investigational drugs targeting somatostatin receptors for treatment of acromegaly and...
TRANSCRIPT
1. Introduction
2. Somatostatin and somatostatin
receptors
3. Somatostatin analogs in the
management of acromegaly
4. Somatostatin analogs in the
management of NETs
5. Expert opinion
Review
Investigational drugs targetingsomatostatin receptors fortreatment of acromegaly andneuroendocrine tumorsAndrea Giustina†, Gherardo Mazziotti, Filippo Maffezzoni, Vito Amoroso &Alfredo Berruti†University of Brescia, Department of Clinical and Experimental Sciences, Brescia, Italy
Introduction: Octreotide long-acting release (LAR) and lanreotide Autogel
(ATG) are the two somatostatin analogs currently approved for treatment
of acromegaly and neuroendocrine tumors (NETs). The strength of
these drugs has been their specificity for somatostatin receptor subtype 2.
However, this peculiarity may become a weakness in some patients
with tumors harboring somatostatin receptors different from the subtype 2.
Another clinically relevant aspect related to the use of octreotide LAR
and lanreotide ATG is the burden of injectable drug regimen that
may adversely impact the quality of life of patients with acromegaly and
NETs.
Areas covered: The authors review the recently published evidence on novel
drugs targeting somatostatin receptors developed for treating acromegaly
and NETs. Within this article, the authors discuss: i) the pharmacology of
somatostatin and traditional somatostatin analogs; ii) the efficacy and safety
of multireceptor-targeted somatostatin analogs in acromegaly and NETs;
iii) the efficacy of chimeric molecules in acromegaly and NETs; iv) the prelimi-
nary data on the use of new injectable, oral and transdermal formulations of
octreotide in acromegaly.
Expert opinion: The development of new somatostatin analogs and new
formulations has opened a new scenario for treatment of acromegaly and
NETs. That being said, even though there have been big steps taken in the
development of new therapies for acromegaly, there are still a number of
unresolved issues, while more trials are necessary for the use of somatostatin
anaologs in the treatment of NETs.
Keywords: acromegaly, investigational somatostatin analogs, lanreotide, neuroendocrine
tumors, octreotide, pasireotide
Expert Opin. Investig. Drugs [Early Online]
1. Introduction
Somatostatin is a neuropeptide that regulates neurotransmission in the brain andhormone secretion from anterior pituitary, pancreas and endocrine cells withinthe gastrointestinal tract [1]. As somatostatin receptors (SSTRs) are densely expressedon human neuroendocrine tumors (NETs) and growth hormone (GH)-secretingpituitary adenomas and the regulatory functions of somatostatin are mainly inhibi-tory, somatostatin analogs have been developed to treat patients with acromegalyand patients harboring islet cell or carcinoid tumors [2,3]. Indeed, the use of naturalsomatostatin in clinical practice is limited due to its short half-life (< 3 min), aswell as the need of intravenous injection and the postinfusion rebound hormone
10.1517/13543784.2014.942728 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 1All rights reserved: reproduction in whole or in part not permitted
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hypersecretion [4]. Synthetic somatostatin analogs with longerhalf-lives have therefore been developed for therapeutic uses.Octreotide long-acting repeatable (LAR) and lanreotide
Autogel (ATG) are the two long-acting somatostatin analogscurrently approved for treatment of acromegaly and NET.These analogs, which are effective and well tolerated, can beadministered once monthly. However, not in all patientstreated with octreotide LAR or lanreotide ATG control ofhormonal hypersecretion and tumor growth can be obtained[5]. It is worthy to be mentioned that octreotide and lanreotidehave a restricted affinity profile for SSTRs targeting specifi-cally SSTR2 [6]. As a matter of fact, a relevant percentage ofthe patients defined as ‘resistant’ to somatostatin analogs doexpress prevalently one of the other four SSTRs in thetumors [7]. Based on these concepts, new SSTR-targetedanalogs have been developed with the rationale to overcomethe ‘resistance’ to octreotide and lanreotide of tumors withlow expression of SSTR2 [8,9].Another clinically relevant aspect related to the use of
octreotide LAR and lanreotide ATG is the burden ofinjectable drug regimen that may adversely impact the qual-ity of life of patients with acromegaly and NETs [10]. For thisreason, new oral and transdermic formulations have beenmanufactured to resolve the low acceptability for intramus-cular and subcutaneous (s.c.) administration of the drugs[11,12].This article will review the recent available evidences pub-
lished and express our personal opinion on the new drugstargeting SSTRs that have been developed over the last yearsfor treatment of acromegaly and NETs. Full-text articles inthe English language were selected from a PubMed search span-ning 1984 -- 2014, for keywords including ‘somatostatin,’‘somatostatin analogs,’ ‘somatostatin receptors,’ ‘acromegaly’and ‘NETs.’ Reference lists in selected papers were also usedto broaden the search.
2. Somatostatin and somatostatin receptors
Somatostatin is a small cyclic peptide widely expressedthroughout the central nervous system and peripheral tissues[13]. The coding gene is on chromosome 3q28, has two exonsand gives rise to a precursor that is processed into biologicallyactive forms, the most prevalent being somatostatin-14 andsomatostatin-28 [14].
Somatostatin exerts its biological effects by activating
specific membrane receptors, which are expressed throughoutthe body, including the central nervous system, hypothalamus,
gastrointestinal tract and pancreas [15,16]. There are five genesencoding six different SSTRs (SSTR1, SSTR2A, SSTR2B,SSTR3, SSTR4 and SSTR5), which allocate on five separated
chromosomes: 14, 17, 22, 20 and 16, respectively [15].SSTR2A and SSTR2B are two splice variants of the same
gene. All SSTRs belong to the superfamily of G protein-coupled receptors characterized by seven transmembrane a-helix domains connected by three intra- and three extracellular
loops [15,16]. A conformational change of the receptor aftersomatostatin binding leads to activation of an associated heter-
otrimeric G protein complex (consisting of a-, b- and g-subunits) and exchange of GTP for GDP on the a-subunit.All somatostatin receptor subtypes inhibit adenylyl cyclase via
the pertussis toxin-sensitive G protein family, Gi/Go. How-ever, the antisecretory action of somatostatin is not limitedonly to cAMP suppression [17] but also includes the activation
of various ion currents (K+ and Ca2+), which lead to membranehyperpolarization and inhibition of depolarization-induced
Ca2+ influx via voltage-sensitive Ca2+ channels [18]. Besidesthe effects on hormonal secretion, somatostatin and its analogshave a potent antiproliferative effect through both direct and
indirect mechanisms. Interestingly, somatostatin activates theserine/threonine MAPK, a pathway usually mediating the
mitogenic action of growth factors, such as epidermal growthfactor, cytokines and hormones [19]. The modulation ofMAPK activity and phosphotyrosine phosphatases, including
SHP1, SHP2 and density-enhanced phosphatase, areconsidered the key factors for the antiproliferative effects of
somatostatin in several tumor cells [19]. As a matter of fact,the activation of MAPK by somatostatin leads to cell cyclearrest with upregulation of two key cell inhibitors (p21 and
p27), which prevent the formation of the cyclin-dependentkinase complexes, arresting the cell cycle at the G1/S transitionphase [20,21]. Moreover, SSTR activation leads to hyperphos-
phorylation of cyclin E and kinase Cdk2, which control theG1/S transition, and regulate Zac1, which is a zinc finger
inducing apoptosis and cell cycle arrest. Although Zac1 is pre-dominant in the normal adenohypophysis, it is downregulatedin most pituitary adenomas. Loss of Zac1 triggers pituitary
cell growth [22] and abolishes the pituitary tumor cell responseto the antiproliferative action of octreotide. It is noteworthy
that cells expressing both SSTR2 and SSTR5 have more effica-cious response to the antiproliferative effects of somatostatin
Article highlights.
. Somatostatin analogs are the mainstay in the treatmentof acromegaly with beneficial effects on growthhormone hypersecretion and tumor growth.
. Somatostatin analogs control the clinical syndromecaused by functioning neuroendocrine tumors (NETs),whereas their effects on tumor shrinkage are minimal inthis clinical setting.
. In NETs, but not in pituitary adenomas, tachyphylaxismay occur with progressive loss of therapeutic efficacyof somatostatin analogs.
. Multireceptor-targeted somatostatin analogs, such aspasireotide, were shown to be effective in acromegalyas well as in NETs.
. New formulations of somatostatin analogs, such as oraland transdermal octreotide, have been developed toimprove the patient acceptability for a long-termtreatment.
This box summarizes key points contained in the article.
A. Giustina et al.
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analogs when compared with cells expressing SSTR2 alone.This finding suggests that amplification of the cell prolifera-tion pathway inhibition may be actually achieved through
receptor heterodimerization [23].Besides its direct effects, somatostatin may indirectly affect
the proliferation of NET and pituitary adenomas by inhibi-tion of angiogenesis. SSTR activation induces inhibitionof angiogenesis through G protein, calcium- and cAMP-dependent pathways, and is independent from PKC and tyro-sine phosphatase [24]. SSTR2 expression on proliferatingangiogenic vessels has been confirmed by immunohistochem-ical staining, suggesting that SSTR2 may be a specific targetfor antiangiogenic therapy with somatostatin analogs [25].Somatostatin was reported to regulate nitric oxide (NO)generation through the modulation of both the endothelialNO synthases (eNOS) and neuronal NO synthases. eNOSinhibition is an important prerequisite for the antiangiogeniceffects of somatostatin [26]. It has been demonstrated thatsomatostatin-induced negative regulation of NO is implicatedin the inhibition of tumor angiogenesis and growth via theSSTR3-mediated negative regulation of eNOS [27].
3. Somatostatin analogs in the managementof acromegaly
Human pituitary gland expresses SSTRs, and somatostatin isphysiologically involved in the regulation of GH secretionby somatotropes [28]. Somatostatin maintains the inhibitoryeffects on GH secretion even in GH-secreting adenomas,which express predominantly SSTR2, but also SSTR5 andSSTR3 [29].
Acromegaly is a relatively rare disease characterized byan excessive GH secretion, generally caused by a pituitary
adenoma resulting in elevations of the circulating levels ofGH and IGF-1 [30]. Acromegaly has an estimated prevalenceof ~ 40 -- 70 patients per million and an incidence of 3 -- 4new cases per million every year [31,32]. Due to slow diseaseprogression and often nonspecific symptoms, diagnosis isdelayed by several years after the first onset of symptomsand systemic complications may develop. As a matter offact, acromegaly is associated with reduced life expectancy instrict relationship with GH hypersecretion and occurrenceof cardiovascular and respiratory complications [33,34].
Aim of therapies for acromegaly is to reduce or controltumor growth, inhibit GH hypersecretion, and normalizeIGF-1 values in order to improve quality of life and restoremorbidity and mortality to that of the control population [35].Treatment possibilities include surgical removal of the pitui-tary adenoma, radiotherapy and medical treatment with astepwise approach [35-37]. According to the current guidelines,somatostatin analogs are the second-line therapy in patientsin whom surgery fails to control GH/IGF-1 hypersecretion,which is a quite frequent occurrence in patients prevalently(» 70%) bearing a macroadenoma [38]. Moreover, over therecent years somatostatin analogs have been also proposed asprimary medical treatment in patients with low chances of sur-gical cure (e.g., lateral extension of the macroadenoma) [39].
Octreotide was the first somatostatin analog approved for thetreatment of acromegaly [40]. This synthetic analog is a cyclicocteopeptide (SMS 201 -- 995: H-[D] Phe-Cys- Phe-[D] Trp-Lys-Thr-Cys-Thr[ol]), containing the required residues of thenatural hormone, highly resistant to enzymatic degradationand stabilized by a cystine bridge [41]. In contrast to the shorthalf-life of native somatostatin, octreotide has a more prolongedhalf-life, of about 90 -- 120 min when administered subcutane-ously [41]. Octreotide has different affinities for SSTRs with high
Table 1. Investigational drugs targeting somatostatin receptor in acromegaly.
Agent Route of
administration
Pharmaceutical
company
Trials Binding
profile
Pasireotide Subcutaneous dailyintramuscular LAR
Novartis NCT00171730NCT01137682NCT00600886NCT01995734
SSTR1,2,3,5
Somatoprim Subcutaneous Aspireo N.A. SSTR2,4,5ITF 2984� Subcutaneous Italfarmaco NCT02111044
NCT01871844SSTR1,2,3,5
Octreotide + Polaxamer Intramuscular Novartis N.A. SSTR2, SSTR5Q-Octreotide Intramuscular Q Chip Ltd N.A. SSTR2, SSTR5CAM-2029� Subcutaneous Camurus N.A. SSTR2,SSTR5Octreolin� Daily oral formulation Chiasma NCT01412424 SSTR2,SSTR5IntravailOctreotide ProTek�
Oral formulation Aegis Therapeutics N.A. SSTR2,SSTR5
Octreotide Hydrogel Transdermal Indevus NCT01295060NCT00765323
SSTR2,SSTR5
OctreotideGP02�
Transdermal Glide N.A. SSTR2,SSTR5
LAR: Long-acting release; N.A.: Not available; SSTR: Somatostatin receptors.
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and NETs
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affinity for SSTR2 and moderate or weak affinity for SSTR5and SSTR3, respectively. The effectiveness of octreotide in con-trolling GH hypersecretion was demonstrated for the first timein the mid-1980s [42] and thereafter confirmed by larger andlonger term trials [43-45]. However, it became soon evident thatthe s.c. regimens of regular octreotide did not guarantee thebest effectiveness of the drug, since the continuous infusion ofthe drug was shown to be more effective than the multiple dailyinjections [46]. For this reason and also to reduce the burdenof multiple daily injections, long-acting somatostatin analogformulations were made available and approved for treatmentof acromegaly.Lanreotide (BIM23014: D-Nal-Cys-Tyr-D-Trp-Lys-Val-
Cys-Thr-NH2) was the second somatostatin analog to be devel-oped for treatment of acromegaly [47]. Lanreotide has slightlyless affinity for SSTR2 and greater affinity for SSTR5 as com-pared with octreotide. Moreover, lanreotide was also shown tohave lower affinity for the SSTR3 than octreotide, althoughthe overall binding affinity for both molecules is modest [48].Lanreotide slow release was the first formulation of lanreotideto be used in clinical practice, with drug incorporated into a bio-degradable polymer microparticle to allow prolonged release.Octreotide LAR and lanreotide ATG are the two long-acting
analogs currently used in the medical treatment of acromegalywith different pharmacokinetic profiles [49] but comparableeffectiveness [50-52]. However, about 50% of patients treatedwith these drugs do not achieve full biochemical control ofacromegaly and this percentage may increase when data fromregistries of unselected patients are considered [5,53,54]. It is note-worthy that just a minority of patients with acromegaly can beconsidered to be completely resistant to somatostatin ana-logs [7,55,56], whereas most patients can be defined as partialresponder to somatostatin analogs and an improved responsecan be achieved by increasing the drug doses [57] or shifting toalternative analogs with different affinity profiles [58-60].
3.1 Multireceptor-targeted somatostatin analogs in
acromegalyPasireotide is a multireceptor-targeted somatostatin analogderived from incorporation of four synthetic and two essentialamino acids of somatostatin in the form of a novel basictrans-(L)-hydroxyproline aminoethyl urethane extension, phe-nyglycine, O-benzyl-tyrosine and D-Trp to correspondingpositions into a stable cyclohexapeptide (Table 1). Pasireotideis currently approved for treatment of Cushing disease, butthere has been also evidence for efficacy of this drug in patientswith acromegaly. One of the peculiar properties of this mole-cule is the broader spectrum of affinity with respect to octreo-tide and lanreotide for different receptor subtypes (SSTR1,2,3,5). In fact, pasireotide exhibits a 20 -- 30 times higher bind-ing affinity to SSTR1, and a 40 -- 100 times higher bindingaffinity to SSTR5, respectively [61]. Interestingly, pasireotidedemonstrates one of the highest binding affinities to SSTR5ever reported for an SSTR ligand, which is even two times
greater than that reported for native somatostatin, with poten-tial advantage in suppressing GH secretion by pituitary adeno-mas [62]. Moreover, the affinity of pasireotide for SSTR3 is fivetimes higher as compared with octreotide [61]. Based on thesedifferences in the binding profile, pasireotide was shown tohave an in vitro potency in inhibiting GH secretion, whichwas three- to fourfold higher as compared to native somato-statin and octreotide [61]. Moreover, in vivo studies demon-strated that pasireotide had longer half-life than octreotidewith more pronounced reduction of plasma GH and IGF-1and no signs of escape even after continuous high-dose infu-sion of drug over 18 weeks [61]. On the basis of these preclinicaldata, clinical trials have been initiated for investigating theefficacy of pasireotide in patients with acromegaly. An earlierproof-of-concept study showed that single doses of s.c. pasireo-tide of 100 and 250 µg suppressed GH and IGF-1 levels in adose-dependent manner in 12 patients with acromegaly, andin 3 of them the pasireotide-induced GH suppression wasgreater than that obtained with octreotide [63]. In subsequentshort- and long-term studies, pasireotide was shown to nor-malize serum IGF-1 values in about 50% of acromegalypatients with a rigorous biochemical control in about one-quarter of treated patients [58,59]. In about 60% of patients,the tumor volume shrank by > 20% [59]. More recently, along-acting pasireotide formulation, similar to octreotideLAR, was obtained with biodegradable polymers to releasethe active drug over an extended period of time in order toallow once-monthly intramuscular administration [64]. In arecent head-to-head trial, naive acromegaly patients resultedto be more likely to achieve biochemical control with pasireo-tide LAR as compared to octreotide LAR (35.8 vs 20.9%) after12 months of treatment [60]. Moreover, in a more recentPhase III randomized study, pasireotide LAR was shown toinduce biochemical control of acromegaly in 20% of patientspreviously not controlled by octreotide LAR or lanreotideATG, suggesting that pasireotide may be a new therapeuticoption in patients nonresponder to conventional somatostatinanalogs [65]. The safety profile of pasireotide was similar tooctreotide, with the exception of the frequency and severityof hyperglycemia-related events [60]. This finding is consistentwith the binding profile of pasireotide characterized by greateraffinity than octreotide for SSTR5, a receptor expressed bypancreatic b-cells and modulating insulin secretion [66]. Stud-ies performed in healthy volunteers showed that pasireotideinhibited insulin secretion and incretin response, with minimalinhibition of glucagon secretion and no impact on insulinsensitivity [67,68]. It is worthy to be mentioned that acromegalypatients may be already affected by glucose intolerance ordiabetes [69,70] and treatment with somatostatin analogs mayimprove the abnormalities of glucose metabolism by control-ling GH hypersecretion [71,72]. However, the clinician shouldbe aware that a clinically significant deleterious glycometaboliceffect may be observed in some patients treated with pasireo-tide, especially when acromegaly is not biochemically con-trolled by the treatment, such as already demonstrated for
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octreotide and lanreotide [71,73,74], and when patients are withglucose disorders before starting treatment [75].
Somatoprim is a novel heptapeptide somatostatin analogwith a novel amino acid sequence and a unique cyclic back-bone [76]. In addition to its affinities to SSTR2 and SSTR5,somatoprim has a nanomolar affinity for SSTR4 (Table 1) [76].Notwithstanding this broad affinity profile, somatoprim wassuggested to have a selective inhibitory effect on GH secretionwithout affecting insulin secretion [76]. In in vitro studies,somatoprim was shown to be effective in suppressing GHsecretion by adenomas nonresponsive to octreotide [77,78].Somatoprim is under development by licensee Aspireo Phar-maceuticals (Tel Aviv, Israel), and clinical trials are ongoingto confirm the preclinical data. In an interim analysis, a ben-eficial side-effect profile was suggested in respect to octreotide(press release, Aspireo Pharmaceuticals) [79].
ITF2984 (Italfarmaco, Milan, Italy) is a novel hexapeptide,pan-agonist of SSTRs with nanomolar affinity for SSTR1, 2,3 and 5 (Table 1). A Phase I trial performed in 2013 evaluatedthe effects of ITF2984 in normal subjects on GH, insulin,glucagon and glucose after exogenous stimuli [80]. A Phase IIstudy in acromegaly patients is in progress to investigate inacromegalic patients the effect of different doses of this pan-agonist of SSTRs (500, 1000 and 2000 µg) on GH andIGF-1 concentrations and to investigate safety and tolerabilityof the three different doses of ITF2984 [81].
3.2 New formulations of octreotide in acromegalyOver the recent years, new formulations of octreotide have beendeveloped to make easier the drug administration as comparedwith currently marketed long-acting somatostatin analogs, inorder to further enhance convenience and compliance forpatients with potentially lifelong need of this therapy. The addi-tion of a surfactant, Poloxamer 188, added to the octreotideLAR formulation has been proposed to improve wettabilityand resuspendability of the microspheres and quality of themicrospheres suspension (Table 1). As compared to the currentvehicle that contains no surfactant, it should allow a morehomogeneous and finer suspension with potential improve-ment in the feasibility of octreotide LAR injection [82]. Anotherpotential formulation of octreotide was proposed by Q ChipLtd. (Q-Octreotide), which developed the application of fluidicdroplet systems (including microfluidic and piezo-based plat-forms) to formulate monodispersed microspheres for the con-trolled release of drugs (Table 1). Q-Octreotide is a 30-dayoctreotide acetate depot formulation, which begins to steadilyrelease the drug immediately, that is, without a lag phase. Fur-ther, bioavailability is reported to be markedly increased ascompared to the marketed product. No information on ongo-ing trials is available [83].
Camurus (Lund, Sweden) developed a ready-to-use liquidcrystal depot formulation of octreotide acetate (CAM-2029)that slowly delivers drug to plasma to improve complianceand create potentially a better therapeutic profile (Table 1)[84]. While traditional depot drugs are frequently based on
complex microsphere technology for intramuscular injection,this formulation allows for s.c. injection of a small volume liq-uid that transforms into a biodegradable liquid crystal gel atthe site of injection. The improved stability of the drug withpossibility to store medication at room temperature and theuse of ready-to-inject syringes with a thin injection needlerepresent two potential major advantages as compared to theoctreotide LAR and lanreotide ATG available formula-tions [84]. The available preclinical and clinical data indicatethat the liquid crystal depot formulation of octreotide acetateprovides extended octreotide release over a period of 28 days,allowing once-monthly administration, and in a recent open-label Phase I study the liquid crystal depot formulation ofoctreotide acetate was shown to provide greater octreotidebioavailability with a more rapid onset and similar durationof effect compared with octreotide LAR [85]. Phase III clinicaltrials are currently underway [86].
One of the major challenges in the field of pharmacology ofsomatostatin analogs has always been the synthesis of moleculesthat could be given orally. Octreotide, lanreotide and pasireo-tide use has been limited to the parenteral route because theyexhibit low and variable systemic bioavailability upon oraladministration. There have been a number of attempts to aug-ment somatostatin analog intestinal absorption [87-89], butonly recently a new formulation of oral octreotide (octreolin)has been manufactured by Chiasma (Jerusalem, Israel) combin-ing the drug with other excipients to form an oily suspension ofhydrophilic particles in a lipophilic medium guaranteeing intes-tinal permeability by transient and reversible loosening ofepithelial tight junctions in the small intestine (Table 1) [90]. APhase II study demonstrated equivalent pharmacokineticparameters using 20 mg of oral octreotide or 100 µg of s.c.octreotide, supporting oral octreotide as an alternative toparenteral formulation to treat acromegaly patients [91]. In aPhase III trial, oral octreotide acetate exhibited quite compara-ble efficacy and similar safety profile to injectable somatostatinanalogs in acromegaly patients treated for at least 7 months [92].
Another oral formulation of octreotide was provided in2011 by Aegis Therapeutics (San Diego, CA, USA), whichused the Intravail technology consisting in the use of a broadclass of chemically synthesizable transmucosal absorptionenhancement agents that allow noninvasive systemic deliveryof several drugs, such as octreotide. In experimental animals,oral delivery of octreotide acetate in Intravail significantlyenhanced total uptake, serum half-life and relative bioavailabil-ity when compared to delivery by s.c. injection [93]. In 2012, theProTek technology was proposed consisting in the use of exci-pients that prevent aggregation of proteins and peptides therebystabilizing them and reducing immunogenicity (Table 1). Pro-Tek technology allows creation of proprietary, easily manufac-turable, homogeneous, stable, aqueous or lyophilized dosageforms for peptide or protein therapeutics that maintain thestructural integrity and physiological activity of many proteinand peptide drugs, making them available for all routes ofadministration including oral, nasal spray or injection [94].
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and NETs
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Octreotide hydrogel implants were shown to be well toler-ated and maintained stable octreotide release and suppressionof IGF-1 and GH over 6 months in patients with acromegaly(Table 1) [12]. With 84 mg implants, serum octreotide concen-trations increased within 8 days and peaked between days 14and 28 after implant insertion [95]. Octreotide hydrogel wasshown to have comparable efficacy and safety to octreotideLAR [95]. Indeed, diarrhea and headache were more frequentwith the implant, whereas cholecystitis and hypertensionwere more frequent with octreotide LAR [95].Glide octreotide acetate (GP02) is a needle-free drug appli-
cation system (Table 1). It relies on a pointed implant contain-ing active pharmaceutical material that is injected through theskin [84]. In Phase I trial, this formulation was bioequivalent tos.c. injections of regular octreotide, and Phase II is currentlyunderway [84].
3.3 Chimeric analogs (dopastatins) in acromegalyDopamine receptor type 2 (DR2) and SSTR2 may have addi-tive effects in suppressing GH secretion and inhibiting cellproliferation [96,97]. The binding to somatostatin analog ordopamine agonist may lead to receptor heterodimerization,resulting in increased affinity for dopamine and increased sig-naling via the dopamine receptor. However, SSTR2 signalingis not altered by heterodimerization with the DR2, but itsendocytic rate is increased as a consequence of this interac-tion [98,99]. The chimeric analog BIM-23A760 or dopastatinis a chimeric compound containing structural elements ofboth somatostatin and dopamine in a single molecule, retain-ing potent and selective binding to both SSTR2 andDR2 [100]. However, clinical studies with dopastatin havebeen halted due to unpredictable dopastatin metaboliteaccumulation showing dopaminergic activity [101].
4. Somatostatin analogs in the managementof NETs
The term NETs encompasses a heterogeneous group ofrelatively rare tumors that originate most frequently fromendocrine organs such as the gastrointestinal tract, pancreasand bronchus. These tumors share similar characteristicssuch as the expression of specific markers associated with thegranules and vesicles characteristic of peptide-producing neu-roendocrine cells, secretion of hormones, the association withinherited syndromes, common activated molecular pathwaysand the expression of membrane SSTRs [102,103]. These char-acteristics translate into a common therapeutic targeting [104].These tumors are G1 and G2 gastrointestinal NETs
according to the WHO classification [105] and typical andatypical lung carcinoids according to the Travis classifica-tion [106]. They are characterized by relatively slow tumorgrowth, hypervascularized stroma and have a distinct behaviorwith respect to neuroendocrine carcinomas that are poorlydifferentiated NETs belonging not only to G3 digestive
neuroendocrine carcinomas but also to large cell and smallcell bronchial carcinomas.
The indolent course of these diseases leads to a relativelygood prognosis, and the survival of patients with metastaticdisease may be so high to reach 100% at 5 years accordingto tumor characteristics. Therefore, prognostic parametersbalanced with safety issues are the key elements in thedecision-making process of the best therapeutic interventionfor each patient.
Somatostatin analogs were developed in the early 1980s,and nowadays these drugs are still playing an important rolein the management of NETs and are considered the bestfirst-line medical treatment both in functioning and in non-functioning well-differentiated NETs (G1-tumors) [107].
The mainstay of therapy of NETs and lung carcinoids issurgery. Complete surgical removal is the only potentiallycurative approach of these neoplasms and has the mostimportant impact on patient’s prognosis. All medical thera-pies, including the somatostatin analogs are currently pre-scribed in the management of patients with advanced/metastatic disease in whom surgical resection cannot beradical. The high expression of SSTRs in NETs gives therationale for the use of somatostatin analogs in the treatmentof these tumors [108], as well as for the use of SSTR-targetedimaging techniques to localize NETs [109]. In gastrointesti-nal--pancreatic NETs, both SSTR-2 and SSTR-5 are foundin ~ 90 and 80% of tumors, respectively [4,110], althoughthere is considerable variation in SSTR density and subtypeexpression among the different tumor types and even amongtumors of the same type [111].
Somatostatin analogs are very well tolerated in the longterm. The most frequent side effects, such as abdominaldiscomfort, bloating and steatorrhea, are usually mild and dis-appear after few weeks. The most important side effect is cho-lestasis with subsequent risk of up to 60% to developcholecystolithiasis. This favorable safety profile allows thepatients to maintain an acceptable quality of life, and this isparticularly relevant in NETs patients who are long-term sur-vivors and therefore need to continue therapy for prolongedperiods of time (years).
Noteworthy, in addition to somatostatin analogs severaltherapeutic options are available for treating patients withadvanced NETs such as debulking surgery, interferon,peptide receptor radiotherapy, chemotherapy and chemo-embolization. More recently, large prospective randomizedclinical trials have demonstrated that antiangiogenetic drugsand m-TOR inhibitors are effective in the management ofadvanced NETs, particularly those of pancreatic origin [112].This raises the question on how can we integrate somato-statin analogs with the other available therapies. To providean answer to this question, we should consider: i) what isthe efficacy of these drugs as single agents in both the controlof the syndrome and the improvement of the patient out-come; ii) which are the data available supporting the syner-gism between somatostatin analogs and other treatments;
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and iii) what are the future perspectives of drugs targetingthe SSTR in NETs.
4.1 Somatostatin analogs as single agents in NETsSomatostatin analogs, in particular octreotide and lanreotide,are well known to be effective in controlling most NEThypersecretion-associated symptoms. Both drugs inhibit amineand peptide secretion by NETs and provide persistent controlof hypersecretion symptoms such as flushing and diarrhea incarcinoid syndrome [113] and watery diarrhea and necrolyticmigratory skin lesions in the glucagonoma syndrome [107].The use of currently available somatostatin analogs may notbe so effective in the management of insulinoma syndrome [114].In fact, the inadequate control of insulin hypersecretion bysomatostatin analogs is likely a consequence of the low expres-sion of SSTR2 and SSTR5 in insulin-secreting NETs, whichalso explains the low prevalence of octreoscan positivity in thesetumors. However, malignant insulinomas, as opposed tobenign insulinomas, often express SSTR2 [115] and thereforecan be targeted therapeutically by long-acting somatostatin ana-logs [116]. Interestingly, a positive s.c. short octreotide test wasfound to be a better marker of the therapeutic response ascompared with a pretreatment-positive octreoscan [116]. Itshould be noted that the somatostatin analog-induced inhibi-tion of contra-regulatory hormones (glucagon, GH andIGF-1) may in part counteract the effects of insulin suppression,thus hampering the effectiveness in the improvement of hypo-glycemia [117]. This effect may be relevant particularly at thebeginning of treatment of malignant insulinoma syndromewith somatostatin analogs; therefore, blood glucose levelsshould be carefully monitored in the first weeks of treatment.
Somatostatinomas are very rare tumors, originating either inthe pancreas or in the small intestine; the symptoms are usuallyrelated to somatostatin hypersecretion (i.e., hyperglycemia,cholelithiasis, diarrhea, steatorrhea and hypochlorhydria) orto the mass effect [118]. Treating patients with symptomsrelated to elevated somatostatin levels with somatostatin ana-logs seems paradoxical. However, in a study of three patientswith metastatic somatostatinomas, octreotide treatment waseffective in reducing plasma levels of somatostatin and inimproving related symptoms [119]. Somatostatin analogs werefound to be effective in the control of VIP-mediated hyperse-cretion of water and electrolytes by the intestinal mucosa,which causes the Verner--Morrison syndrome, characterizedby watery diarrhea, hypokalemia, achlorhydria and metabolicacidosis [107,120]. Overall 40 -- 60% of patients with secretoryNETs can obtain an effective control of the syndrome bysomatostatin analogs.
Loss in the control of hypersecretion-related symptoms afteran initial response in patients with NETs has been attributed bytachyphylaxis, whose precise mechanism is not fully elucidated.It may be due to desensitization, downregulation or alteredinternalization process of SSTRs [121], as well as to neutralizingantibodies to somatostatin or SSTR gene mutations [122].Tachyphylaxis is reported to occur within 9 -- 12 months after
beginning of treatment. At least initially, tachyphylaxis can bereversed by increasing the somatostatin analog dose [123].
Noteworthy, a true form of tachyphylaxis is not describedin pituitary adenomas, so this event seems to be confined toNETs, although both neoplastic tissues express the samereceptors (albeit in different amounts). This suggests thatthis form of acquired resistance could be prevalently down-streaming/intracitoplasmatic than due to receptor density oncell surface and may be related to biological changes of thetumor with development of resistant cells [107].
While the efficacy of somatostatin analogs in the control ofthe syndromes of functioning neuroendocrine neoplasms isvery well known since decades, only recently there was thedemonstration that these drugs also have an antiproliferativeactivity and may be effective in delaying the disease progres-sion in both functioning and nonfunctioning tumors. In thenine single-arm Phase II studies published between1996 and 2003 enrolling 266 patients (recently reviewedby Oberg [124]), the administration of somatostatin analogs,octreotide and lanreotide to patients with progressing meta-static NETs led to a response rate (complete + partial) inonly 5% of patients according to the WHO criteria while50% of patients obtained disease stabilization. However, thehigh rate of disease stabilization in tumors displaying notori-ously a rather indolent disease course could not be interpretedas a proof of antiproliferative activity of these drugs.
Recently, two prospective multicenter randomized clinicaltrials provided evidence that the long-acting somatostatin ana-logs may also be effective as antiproliferative agents in themanagement of advanced NETs. In fact, the PROMID trialevaluated the effects of octreotide LAR (30 mg every 4 weeks)versus placebo on progression-free survival of metastatic mid-gut NETs. Eighty-five patients were randomized to receiveoctreotide LAR (42 patients) or placebo (43 patients). Theyhad well-differentiated tumors with Ki67 expression < 2 in95% of cases (G1). A significant progression-free survivalimprovement in the octreotide treatment arm (14.3 months)as compared to placebo (6 months) was observed [125]. Also,the disease stabilization rate was significantly higher in theoctreotide LAR arm versus placebo. The efficacy of octreotideLAR in prolonging the progression-free survival was similar inpatients with either secreting or non-secreting tumors. Theseresults led to a change in the international guidelines forNETs [126]. However, they were limited to a specific subsetof patients with well-differentiated intestinal NETs and noinformation was provided on the efficacy of somatostatinanalogs in patients bearing other primary NETs. This wasaccomplished in part by the CLARINET study, a large pro-spective Phase III trial that evaluated the antiproliferativeeffects of lanreotide ATG versus placebo in 204 patients withadvanced/metastatic nonfunctioning, well or moderately dif-ferentiated gastro.enteropancreatic NET [127]. The primaryend point, that is, progression-free survival, was similar tothat of PROMID study. However, eligibility criteria includedpancreatic NETs, gastrointestinal tumors (both midgut and
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hindgut) and NETs of unknown primary origin. All eligiblepatients had tumors with < 10% expression of the proliferationmarker Ki67 and stable disease at randomization. The resultsof this study indicated that at a time point of 2 years followinginitiation of treatment, neither progression of disease nordeath occurred in 62% of lanreotide ATG patients as com-pared to 22% of placebo patients [127]. At the first plannedCLARINET extension study analysis, lanreotide ATG main-tained the antitumor effects with long-term safety/tolerabilityconsistent with its already known profile [128].Both the PROMID and CLARINET studies demonstrated
that, although somatostatin analogs have limited activity interms of tumor shrinkage, they are able to stabilize tumorgrowth over long periods of time, leading to a significant delayin disease progression. This is an unequivocal proof that theantineoplastic effect of these drugs is mainly antiproliferative.However, there is a subset of tumors, that is type 1 or 2 gastriccarcinoids, in which the administration of somatostatin ana-logs may lead to tumor shrinkage and even complete tumorresponse in a high percentage of treated patients. Gastriccarcinoids originate from enterochromaffin-like cells. Type 1(75%) is associated with chronic atrophic gastritis, andtype 2 (5 -- 10%) is associated with gastrin-secreting NETs(Zollinger--Ellison and MEN-1). Both tumors have in com-mon the coexistence of high levels of gastrinemia. In a casereport of a patient with multiple type 1 gastric carcinoids,treatment with the long-acting somatostatin analog octreotideLAR for a period of 9 months induced normalization of serumgastrin levels and permanent disappearance of the tumors [129].In another study, five patients with hypergastrinemia and gas-tric carcinoids were treated for 1 year with monthly injectionsof octreotide LAR; at the end of the study, although gastrin lev-els did not totally normalize, there was a significant reductionin tumor load, enterochromaffin-like cell density and normal-ization of circulating chromogranin A levels [130]. In a furtherstudy, three patients suffering from Zollinger--Ellison syn-drome showed a significant reduction in the gastrin levelsand no evidence of the tumor after 1 year treatment with lan-reotide or octreotide [131]. Since both type 1 and 2 gastric car-cinoids notoriously develop as a consequence of long-termexposure of gastric mucosa to elevated concentration of gastrin,these tumors maintain an absolute hormone dependency andmay undergo apoptosis when gastrin levels significantlydecrease after somatostatin analog administration. This is themost important and plausible mechanism of the significanttumor shrinkage obtained in these tumors by somatostatinanalogs, although other mechanisms of somatostatin analog-induced apoptosis cannot be excluded [132].
4.2 Somatostatin analogs in combinations with other
agents in NETsThe favorable safety profile and the peculiar mechanism ofactions make somatostatin analogs attractive for a combinationwith other biotherapies or molecular-targeted therapies [133].
However, a few data are available on the potential synergismbetween somatostatin analog and other active drugs in themanagement of NETs.
Interferon is a biotherapy that can be used in NETs with thesame indication of somatostatin analogs. The activity of inter-feron (at a median doses of 3 -- 5 million units thrice weekly)in the management of advanced NETs was assessed in 37 pub-lished studies involving 679 patients [124]. In these studies, thisagent demonstrated both antisecretive and antiproliferativeactivities. The antiproliferative effect of interferon is probablydue to a blockade of the cell cycle in the G0 -- G1 transi-tion [134,135]. The side effects of interferon limit its use in thelong term. Therefore, interferon is generally used in patientswith progressive symptomatic disease on somatostatin analogs.
However, somatostatin analogs and interferon have differ-ent mechanisms of action and this provides the rationale fortheir synergistic activity. In addition, a-interferon mightupregulate SSTRs on tumor cells [124].
The efficacy of the combination of somatostatin analogsand interferon versus somatostatin analogs alone was testedin three prospective randomized clinical studies. In the firststudy, Kolby et al. studied the effect of a-interferon inaddition to octreotide versus octreotide alone after liver embo-lization [136]. Sixty-eight patients with metastatic midgut car-cinoid were included; the primary end point was the time totumor progression (or death). After a follow-up rangingbetween 33 and 120 months, disease progression wasobserved in 19 out of 35 patients randomized to octreotidealone as opposed to only 6 out of 33 randomized tooctreotide + interferon (hazard ratio: 0.28, 95% confidenceinterval 0.16 -- 0.45; p < 0.008). The second randomized trial,by Arnold et al. included 109 patients with advanced gastro-enteric--pancreatic NETs that were randomized to octreotideversus octreotide plus interferon [137]. The primary aim wasthe time of treatment failure, which included death, progres-sion and intolerable adverse events. There were more progres-sions as reason for treatment failure in the octreotide andmore adverse events in the combination arm. After 12 months,no significant advantage in terms of time to treatment failurewas observed between the two treatment arms (hazard ratio:0.89, 95% confidence interval 0.59 -- 1.35). In the third trial,Faiss et al. randomized 84 untreated patients with metastaticprogressive NETs to lanreotide or a-interferon, or a combina-tion of the two drugs [138]. The primary end point was time totumor progression (within 12 months of therapy). The distri-bution of progressive disease among the three treatment armswas: 14/25, 15/27 and 14/28 in patients receiving lanreotide,interferon or both drugs. These three studies were heteroge-neous with respect to study design, patient populationenrolled and primary end point. Only one study was positive.The statistical power of these studies was low; however, twostudies reported explorative information on overall survival.In both studies, the combination somatostatin analog plusinterferon was associated with a nonsignificant reductionof the risk of death. We did a pooled analysis of both trials
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that showed that the somatostatin analog + interferonobtained a reduction in the risk of death by 24% that justfailed to attain the statistical significance (hazard ratio: 0.74,95% confidence interval: 0.51 -- 1.08, p = 0.11) (Figure 1).
The development of target therapies in the recent years,including inhibitors of mTOR and VEGF pathways, hasopened a new era in the treatment of NETs [133]. PivotalPhase III studies of everolimus (an mTOR inhibitor) and suni-tinib (a multi-target angiogenesis inhibitor) have shown thatboth drugs slow tumor growth and improve progression-freesurvival particularly in pancreatic neuroendocrine cancerpatients [112,133,139,140]. The question of whether the additionof somatostatin analogs such as octreotide, lanreotide andpasireotide can further improve the outcome of these newagents has not yet obtained an appropriate answer.
Successful mTOR inhibition leads to an increase inupstream p-AKT. Although AKT activation is associatedwith a more aggressive clinical course of NET [141], it is nota marker of resistance to allosteric mTOR inhibitors. Preclin-ical studies, in fact, have found that AKT activation is acommon feature in many tumor cell models that are sensitiveto mTOR inhibition [142-144] and data from a Phase II trial ofeverolimus-based therapy for NETs in which pretreatmentand posttreatment tumor tissues were obtained suggestedthat p-AKT increases more in responders as compared tononresponders. However, feedback loop AKT activationmay still limit the antitumor efficacy of rapamycin and ana-logs. Therefore, approaches to prevent AKT activation, suchas use of inhibitors of upstream signaling, are being pursued.
Somatostatin analogs can potentially inhibit the PI3K/AKTpathway by reducing IGF-1 and may have a synergistic activitywith mTOR inhibitors. The RADIANT-1 study is a Phase IIstudy in which advanced NET patients received everolimusalone or everolimus plus octreotide LAR according to whetherthe tumor was functional or not. The results showed that thecohort of patients receiving the combination of everolimusand octreotide LAR had longer median progression-free sur-vival (16.7 vs 9.7 months) [145]. The efficacy of everolimus
versus placebo was assessed in two randomized Phase III studies:RADIANT-2 that enrolled patients with advanced NETs andassociated carcinoid syndrome [146], and RADIANT-3 thatenrolled patients with advanced pancreatic cancer [139]. Inboth studies, everolimus demonstrated a significant advantageover placebo in terms of progression-free survival irrespectiveof pretreatment with somatostatin analogs. However, in noneof them it was possible to extrapolate data on the potential syn-ergism between somatostatin analogs and everolimus sinceoctreotide LAR was administered in both arms of theRADIANT-2 trial and a subanalysis of the efficacy of concom-itant treatment with somatostatin analogs versus no concomi-tant treatment was not performed in patients enrolled in theRADIANT-3 study.
4.3 High doses of somatostatin analogs in NETsThe improvement of the efficacy of somatostatin analogs inthe treatment of NETs can be potentially obtained by:i) increasing the doses of currently available somatostatinanalogs; ii) introducing multireceptor-targeted somatostatinanalogs; iii) developing new chimeric compounds.
It was suggested that higher than usual doses of somato-statin analogs (> 3.000 µg/day) may enhance their antiproli-ferative effect, especially in those patients already respondingto standard doses [147]. In a study where biopsy specimenswere taken before and during somatostatin analog treatment,it was shown that the treatment with high-dose somatostatinanalogs induced apoptosis in NETs, while this was not foundduring treatment with low-dose somatostatin analogs [148].We currently do not know what is the dose of somatostatinanalogs that is able to obtain the greatest antineoplasticactivity. Therefore, prospective randomized clinical trials areneeded to address this issue.
4.4 Multireceptor-targeted somatostatin analogs in
NETsAs previously underlined, after 9 -- 12months of treatment withoctreotide or lanreotide, one-third of NET patients experienced
0.62
0.82Kolby et al. (2003) [136]
Arnold et al. (2005) [137]
Overall0.74
In favour of IFN Against IFN
Hazard ratio
p value 0.11
0.75 1.0 1.250.500.25
Figure 1. Cumulative hazard ratio of death of IFN plus somatostatin analogs in randomized clinical trials.
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tachyphylaxis. Pasireotide shows a lower degree in SSTR2 inter-nalization and induces fast recycling to the plasma membrane,counteracting desensitization and resulting in a longer-lastingresponse [149,150]. Early data from a series of patients with met-astatic carcinoid syndrome refractory to octreotide LAR showedthat administration of pasireotide (450 -- 1200 µg) twice dailyresulted in control of symptoms in 33% of patients [151]. Similarpercentages of symptom control were confirmed years later in aPhase II, open-label, multicenter study of pasireotide in patientswith advanced NET whose symptoms of carcinoid syndrome(diarrhea/flushing) were inadequately controlled by octreotideLAR. Pasireotide 600 -- 900 µg s.c. bid effectively controlleddiarrhea and flushing in 27% of patients, and stable diseasewas reported in 57% of patients [152].A randomized, double-blind multicenter study was then
designed to assess whether pasireotide was superior to relativelyhigh doses of octreotide LAR for symptom control [153].Patients with breakthrough carcinoid syndrome symptomsdespite maximum doses of commercially available somatostatinanalogs were randomized to receive either long-acting pasireo-tide 60 mg or octreotide LAR 40 mg every 28 days. Symptomswere assessed daily. The results of this trial recently presented asa meeting abstract showed that pasireotide and octreotide had asimilar efficacy in terms of symptom control. However,patients on pasireotide obtained a median progression-free sur-vival of 11.8 months that was significantly higher than the6.8 months obtained in patients in the octreotide arm (hazardratio = 0.46; p = 0.045) [154]. Since progression-free survivalwas not the primary end point of the study, these results war-rant a large Phase III trial to clarify whether pasireotide ismore effective than octreotide as a therapy for NETs.The efficacy of pasireotide versus everolimus or the combi-
nation of both drugs is being tested in a randomized Phase IItrial involving patients with lung or thymus NETs. This trialis currently recruiting patients [155].
4.5 Chimeric analogs (dopastatins) in NETsThe chimeric somatostatin--dopamine compounds (dopasta-tins) with high affinity for SSTRs 2 and DR2 (BIM-23A387)or to SSTRs 2, 5 and DR2 (BIM-23A760) have shown toinhibit cell proliferation of the non-small cell lung cancer cellline Calu-6, which expresses SSTRs 2, 5 and DR2 with higherpotency and efficacy than SSTR2 and DR2 analogs [156].BIM23A760 was found to also inhibit ECL cell proliferationwith similar potency but with higher efficacy than lanreotideand DR2 analog [156]. The enhanced potency/efficacy ofBIM-23A387 and BIM-23A760 may in part be due to thehigh affinity of these compounds for SSTR2. However,SSTR2 can heterodimerize with SSTR5, and SSTRs 2 and5 can form heterodimers with DR2, which can alter receptorligand-binding affinity and/or signaling and/or receptor traf-ficking [157,158]. O’Toole et al. found that SSTR-2 and DR2were co-expressed in 100% of cases in a series of 35 patientswith GEP-NETs, suggesting that BIM-23A760 could haveactivity in these tumors [159]. To date, however, the activity of
chimeric molecules in the management of NETs has not beentested in prospective clinical trials.
5. Expert opinion
5.1 AcromegalyAcromegaly is a chronic disease that not infrequently needsa lifelong medical treatment. Reduction of mortality rateswith the improved care in the last decades has consistentlyincreased the length of treatment for each patient as well asthe absolute number of patients who are likely to be exposedto medical treatment.
Somatostatin analogs are the mainstay in the treatment ofacromegaly with a consolidated favorable benefit versus risksprofile. After the first experience with s.c. octreotide, researchwas driven to develop long-acting formulations to overcomethe burden of multiple daily injections of the drug and improvepatients’ compliance. Moreover, the long-acting formulationswere shown to bemore effective than s.c. octreotide consistentlywith the concept that prolonged exposure to the drug was morebeneficial than the intermittent administration [46]. Indeed, overthe last 20 years, long-acting octreotide and lanreotide havebeen extensively used to treat several thousands of patientswith acromegaly, allowing the clinician to rely on substantialevidence of their efficacy and safety in the day-to-day practice.Therefore, it could be surprising that after 30 years from theirappearance in the pharmacotherapy scenario there is still theneed to search for new analogs targeting SSTRs in acromegaly.
The strength of octreotide LAR and lanreotide ATG hasbeen their specificity for SSTR2, which has the major role inregulating GH secretion at the pituitary level in physiologyand was reported to be the most abundantly expressed in pitu-itary GH-secreting adenomas. However, this peculiarity ofoctreotide and lanreotide may become a weakness in somepatients. In fact, in real life, > 50% of patients fail to achievea rigorous biochemical control of acromegaly during treatmentwith octreotide LAR or lanreotide ATG. The current guide-lines recommend the patients to be shifted to pegvisomantwhen somatostatin analogs are ineffective to normalize GHand IGF-1 values [38]. However, pegvisomant is not a tumor-targeted therapy and the possible increase in tumor massduring treatment with this drug may be a clinical concern.
In several patients ‘resistant’ to octreotide and lanreotide,the analysis of receptor profile on the tumors revealed theabsence of SSTR2. However, since these tumors oftenexpressed other SSTRs, the theoretical possibility exists thatthey can be targeted by other somatostatin analogs withdifferent receptor affinity profiles. In fact, in these patients,the multireceptor-targeted somatostatin analogs, such aspasireotide and somatropin, may be used since these drugswere shown to be more effective than octreotide in control-ling GH hypersecretion. The use of multireceptor targetedanalogs is a significant advancement since these drugs havea receptor affinity pattern very close to that of nativesomatostatin, with the advantage to target multiple receptors
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on the tumors. However, SSTRs are diffusely expressed inseveral tissues and organs and the multiple receptor targetingmay also cause undesired effects, such as abnormalities ofglucose homeostasis [67]. In this context, somatoprim wassuggested to have less negative impact on glucose metabolismthan that already reported with pasireotide [76]. At the sametime, through their extrapituitary effects, multireceptor-targeted analogs may have potential positive effects on chroniccomplications of acromegaly regardless of the degree ofbiochemical control of the disease [160-163].
Which is the potential clinical use of these multireceptor-targeted analogs? In patients partially responder to availablesomatostatin analogs, an increase of the dose should be triedbefore shifting toward alternative drugs. In patients inwhom GH and IGF-1 levels undergo minimal changes duringoctreotide and lanreotide, pasireotide could be consideredespecially when tumor growth is a concern. There are norobust clinical experiences with somatoprim, which indeedcould have a place in patients with derangement of glucosemetabolism. In fact, at variance of Cushing patients forwhom a few other medical treatment options exist [164], thisside effect may represent a clinical problem in acromegalypatients for whom several other options, also beneficial forglucose metabolism such as pegvisomant, do exist [165].
Another aspect addressed by this Expert Opinion concernsthe potential improvement of compliance of patients in usingthe new formulations of octreotide. Octreotide LAR injec-tions are not easy to perform. In fact, the compound tendsto solidify into the syringe and the intramuscular injectionneeds to be performed long term by a trained doctor or nurse.Moreover, due to difficulties in the injections displacement ofoctreotide delivery in s.c. tissue may occur particularly infemales [166]. These shortcomings may be overcome by lanreo-tide ATG (also potentially by octreotide aqueous formula-tion) which is avaliable in read-to use prefilled syringes,possibly allowing (deep s.c. injections) the self-administrationby the patients [167]. Moreover, the parenteral route of admin-istration may anyway adversely impact the quality of life insome patients [10]. From this point of view, the new formula-tions of octreotide (oral and transdermal) may be of help formany patients, provided that risk/benefit profile is proven tobe similar to injectable octreotide.
Despite the enormous progress made so far in the treat-ment of acromegaly, several issues remain unresolved. Infact, as for all treatments of chronic diseases, personalizationis the key of success. But only with the increase in the treat-ment options, both in terms of different spectrum of actionand on modality of administration, appropriate tailoringof treatment can be performed. In these terms, the scenarioopened by the various experimental somatostatin analogs ispromising and personalization of treatment of acromegalywith optimal efficacy and compliance seems no more to be adream but a concrete possibility in a not-so-far future.
5.2 NETsThe somatostatin analogs octreotide and lanreotide have beenused for decades in the management of NETs with the aimto obtain a durable control of syndromes due to hormone hyper-secretion. The results of two prospective clinical trials(PROMID and CLARINET) have demonstrated that somato-statin analogs are effective in prolonging the progression-free sur-vival of patients with NETs of gastrointestinal or pancreaticorigin even without hormone hypersecreting syndromes[125,127,128]. No demonstration of efficacy of somatostatin analogsis actually available in the treatment of lung carcinoids.
Other drugs, such as molecular target agents (sunitinib andeverolimus) or interferon, have demonstrated to be effective inthe treatment of patients with NETs. Due to their favorabletoxicity profiles, somatostatin analogs are the preferred first-line treatment for non-progressing, grade 1, metastatic NETs.There is also a rationale to suggest a synergism between somato-statin analogs and other currently available drugs for NETs.
A pooled analysis of two trials performed in the presentpaper showed a reduction in the risk of death by 24% thatjust failed to attain the statistical significance with the addi-tion of interferon to somatostatin analogs in the treatmentof patients with metastatic NETs [136,137]. This observationmay renew the interest for these drugs whose use is dimin-ished and almost abandoned in several centers with the intro-duction in clinical routine of new molecular-targeted agents.
Multireceptor-targeted somatostatin analogs are effective inthe syndrome control of hypersecreting NETs that escape ordo not respond to currently available somatostatin analogs.Interestingly, the results of a randomized perspective Phase IItrial suggested that pasireotide may be more effective than rel-atively high-dose octreotide in prolonging the progression-freesurvival of metastatic hormone-secreting NETs with uncon-trolled syndrome by standard dose of octreotide [152]. Thesedata warrant the design of Phase III trial to assess the efficacyof pasireotide as opposed to octreotide (or lanreotide) in thetreatment of NETs. The LUNA trial is the first prospectiverandomized study even conducted in the management oflung carcinoids. This trial will explore the efficacy of eitherpasireotide or everolimus as well as the synergism betweenthe two drugs in affected patients.
Declaration of interest
A Giustina is a consultant for Ipsen, Novartis and Pfizer, Inc.,G Mazziotti has received consultancy fees from Novartis andlecture fees from Ipsen. A Berruti is on the advisory boardfor Italfarmaco S.p.A. and Ipsen, and has received lecturefees from Novartis, Ipsen and Italfarmaco S.p.A. The authorshave no other relevant affiliations or financial involvementwith any organization or entity with a financial interest in orfinancial conflict with the subject matter or materials dis-cussed in the manuscript apart from those disclosed.
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and NETs
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BibliographyPapers of special note have been highlighted as
either of interest (�) or of considerable interest(��) to readers.
1. Brazeau P, Vale W, Burgus R, et al.
Hypothalamic polypeptide that inhibits
the secretion of immunoreactive pituitary
growth hormone. Science 1973;179:77-9
.. The seminal paper reporting the
discovery of somatostatin.
2. Giustina A, Zaltieri G, Negrini F, et al.
The pharmacological aspects of the
treatment of acromegaly. Pharmacol Res
1996;34(5-6):247-68
3. Deghenghi R. Somatostatin analogues in
the treatment of the carcinoid syndrome.
Biomed Pharmacother 1988;42:585-8
4. Lamberts SW, van der Lely AJ,
de Herder WW, et al. Octreotide.
N Engl J Med 1996;334:246-54
5. Carmichael JD, Bonert VS, Nuno M,
et al. Acromegaly clinical trial
methodology impact on reported
biochemical efficacy rates of somatostatin
receptor ligand treatments- a
meta-analysis. J Clin Endocrinol Metab
2014;99:1825-33
6. Grasso LF, Pivonello R, Colao A.
Investigational therapies for acromegaly.
Expert Opin Investig Drugs
2013;22:955-63
7. Gola M, Bonadonna S, Mazziotti G,
et al. Resistance to somatostatin analogs
in acromegaly: an evolving concept?
J Endocrinol Invest 2006;29:86-93
8. Weckbecker G, Briner U, Lewis I,
Bruns C. SOM230: a new somatostatin
peptidomimetic with potent inhibitory
effects on the growth hormone/insulin-
like growth factor-I axis in rats, primates,
and dogs. Endocrinology
2002;143:4123-30
9. Cuevas-Ramos D, Fleseriu M.
Somatostatin receptor ligands and
resistance to treatment in pituitary
adenomas. J Mol Endocrinol
2014;52(3):R223-40
10. Ben-Shlomo A, Sheppard MC,
Stephens JM, et al. Clinical, quality of
life, and economic value of acromegalic
disease control. Pituitary 2011;14:284-94
11. Tuvia S, Pelled D, Marom K, et al.
A Novel suspension formulation
enhances intestinal absorption of
macromolecules via transient and
reversible transport mechanisms.
Pharm Res 2014. [Epub ahead of print]
12. Gadelha MR, Chieffo C, Bai SA, et al.
A subcutaneous octreotide hydrogel
implant for the treatment of acromegay.
Endocr Pract 2012;18:870-81
13. Guillemin R. Peptides in the brain: the
new endocrinology of the neuron.
Science 1978;202:390-402
14. Mandarino L, Stenner D, Blanchard W,
et al. Selective effects of somatostatin-14,
25 and -28 on in vitro insulin and
glucagonsecretion. Nature 1981;291:76-7
15. Reisine T, Bell GI. Molecular biology of
somatostatin receptors. Endocr Rev
1995;16:427-42
16. Patel YC. Somatostatin and its receptor
family. Front Neuroendocrinol
1999;20:157-98
17. Sims SM, Lussier BT, Kraicer J.
Somatostatin activates an inwardly
rectifying K+ conductance in freshly
dispersed rat somatotrophs. J Physiol
1991;441:615-37
18. Csaba Z, Dournaud P. Cellular biology
of somatostatin receptors. Neuropeptides
2001;35:1-23
19. Seger R, Krebs EG. The MAPK
signaling cascade. FASEB J
1995;9:726-35
20. Cheung NW, Boyages SC.
Somatostatin-14 and its analog octreotide
exert a cytostatic effect on GH3 rat
pituitary tumor cell proliferation via a
transient G0/G1 cell cycle block.
Endocrinology 1995;136:4174-81
21. Cerovac V, Monteserin-Garcia J,
Rubinfeld H, et al. The somatostatin
analogue octreotide confers sensitivity to
rapamycin treatment on pituitary tumor
cells. Cancer Res 2010;70:666-74
22. Pagotto U, Arzberger T, Ciani E, et al.
Inhibition of Zac1, a new gene
differentially expressed in the anterior
pituitary, increases cell proliferation.
Endocrinology 1999;140:987-96
23. Rocheville M, Lange DC, Kumar U,
et al. Subtypes of the somatostatin
receptor assemble as functional homo-
and heterodimers. J Biol Chem
2000;275:7862-9
24. Patel PC, Barrie R, Hill N, et al.
Postreceptor signal transduction
mechanisms involved in octreotide-
induced inhibition of angiogenesis.
Surgery 1994;116:1148-52
25. Adams RL, Adams IP, Lindow SW, et al.
Somatostatin receptors 2 and 5 are
preferentially expressed in proliferating
endothelium. Br J Cancer
2005;92:1493-8
26. Badway AC, Blake AD. Somatostatin:
a hormone for the heart?
Curr Vasc Pharmacol 2005;3:125-31
27. Morini M, Villa V, Arena S, et al.
Somatostatin inhibits tumor angiogenesis
and growth via somatostatin
receptor-3-mediated regulation of
endothelial nitric oxide synthase and
mitogen-activated protein kinase
activities. Endocrinology
2003;144:1574-84
28. Giustina A, Veldhuis JD.
Pathophysiology of the neuroregulation
of growth hormone secretion in
experimental animals and the human.
Endocr Rev 1998;19:717-97
.. The most extensive review describing
the mechanisms involved in the
regulation of growth hormone (GH)
secretion in animals and humans.
29. Greenman Y, Melmed S. Heterogeneous
expression of two somatostatin receptor
subtypes in pituitary tumors. J Clin
Endocrinol Metab 1994;78:398-403
30. Melmed S. Medical progress: acromegaly.
N Engl J Med 2006;355:2558-73
31. Holdaway IM, Rajasoorya C.
Epidemiology of acromegaly. Pituitary
1999;2:29-41
32. Daly AF, Rixhon M, Adam C, et al.
High prevalence of pituitary adenomas:
a cross-sectional study in the province of
Liege, Belgium. J Clin Endocrinol Metab
2006;91:4769-75
33. Rajasoorya C, Holdaway IM,
Wrightson P, et al. Determinants of
clinical outcome and survival in
acromegaly. Clin Endocrinol (Oxf)
1994;41:95-102
. The first study providing information
on the predictors of mortality
in acromegaly.
34. Holdaway IM, Rajasoorya RC,
Gamble GD. Factors influencing
mortality in acromegaly. J Clin
Endocrinol Metab 2004;89:667-74
35. Melmed S, Casanueva FF, Cavagnini F,
et al. Acromegaly treatment consensus
workshop participants. Guidelines for
A. Giustina et al.
12 Expert Opin. Investig. Drugs (2014) 23(12)
Exp
ert O
pin.
Inv
estig
. Dru
gs D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y C
olor
ado
Stat
e U
nive
rsity
on
08/2
3/14
For
pers
onal
use
onl
y.
acromegaly management. J Clin
Endocrinol Metab 2002;87:4054-8
.. The first guideline for the management
of acromegaly.
36. Melmed S, Casanueva F, Cavagnini F,
et al. Consensus statement: medical
management of acromegaly.
Eur J Endocrinol 2005;153:737-40
.. The first guideline for medical
treatment of acromegaly.
37. Melmed S, Colao A, Barkan A, et al.
Guidelines for acromegaly management:
an update. J Clin Endocrinol Metab
2009;94:1509-17
. An update of guidelines for
management of acromegaly published
for the first time in 2002.
38. Giustina A, Chanson P, Kleinberg D,
et al. Expert consensus document:
a consensus on the medical treatment of
acromegaly. Nat Rev Endocrinol
2014;10:243-8
. An update of guidelines for medical
treatment of acromegaly published for
the first time in 2005.
39. Giustina A, Bronstein MD,
Casanueva FF, et al. Current
management practices for acromegaly:
an international survey. Pituitary
2011;14:125-33
.. An extensive worldwide survey on the
management of acromegaly in the real-
life.
40. Giustina A, Karamouzis I, Patelli I, et al.
Octreotide for acromegaly treatment:
a reappraisal. Expert Opin Pharmacother
2013;14:2433-47
41. Bauer W, Briner U, Doepfner W, et al.
SMS 201-995: a very potent and
selective octapeptide analogue of
somatostatin with prolonged action.
Life Sci 1982;31:1133-40
42. Lamberts SW, Uitterlinden P,
Verschoor L, et al. Long-term treatment
of acromegaly with the somatostatin
analogue SMS 201-995. N Engl J Med
1985;313(25):1576-80
.. The seminal study investigating the
effectiveness of regular octreotide
in acromegaly
43. Sassolas G, Harris AG, James-Deidier A.
Long term effect of incremental doses of
the somatostatin analog SMS 201-995 in
58 acromegalic patients. French SMS
201-995 approximately equal to
Acromegaly Study Group. J Clin
Endocrinol Metab 1990;71:391-7
44. Vance ML, Harris AG. Long-term
treatment of 189 acromegalic patients
with the somatostatin analog octreotide.
Results of the International Multicenter
Acromegaly Study Group.
Arch Intern Med 1991;151:1573-8
45. Ezzat S, Snyder PJ, Young WF, et al.
Octreotide treatment of acromegaly.
A randomized, multicenter study.
Ann Intern Med 1992;117:711-18
46. Christensen SE, Weeke J, Orskov H,
et al. Continuous subcutaneous pump
infusion of somatostatin analogue SMS
201-995 versus subcutaneous injection
schedule in acromegalic patients.
Clin Endocrinol (Oxf) 1987;27:297-306
. A clinical evidence that different
modalities of administration of
octreotide influence the
therapeutic efficacy.
47. Heron I, Thomas F, Dero M, et al.
Pharmacokinetics and efficacy of a long-
acting formulation of the new
somatostatin analog BIM 23014 in
patients with acromegaly. J Clin
Endocrinol Metab 1993;76:721-7
48. Coy DH, Taylor JE. Receptor-specific
somatostatin analogs: correlations with
biological activity. Metabolism
1996;45(8 Suppl 1):21-3
49. Astruc B, Marbach P, Bouterfa H, et al.
Long-acting octreotide and prolonged-
release lanreotide formulations have
different pharmacokinetic profiles.
J Clin Pharmacol 2005;45:836-44
50. van Thiel SW, Romijn JA, Biermasz NR,
et al. Octreotide long-acting repeatable
and lanreotide Autogel are equally
effective in controlling growth hormone
secretion in acromegalic patients.
Eur J Endocrinol 2004;150:489-95
51. Alexopoulou O, Abrams P, Verhelst J,
et al. Efficacy and tolerability of
lanreotide Autogel therapy in acromegalic
patients previously treated with
octreotide LAR. Eur J Endocrinol
2004;151:317-24
52. Ashwell SG, Bevan JS, Edwards OM,
et al. The efficacy and safety of
lanreotide Autogel in patients with
acromegaly previously treated with
octreotide LAR. Eur J Endocrinol
2004;150:473-80
53. Mestron A, Webb SM, Astorga R, et al.
Epidemiology, clinical characteristics,
outcome, morbidity and mortality in
acromegaly based on the Spanish
Acromegaly Registry (Registro Espanol
de Acromegalia, REA). Eur J Endocrinol
2004;151:439-46
54. Bex M, Abs R, T’Sjoen G, et al. AcroBel
-the Belgian registry on acromegaly:
a survey of the ’real-life’ outcome in
418 acromegalic subjects.
Eur J Endocrinol 2007;157:399-409
55. Giustina A, Barkan A, Casanueva FF,
et al. Criteria for cure of acromegaly:
a consensus statement. J Clin
Endocrinol Metab 2000;85:526-9
.. The first guideline defining the criteria
for diagnosis and cure of acromegaly.
56. Giustina A, Chanson P, Bronstein MD,
et al. A consensus on criteria for cure of
acromegaly. J Clin Endocrinol Metab
2010;95:3141-8
. An update of guidelines for definition
of criteria of cure of acromegaly
published for the first time in 2000.
57. Giustina A, Bonadonna S, Bugari G,
et al. High-dose intramuscular octreotide
in patients with acromegaly inadequately
controlled on conventional somatostatin
analogue therapy: a randomised
controlled trial. Eur J Endocrinol
2009;161:331-8
.. The first trial on the effectiveness of
high doses of octreotide in acromegaly.
58. Petersenn S, Schopohl J, Barkan A, et al.
Pasireotide (SOM230) demonstrates
efficacy and safety in patients with
acromegaly: a randomized, multicenter,
phase II trial. Pasireotide Acromegaly
Study Group. J Clin Endocrinol Metab
2010;95:2781-9
. The first evidence that pasireotide is
effective in patients with acromegaly.
59. Petersenn S, Farrall AJ, Block C, et al.
Long-term efficacy and safety of
subcutaneous pasireotide in acromegaly:
results from an open-ended, multicenter,
Phase II extension study. Pituitary
2013;17:132-40
60. Colao A, Bronstein M, Freda P, et al.
Pasireotide versus octreotide in
acromegaly: a head-to-head superiority
study. J Clin Endocrinol Metab
2014;99:791-9
. The first evidence that pasireotide
long-acting release (LAR) could be
more effective than octreotide LAR in
patients with acromegaly.
61. Bruns C, Lewis I, Briner U, et al.
SOM230: a novel somatostatin
peptidomimetic with broad,
somatotropin release inhibiting factor
(SRIF) receptor binding and a unique
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and NETs
Expert Opin. Investig. Drugs (2014) 23(12) 13
Exp
ert O
pin.
Inv
estig
. Dru
gs D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y C
olor
ado
Stat
e U
nive
rsity
on
08/2
3/14
For
pers
onal
use
onl
y.
antisecretory profile. Eur J Endocrinol
2002;146:707-16
62. Tulipano G, Bonfanti C, Milani G, et al.
Differential inhibition of growth
hormone secretion by analogs selective
for somatostatin receptor subtypes 2 and
5 in human growth-hormone-secreting
adenoma cells in vitro.
Neuroendocrinology 2001;73:344-51
63. van der Hoek J, de Herder WW,
Feelders RA. A single-dose comparison of
the acute effects between the new
somatostatin analog SOM230 and
octreotide in acromegalic patients. J Clin
Endocrinol Metab 2004;89:638-45
64. Dietrich H, Hu K, Ruffin M, et al.
Safety, tolerability, and pharmacokinetics
of a single dose of pasireotide long-acting
release in healthy volunteers: a single-
center Phase I study. Eur J Endocrinol
2012;166:821-8
65. Colao A, Bronstein M, Brue T, et al.
Phase III, multicenter, randomized study
(PAOLA) demonstrating that pasireotide
LAR has superior efficacy over octreotide
LAR and lanreotide Autogel in patients
with inadequately controlled acromegaly.
ICE/ENDO Meeting; 21 -- 24 June
2014; Chicago, IL, USA
66. Mazziotti G, Gazzaruso C, Giustina A.
Diabetes in Cushing syndrome: basic and
clinical aspects.
Trends Endocrinol Metab
2011;22:499-506
67. Henry RR, Ciaraldi TP, Armstrong D,
et al. Hyperglycemia associated with
pasireotide: results from a mechanistic
study in healthy volunteers. J Clin
Endocrinol Metab 2013;98:3446-53
68. Beglinger C, Hu K, Wang Y, et al.
Multiple once-daily subcutaneous doses
of pasireotide were well tolerated in
healthy male volunteers: a randomized,
double-blind, placebo-controlled, cross-
over, Phase I study. Endocrine
2012;42:366-74
69. Giustina A, Casanueva FF, Cavagnini F,
et al. Diagnosis and treatment of
acromegaly complications.
J Endocrinol Invest 2003;26:1242-7
.. The first guideline for the management
of complications of acromegaly.
70. Melmed S, Casanueva FF, Klibanski A,
et al. A consensus on the diagnosis and
treatment of acromegaly complications.
Pituitary 2013;16:294-302
. An update of the guidelines on the
management of complications of
acromegaly published for the first time
in 2003.
71. Mazziotti G, Floriani I, Bonadonna S,
et al. Effects of somatostatin analogs on
glucose homeostasis: a metaanalysis of
acromegaly studies. J Clin
Endocrinol Metab 2009;94:1500-8
. The first meta-analysis on the effects of
somatostatin analogs glucose
metabolism in acromegaly.
72. Mazziotti G, Porcelli T, Bogazzi F, et al.
Effects of high-dose octreotide LAR on
glucose metabolism in patients with
acromegaly inadequately controlled by
conventional somatostatin analog
therapy. Eur J Endocrinol
2011;164:341-7
73. Arosio M, Macchelli S, Rossi CM, et al.
Effects of treatment with octreotide in
acromegalic patients–a multicenter Italian
study. Italian Multicenter Octreotide
Study Group. Eur J Endocrinol
1995;133:430-9
74. Ronchi CL, Orsi E, Giavoli C, et al.
Evaluation of insulin resistance in
acromegalic patients before and after
treatment with somatostatin analogues.
J Endocrinol Invest 2003;26:533-8
75. Schmid HA, Brue T, Colao A, et al.
Exploratory data evaluating of pasireotide
on GH, IGF-1, IGFBP-2, IGFBP-3,
HbA1c and Glucose in Patients
withInadequately Controlled Acromegaly
Enrolled in a 24-Week Study (PAOLA).
ICE/ENDO Meeting; 21 -- 24June 2014;
Chicago, IL, USA
76. Afargan M, Janson ET, Gelerman G,
et al. Novel long-acting somatostatin
analog with endocrine selectivity: potent
suppression of growth hormone but not
of insulin. Endocrinology
2001;142:477-86
. The first evidence that somatoprim
decreases GH secretion without
affecting glucose metabolism.
77. Shimon I, Rubinek T, Hadani M, et al.
PTR-3173 (somatoprim), a novel
somatostatin analog with affinity for
somatostatin receptors 2, 4 and 5 is a
potent inhibitor of human GH secretion.
J Endocrinol Invest 2004;27:721-7
78. Pl€ockinger U, Hoffmann U, Geese M,
et al. DG3173 (somatoprim), a unique
somatostatin receptor subtypes 2-, 4- and
5-selective analogue, effectively reduces
GH secretion in human GH-secreting
pituitary adenomas even in Octreotide
non-responsive tumours.
Eur J Endocrinol 2012;166:223-34
79. Aspireo Pharma website. Available from:
http://www.aspireopharma.com/
somatoprim [Last accessed 11 May 2014]
80. ITF2984 Repeated Doses Study in
Healthy Volunteers (MAD). Available
from: http://www.clinicaltrials.gov/ct2/
show/NCT01871844 [Last accessed
11 May 2014]
81. Phase II Study With ITF2984 in
Acromegalic Patients (POC). Available
from: http://www.clinicaltrials.gov/ct2/
show/NCT02111044 [Last accessed
11 May 2014]
82. Erfani Jabarian L, Rouini MR, Atyabi F,
et al. In vitro and in vivo evaluation of
an in situ gel forming system for the
delivery of PEGylated octreotide. Eur J
Pharm Sci 2013;48:87-96
83. Q Chip Ltd. Drug delivery company
[Cardiff, UK]. Available from: http://
www.q-chip.com. [Last accessed 11 May
2014]
84. St€ormann S, Schopohl J. Emerging drugs
for acromegaly. Expert Opin
Emerg Drugs 2014;19:79-97
85. Roberts J, Linden M, Cervin C, et al.
Randomized study demonstrating that
octreotide fluid crystal provides sustained
octreotide bioavailability and similar
IGF-1 suppression to octreotide LAR
(Sandostatin LAR) in healthy volunteers.
ICE/ENDO Meeting; 21 -- 24 June
2014; Chicago, IL, USA
86. CAM2029: new ready-to-use, long-acting
octreotide product for treatment of
acromegaly and carcinoid tumours.
Avilable from http://www.camurus.com/
index.asp?DocumentIDSub=3&
DocumentID=2&ShowSub=(2)&Show=
(3)&main=Products [Last accessed
11 May 2014]
87. Drewe J, Fricker G, Vonderscher J, et al.
Enteral absorption of octreotide:
absorption enhancement by
polyoxyethylene- 24-cholesterol ether.
Br J Pharmacol 1993;108:298-303
88. Thanou M, Verhoef JC, Marbach P,
et al. Intestinal absorption of octreotide:
N-trimethyl chitosan chloride (TMC)
ameliorates the permeability and
absorption properties of the somatostatin
analogue in vitro and in vivo.
J Pharm Sci 2000;89:951-7
89. Dorkoosh FA, Verhoef JC,
Verheijden JH, et al. Peroral absorption
A. Giustina et al.
14 Expert Opin. Investig. Drugs (2014) 23(12)
Exp
ert O
pin.
Inv
estig
. Dru
gs D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y C
olor
ado
Stat
e U
nive
rsity
on
08/2
3/14
For
pers
onal
use
onl
y.
of octreotide in pigs formulated in
delivery systems on the basis of
superporous hydrogel polymers.
Pharm Res 2002;19:1532-6
90. Tuvia S, Salama P, Weinstein I, et al.
Octreolin a safe oral alternative for
parenteral octreotide treatment.
Growth Horm IGF Res 2010;20:S35-6
91. Tuvia S, Atsmon J, Teichman SL, et al.
Oral octreotide absorption in human
subjects: comparable pharmacokinetics to
parenteral octreotide and effective growth
hormone suppression. J Clin
Endocrinol Metab 2012;97:2362-9
. The first evidence that oral octreotide
is effective in suppressing GH secretion
in healthy subjects.
92. Melmed S, Popovic-Brkic V,
Bidlingmaier M, et al. Efficacy and safety
of oral octreotide in acromegaly: results
of a multicenter phase III trial in
155 patients. ICE/ENDO Meeting; 21 --
24 June 2014; Chicago, IL, USA
93. Maggio ET, Grasso P. Oral delivery of
octreotide acetate in Intravail� improves
uptake, half-life, and bioavailability over
subcutaneous administration in male
Swiss webster mice. Regul Pept
2011;167:233-8
94. Aegis Hydrogel� and ProTek�Technology. Avilable from http://
aegisthera.com/technology/#protek [Last
accessed 11 May 2014]
95. Chieffo C, Cook D, Xiang Q, et al.
Efficacy and safety of an octreotide
implant in the treatment of patients with
acromegaly. J Clin Endocrinol Metab
2013;98:4047-54
. The first evidence that octreotide
implant is effective in suppressing GH
secretion in patients with acromegaly.
96. Marazuela M, Ramos-Levı A,
Sampedro-N�unez M, et al. Cabergoline
treatment in acromegaly: pros. Endocrine
2014;46:215-19
97. Kasuki L, Vieira Neto L, Gadelha MR.
Cabergoline treatment in acromegaly:
cons. Endocrine 2014;46:220-5
98. Ben-Shlomo A, Melmed S. Pituitary
somatostatin receptor signaling.
Trends Endocrinol Metab
2010;21:123-33
99. Saveanu A, Jaquet P.
Somatostatin-dopamine ligands in the
treatment of pituitary adenomas.
Rev Endocr Metab Disord
2009;10:83-90
100. Jaquet P, Gunz G, Saveanu A, et al.
BIM-23A760, a chimeric molecule
directed towards somatostatin and
dopamine receptors, vs universal
somatostatin receptors ligands in GH-
secreting pituitary adenomas partial
responders to octreotide.
J Endocrinol Invest 2005;28:21-7
101. Culler MD. Somatostatin-dopamine
chimeras: a novel approach to treatment
of neuroendocrine tumors.
Horm Metab Res 2011;43:854-7
102. Baudin E. Gastroenteropancreatic
endocrine tumors: clinical
characterization before therapy. Nat Clin
Pract Endocrinol Metab 2007;3:228-39
103. Modlin IM, Oberg K, Chung DC, et al.
Gastroenteropancreatic neuroendocrine
tumours. Lancet Oncol 2008;9:61-72
104. Pavel M, Baudin E, Couvelard A, et al.
ENETS Consensus Guidelines for the
management of patients with liver and
other distant metastases from
neuroendocrine neoplasms of foregut,
midgut, hindgut, and unknown primary.
Neuroendocrinology 2012;95:157-76
105. Klimstra DS, Arnold R, Capella C, et al.
Neuroendocrine neoplasms of the
pancreas [chapter 12]. In: Bosman FT,
Carneiro F, Hruban RH, Theise ND,
editors. WHO classification of tumours
of the digestive system. IARC; Lyon:
2010 p. 322-6
106. Travis WD. Lung tumors with
neuroendocrine differentiation.
Eur J Cancer 2009;45:1:251-66
107. Oberg KE, Reubi JC, Kwekkeboom DJ,
et al. Role of somatostatins in
gastroenteropancreatic neuroendocrine
tumor development and therapy.
Gastroenterology 2010;39:742-53
108. Reubi JC. Peptide receptors as molecular
targets for cancer diagnosis and therapy.
Endocr Rev 2003;24:389-427
109. €Oberg K. Gallium-68 somatostatin
receptor PET/CT: is it time to replace
(111)Indium DTPA octreotide for
patients with neuroendocrine tumors?
Endocrine 2012;42:3-4
110. Wulbrand U, Wied M, Zofel P, et al.
Growth factor receptor expression in
human gastroenteropancreatic
neuroendocrine tumours. Eur J
Clin Invest 1998;28:1038-49
111. de Herder WW, Hofland LJ,
van der Lely AJ, et al. Somatostatin
receptors in gastroentero-pancreatic
neuroendocrine tumours.
Endocr Relat Cancer 2003;10:451-8
112. Alexandraki KI, Kaltsas G.
Gastroenteropancreatic neuroendocrine
tumors: new insights in the diagnosis and
therapy. Endocrine 2012;41:40-52
. An extensive and updated review on
the new insights in the diagnosis and
treatments of gastroenteropancreatic
neuroendocrine tumors (NETs).
113. Kvols LK, Moertel CG, O’Connell MJ,
et al. Treatment of the malignant
carcinoid syndrome. Evaluation of a
long-acting somatostatin analogue.
N Engl J Med 1986;315:663-6
.. The first trial on the effectiveness of
octreotide in patients with
carcinoid syndrome.
114. Scarpignato C, Pelosini I. Somatostatin
analogs for cancer treatment and
diagnosis: an overview. Chemotherapy
2001;47:1-29
115. Wild D, Christ E, Caplin ME, et al.
Glucagon-like peptide-1 versus
somatostatin receptor targeting reveals
2 distinct forms of malignant
insulinomas. J Nucl Med
2011;52:1412-17
116. Vezzosi D, Bennet A, Rochaix P, et al.
Octreotide in insulinoma patients:
efficacy on hypoglycemia, relationships
with Octreoscan scintigraphy and
immunostaining with anti-sst2A and
anti-sst5 antibodies. Eur J Endocrinol
2005;152:757-67
117. Scarpignato C. The place of octreotide in
the medical management of the dumping
syndrome. Digestion 1996;57:114-18
118. He X, Wang J, Wu X, et al. Pancreatic
somatostatinoma manifested as severe
hypoglycemia. J Gastrointestin Liver Dis
2009;18:221-4
119. Angeletti S, Corleto VD, Schillaci O,
et al. Use of the somatostatin analogue
octreotide to localise and manage
somatostatin-producing tumours. Gut
1998;42:792-4
120. Schwartz CJ, Kimberg DV, Sheerin HE,
et al. Vasoactive intestinal peptide
stimulation of adenylate cyclase and
active electrolyte secretion in intestinal
mucosa. J Clin Invest 1974;54:536-44
121. Tulipano G, Stumm R, Pfeiffer M, et al.
Differential beta-arrestin trafficking and
endosomal sorting of somatostatin
receptor subtypes. J Biol Chem
2004;279:21374-82
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and NETs
Expert Opin. Investig. Drugs (2014) 23(12) 15
Exp
ert O
pin.
Inv
estig
. Dru
gs D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y C
olor
ado
Stat
e U
nive
rsity
on
08/2
3/14
For
pers
onal
use
onl
y.
122. Hofland LJ, Lamberts SW. The
pathophysiological consequences of
somatostatin receptor internalization and
resistance. Endocr Rev 2003;24:28-47
.. An extensive review on the mechanisms
underlying tachyphylaxis and
resistance to somatostatin analogs.
123. Eriksson B, €Oberg K. Summing up
15 years of somatostatin analog therapy
in neuroendocrine tumors: future
outlook. Ann Oncol 1999;10:S31-8
124. €Oberg K. Biotherapies for GEP-NETs.
Best Pract Res Clin Gastroenterol
2012;26:833-41
. An updated review on the new targeted
therapies in gastroenteropancreatic
NETs.
125. 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 2009;27:4656-63
.. The first trial demonstrating that
octreotide LAR stabilizes tumor growth
in patients with NET.
126. Clark OH, Benson AB III, Berlin JD,
et al. NCCN Clinical Practice Guidelines
in Oncology: neuroendocrine tumors.
J Natl Compr Canc Netw
2009;7:712-47
127. Caplin M, Ruszniewski P, Pavel M, et al.
A randomized, double-blind, placebo-
controlled study of lanreotide
antiproliferative response in patients with
gastroenteropancreatic neuroendocrine
tumors (CLARINET) [abstract 3].
European Cancer Congress 2013;
28 September 2013, Amsterdam, NL
. A trial confirming that somatostatin
analogs stabilize tumor growth in
patients with NET.
128. Caplin ME, Ruszniewski P, Pavel M,
et al. Lanreotide Autogel/depot shows
antitumor effects in patients with
metastatic enteropancreatic NETs: results
of the Clarinet Extension Study. ICE/
ENDO Meeting; 21 -- 24June 2014;
Chicago, IL, USA
129. Prommegger R, Bale R, Ensinger C,
et al. Gastric carcinoid type I tumour:
new diagnostic and therapeutic method.
Eur J Gastroenterol Hepatol
2003;15:705-7
130. Fykse V, Sandvik AK, Qvigstad G, et al.
Treatment of ECL cell carcinoids with
octreotide LAR. Scand J Gastroenterol
2004;39:621-8
131. Tomassetti P, Migliori M, Caletti GC,
et al. Treatment of type II gastric
carcinoid tumors with somatostatin
analogues. N Engl J Med
2000;343:551-4
132. Wang S, Bao Z, Liang QM, et al.
Octreotide stimulates somatostatin
receptor-induced apoptosis of
SW480 colon cancer cells by activation
of glycogen synthase kinase-3beta,
A Wnt/beta-catenin pathway modulator.
Hepatogastroenterology 2013;60:1639-46
133. Yim KL. Role of biological targeted
therapies in gastroenteropancreatic
neuroendocrine tumours. Endocrine
2011;40:181-6
134. Oberg K, Eriksson B. The role of
interferons in the management of
carcinoid tumours. Br J Haematol
1991;79:74-7
135. Oberg K. The action of interferon alpha
on human carcinoid tumours.
Semin Cancer Biol 1992;3:35-41
136. Kolby L, Persson G, Franzen S, et al.
Randomized clinical trial of the effect of
interferon alpha on survival in patients
with disseminated midgut carcinoid
tumours. Br J Surg 2003;90:687-93
. A trial investigating the efficacy of
combination therapy (somatostatin
analog plus interferon) in patients
with NETs.
137. Arnold R, Rinke A, Klose KJ, et al.
Octreotide versus octreotide plus
interferon-alpha in endocrine
gastroenteropancreatic tumors:
a randomized trial.
Clin Gastroenterol Hepatol
2005;3:761-71
. A trial investigating the efficacy of
combination therapy (somatostatin
analog plus interferon) in patients
with NETs.
138. Faiss S, Pape UF, Bohmig M, et al.
Prospective, randomized, multicenter trial
on the antiproliferative effect of
lanreotide, interferon alfa, and their
combination for therapy of metastatic
neuroendocrine gastroenteropancreatic
tumors--the International Lanreotide and
Interferon Alfa Study Group.
J Clin Oncol 2003;21:2689-96
. A trial investigating the efficacy of
combination therapy (somatostatin
analog plus interferon) in patients
with NETs.
139. Yao JC, Shah MH, Ito T, et al.
Everolimus for advanced pancreatic
neuroendocrine tumors. N Engl J Med
2011;364:514-23
140. Raymond E, Dahan L, Raoul JL, et al.
Sunitinib malate for the treatment of
pancreatic neuroendocrine tumors.
N Engl J Med 2011;364:501-13
141. Meric-Bernstam F, Akcakanat A,
Chen H, et al. PIK3CA/PTEN
mutations and Akt activation as markers
of sensitivity to allosteric mTOR
inhibitors. Clin Cancer Res
2012;18:1777-89
142. Breuleux M, Klopfenstein M, Stephan C,
et al. Increased AKT
S473 phosphorylation after
mTORC1 inhibition is rictor dependent
and does not predict tumor cell response
to PI3K/mTOR inhibition.
Mol Cancer Ther 2009;8:742-53
143. O’Reilly KE, Rojo F, She QB, et al.
mTOR inhibition induces upstream
receptor tyrosine kinase signaling and
activates Akt. Cancer Res
2006;66:1500-8
144. Moreno A, Akcakanat A, Munsell MF,
et al. Antitumor activity of rapamycin
and octreotide as single agents or in
combination in neuroendocrine tumors.
Endocr Relat Cancer 2008;15:257-66
145. Yao JC, Lombard-Bohas C, Baudin E,
et al. Daily oral everolimus activity in
patients with metastatic pancreatic
neuroendocrine tumors after failure of
cytotoxic chemotherapy: a phase II trial.
J Clin Oncol 2010;28:69-76
. The first trial investigating the efficacy
of combination therapy (somatostatin
analog plus everolimus) in patients
with NETs.
146. Pavel ME, Hainsworth JD, Baudin E,
et al. RADIANT-2 Study Group.
Everolimus plus octreotide long-acting
repeatable for the treatment of advanced
neuroendocrine tumours associated with
carcinoid syndrome (RADIANT-2):
a randomised, placebo-controlled,
phase 3 study. Lancet
2011;378(9808):2005-12
147. Welin SV, Janson ET, Sundin A, et al.
High-dose treatment with a long-acting
somatostatin analogue in patients with
advanced midgut carcinoid tumours.
Eur J Endocrinol 2004;151:107-12
A. Giustina et al.
16 Expert Opin. Investig. Drugs (2014) 23(12)
Exp
ert O
pin.
Inv
estig
. Dru
gs D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y C
olor
ado
Stat
e U
nive
rsity
on
08/2
3/14
For
pers
onal
use
onl
y.
148. Imam H, Eriksson B, Lukinius A, et al.
Induction of apoptosis in neuroendocrine
tumors of t he digestive system during
treatment with somatostatin analogs.
Acta Oncol 1997;36:607-14
. A study demonstrating that high doses
of somatostatin analogs induced
apoptosis in NET.
149. Lesche S, Lehmann D, Nagel F, et al.
Differential effects of octreotide and
pasireotide on somatostatin receptor
internalization and trafficking in vitro.
J Clin Endocrinol Metab
2009;94:654-61
150. Schmid HA. Pasireotide (SOM230):
development, mechanism of action and
potential applications.
Mol Cell Endocrinol 2008;286:69-74
151. Kvols L, Wiedenmann B, Oberg K, et al.
The SOM230 Carcinoid Study Group.
Safety and efficacy of pasireotide
(SOM230) in patients with metastatic
carcinoid tumors refractory or resistant to
octreotide LAR: results of a phase II
study [abstract 171]. ASCO GI Cancers
Symposium, S. Francisco, CA, USA;
2006
. The first study demonstrating that
pasireotide is effective in patients
with NET.
152. Kvols LK, Oberg KE, O’Dorisio TM,
et al. Pasireotide (SOM230) shows
efficacy and tolerability in the treatment
of patients with advanced neuroendocrine
tumors refractory or resistant to
octreotide LAR: results from a phase II
study. Endocr Relat Cancer
2012;19:657-66
153. Efficacy and safety of pasireotide long
acting release vs. octreotide long acting
release in patients with metastatic
carcinoid disease. Available from: http://
clinicaltrials.gov/ct2/show/study/
NCT00690430 [Last accessed 11 May
2014]
154. Wolin EM, Jarzab B, Eriksson B, et al.
A multicenter, randomized, blinded,
phase III study of pasireotide LAR versus
octreotide LAR in patients with
metastatic neuroendocrine tumors (NET)
with disease-related symptoms
inadequately controlled by somatostatin
analogs. J Clin Oncol
2013;31(Suppl):abstract 4031
(2013 ASCO Annual Meeting)
. The first study demonstrating that
pasireotide LAR is more effective than
octreotide LAR in patients with NET.
155. 3-arm Trial to Evaluate Pasireotide LAR/
Everolimus Alone/in Combination in
Patients With Lung/Thymus NET -
LUNA Trial. Available from: http://
clinicaltrials.gov/ct2/show/record/
NCT01563354 [Last accessed 11 May
2014]
156. Kidd M, Modlin IM, Black JW, et al.
A comparison of the effects of gastrin,
somatostatin and dopamine receptor
analogs on rat gastric enterochromaffin-
like cell secretion and proliferation.
Regul Pept 2007;143:109-17
157. Sharif N, Gendron L, Wowchuk J, et al.
Coexpression of somatostatin receptor
subtype 5 affects internalization and
trafficking of somatostatin receptor
subtype 2. Endocrinology
2007;148:2095-105
158. Baragli A, Alturaihi H, Watt HL, et al.
Heterooligomerization of human
dopamine receptor 2 and somatostatin
receptor 2. Co-immunoprecipitation and
fluorescence resonance energy transfer
analysis. Cell Signal 2007;19:2304-16
159. O’Toole D, Saveanu A, Couvelard A,
et al. The analysis of quantitative
expression of somatostatin and dopamine
receptors in gastro-entero-pancreatic
tumours opens new therapeutic strategies.
Eur J Endocrinol 2006;155:849-57
160. Bonadonna S, Mazziotti G, Nuzzo M,
et al. Increased prevalence of radiological
spinal deformities in active acromegaly:
a cross-sectional study in postmenopausal
women. J Bone Miner Res
2005;20:1837-44
.. The seminal study demonstrating that
vertebral fractures are a complication
of acromegaly.
161. Maison P, Tropeano AI,
Macquin-Mavier I, et al. Impact of
somatostatin analogs on the heart in
acromegaly: a metaanalysis. J Clin
Endocrinol Metab 2007;92:1743-7
. A meta-analysis on the effects of
somatostatin analogs on cardiovascular
outcomes in acromegaly.
162. De Marinis L, Bianchi A, Mazziotti G,
et al. The long-term cardiovascular
outcome of different GH-lowering
treatments in acromegaly. Pituitary
2008;11:13-20
163. Mazziotti G, Bianchi A, Porcelli T, et al.
Vertebral fractures in patients with
acromegaly: a 3-year prospective study.
J Clin Endocrinol Metab
2013;98:3402-10
. The first prospective study reporting
the incidence of vertebral fractures
in acromegaly.
164. Mancini T, Porcelli T, Giustina A.
Treatment of cushing disease: overview
and recent findings. Ther Clin
Risk Manag 2010;6:505-16
165. Giustina A, Ambrosio MR,
Beck-Peccoz P, et al. Use of pegvisomant
in acromegaly. An Italian Society of
Endocrinology guideline.
J Endocrinol Invest 2014;
DOI:10.1007/s40618-014-0114-5
166. Boyd AE, DeFord LL, Mares JE, et al.
Improving the success rate of gluteal
intramuscular injections. Pancreas
2013;42:878-82
167. Salvatori R, Nachtigall LB, Cook DM,
et al. SALSA Study Group. Effectiveness
of self- or partner-administration of an
extended-release aqueous-gel formulation
of lanreotide in lanreotide-naıve patients
with acromegaly. Pituitary
2010;13:115-22
AffiliationAndrea Giustina†1 MD,
Gherardo Mazziotti2 MD PhD,
Filippo Maffezzoni2 MD, Vito Amoroso3 MD&
Alfredo Berruti4 MD†Author for correspondence1Professor, Chair of Endocrinology,
University of Brescia, Department of Clinical and
Experimental Sciences, 25123 Brescia, Italy
Tel: +390303996520;
Fax: +390302092540;
E-mail: [email protected] of Endocrinology,
University of Brescia, Department of Clinical and
Experimental Sciences, 25123 Brescia, Italy3Chair of Medical Oncology,
University of Brescia, Brescia, Italy4Professor, Chair of Medical Oncology,
University of Brescia, Brescia, Italy
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and NETs
Expert Opin. Investig. Drugs (2014) 23(12) 17
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ahea
lthca
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