedimprovementofglucosetolerance in pasireotide treatment,while18%developeddiabetes, Cushing’s disease hyperglycemia was diagnosed during administration ofthedrug.Inabout40%patientswith metabolism, which did not improve during continued firstinjectiononadeteriorationofglucose from thevery 17 patientsafter80days( with alevelbelowthelowerlimitofnormalrangein9 decreased overtimeduringpasireotideadministration, (upper right).AdaptedfromRef.( adenoma cellsfrompatient6(upperleft)and12 pasireotide (10 nM)onGHsecretionbyculturedpituitary and patient12(lowerright).Effectsofoctreotide(10 nM) GH-secreting pituitaryadenomatissueofpatient6(lowerleft) expression (patient12).RelativeSST2andSST5in cultured cellswithhighSST5expression,comparedtoSST2 preferential inhibitionofGHsecretion In vitro Figure 5 70

relative copy number hGH release (% control) Review 100 120 100 150 200 60 80 50 ). Pasireotideinducesglucoseintoleranceanddiabetes 0 In allclinicalstudiesreportedsofarpasireotidecaused CONTROL dataoftwoacromegalicpatients,demonstratinga SSTR2 Adenoma patient6A OCT (10nM)

relative copy number * 400 500 600 700 800 SOM230 (10nM) SSTR5 * 75 ). 72 hGH release (% control) 120 relative copy number 100 100 150 200 ). 60 80 L JHofland S WJLambertsand 50 0 CONTROL in vitro SSTR2 denoma patient12 bypasireotidein OCT (10nM)

relative copy number 400 500 600 700 800 SOM230 (10nM) SSTR5 * patients ( targeted radiotherapywillbe afeasibleoptioninsome transient upregulationofSST2 toenhancetheeffectof studies suggest that pharmacologically driven Preliminary their qualityoflife.Apartfromcontrolhormonal of octreotidemeantanenormousimprovementin cases ( injections ofaGHreceptorantagonistissuccessfulinmost endpoints aredefined.Additionofoncedailyorweekly biochemical curedependsonhowstrictcomposite of patientsinwhichoctreotideeventuallyinducesa intact, whilenoescapefromtherapyoccurs.Thenumber functionremains long-term follow-up;alsopituitary tumor sizeintwo-thirdofcaseswithoutgrowthduring symptomatology andqualityoflife,itshrinkspituitary tolerated. Inacromegalyoctreotiderapidlyimproves safeandwell on normalorgansmakesthedrug very clinical introduction( an oralformulationofoctreotideisonthehorizonfor of bothdrugscanbeinterchanged intheclinic.Only and safety profile. The long-acting depot preparations earlier octreotide and lanreotide have a similar efficacy with thisdrugoccurredoverperiod.Asmentioned make themeligible for SST2-targeted radiotherapy ( patients havetumorsthatdonotexpresssufficientSST to Moreover, depending on the tumor type, 10–50% of NET the optimalmomentforSST2-targetedradiotherapy. of SST2expression.Itiscrucialtodefineinagivenpatient related tolossoftumordifferentiationandeventually occurs withanescapefromtreatment.This is therapy withoctreotideeventuallylossofsensitivity of SST2expressiononthetumors:duringlong-term NETs ishowtooptimally usethewindowofopportunity The centralproblemtobesolvedinpatientswithGEP- aswell). (proven shrinkage and prolonged survival growth), astotheuseofSST2-targetedradiotherapy analogs (hormonal hypersecretion and controloftumor applies bothtothetreatmentwith‘cold’somatostatin sensitivity ofthetumortissuetooctreotide:this unknown metastases, whileapositive scan predicts tumor,primary as well as their often previously patients: the scan indicates the localization of the revolutionized diagnosisandtreatmentofGEP-NET continuing efficacyandwithoutnotableadverseeffects. patients arecurrentlytreatedformorethan25yearswith Although notreportedindetail,anumberofacromegalic delay intumorgrowthprogression,aswellsurvival. have anti-proliferativeeffectsaswell,demonstratedby hypersecretion somatostatinanalogswereprovento Octreotide SST2 visualization and SST2-targeted radiotherapy 77 ). ForpatientswithGEP-NETs theintroduction 79 ). SST-targeted radiotherapyisaninnovative 76 Downloaded fromBioscientifica.com at09/23/202109:50:19AM ). TherapidadaptationofSST2 https://eje.bioscientifica.com 181 :5 R179 78 via freeaccess ).

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