Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors

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<ul><li><p>1. Introduction</p><p>2. Somatostatin and somatostatin</p><p>receptors</p><p>3. Somatostatin analogs in the</p><p>management of acromegaly</p><p>4. Somatostatin analogs in the</p><p>management of NETs</p><p>5. Expert opinion</p><p>Review</p><p>Investigational drugs targetingsomatostatin receptors fortreatment of acromegaly andneuroendocrine tumorsAndrea Giustina, Gherardo Mazziotti, Filippo Maffezzoni, Vito Amoroso &amp;Alfredo BerrutiUniversity of Brescia, Department of Clinical and Experimental Sciences, Brescia, Italy</p><p>Introduction: Octreotide long-acting release (LAR) and lanreotide Autogel</p><p>(ATG) are the two somatostatin analogs currently approved for treatment</p><p>of acromegaly and neuroendocrine tumors (NETs). The strength of</p><p>these drugs has been their specificity for somatostatin receptor subtype 2.</p><p>However, this peculiarity may become a weakness in some patients</p><p>with tumors harboring somatostatin receptors different from the subtype 2.</p><p>Another clinically relevant aspect related to the use of octreotide LAR</p><p>and lanreotide ATG is the burden of injectable drug regimen that</p><p>may adversely impact the quality of life of patients with acromegaly and</p><p>NETs.</p><p>Areas covered: The authors review the recently published evidence on novel</p><p>drugs targeting somatostatin receptors developed for treating acromegaly</p><p>and NETs. Within this article, the authors discuss: i) the pharmacology of</p><p>somatostatin and traditional somatostatin analogs; ii) the efficacy and safety</p><p>of multireceptor-targeted somatostatin analogs in acromegaly and NETs;</p><p>iii) the efficacy of chimeric molecules in acromegaly and NETs; iv) the prelimi-</p><p>nary data on the use of new injectable, oral and transdermal formulations of</p><p>octreotide in acromegaly.</p><p>Expert opinion: The development of new somatostatin analogs and new</p><p>formulations has opened a new scenario for treatment of acromegaly and</p><p>NETs. That being said, even though there have been big steps taken in the</p><p>development of new therapies for acromegaly, there are still a number of</p><p>unresolved issues, while more trials are necessary for the use of somatostatin</p><p>anaologs in the treatment of NETs.</p><p>Keywords: acromegaly, investigational somatostatin analogs, lanreotide, neuroendocrine</p><p>tumors, octreotide, pasireotide</p><p>Expert Opin. Investig. Drugs [Early Online]</p><p>1. Introduction</p><p>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 (&lt; 3 min), aswell as the need of intravenous injection and the postinfusion rebound hormone</p><p>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</p><p>Exp</p><p>ert O</p><p>pin.</p><p> Inv</p><p>estig</p><p>. Dru</p><p>gs D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y C</p><p>olor</p><p>ado </p><p>Stat</p><p>e U</p><p>nive</p><p>rsity</p><p> on </p><p>08/2</p><p>3/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p><p></p></li><li><p>hypersecretion [4]. Synthetic somatostatin analogs with longerhalf-lives have therefore been developed for therapeutic uses.Octreotide long-acting repeatable (LAR) and lanreotide</p><p>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</p><p>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-</p><p>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, acromegalyand NETs. Reference lists in selected papers were also usedto broaden the search.</p><p>2. Somatostatin and somatostatin receptors</p><p>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].</p><p>Somatostatin exerts its biological effects by activating</p><p>specific membrane receptors, which are expressed throughoutthe body, including the central nervous system, hypothalamus,</p><p>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</p><p>chromosomes: 14, 17, 22, 20 and 16, respectively [15].SSTR2A and SSTR2B are two splice variants of the same</p><p>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</p><p>loops [15,16]. A conformational change of the receptor aftersomatostatin binding leads to activation of an associated heter-</p><p>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</p><p>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</p><p>of various ion currents (K+ and Ca2+), which lead to membranehyperpolarization and inhibition of depolarization-induced</p><p>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</p><p>indirect mechanisms. Interestingly, somatostatin activates theserine/threonine MAPK, a pathway usually mediating the</p><p>mitogenic action of growth factors, such as epidermal growthfactor, cytokines and hormones [19]. The modulation ofMAPK activity and phosphotyrosine phosphatases, including</p><p>SHP1, SHP2 and density-enhanced phosphatase, areconsidered the key factors for the antiproliferative effects of</p><p>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</p><p>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-</p><p>phorylation of cyclin E and kinase Cdk2, which control theG1/S transition, and regulate Zac1, which is a zinc finger</p><p>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</p><p>cell growth [22] and abolishes the pituitary tumor cell responseto the antiproliferative action of octreotide. It is noteworthy</p><p>that cells expressing both SSTR2 and SSTR5 have more effica-cious response to the antiproliferative effects of somatostatin</p><p>Article highlights.</p><p>. Somatostatin analogs are the mainstay in the treatmentof acromegaly with beneficial effects on growthhormone hypersecretion and tumor growth.</p><p>. Somatostatin analogs control the clinical syndromecaused by functioning neuroendocrine tumors (NETs),whereas their effects on tumor shrinkage are minimal inthis clinical setting.</p><p>. In NETs, but not in pituitary adenomas, tachyphylaxismay occur with progressive loss of therapeutic efficacyof somatostatin analogs.</p><p>. Multireceptor-targeted somatostatin analogs, such aspasireotide, were shown to be effective in acromegalyas well as in NETs.</p><p>. New formulations of somatostatin analogs, such as oraland transdermal octreotide, have been developed toimprove the patient acceptability for a long-termtreatment.</p><p>This box summarizes key points contained in the article.</p><p>A. Giustina et al.</p><p>2 Expert Opin. Investig. Drugs (2014) 23(12)</p><p>Exp</p><p>ert O</p><p>pin.</p><p> Inv</p><p>estig</p><p>. Dru</p><p>gs D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y C</p><p>olor</p><p>ado </p><p>Stat</p><p>e U</p><p>nive</p><p>rsity</p><p> on </p><p>08/2</p><p>3/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p><p></p></li><li><p>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</p><p>receptor heterodimerization [23].Besides its direct effects, somatostatin may indirectly affect</p><p>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].</p><p>3. Somatostatin analogs in the managementof acromegaly</p><p>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].</p><p>Acromegaly is a relatively rare disease characterized byan excessive GH secretion, generally caused by a pituitary</p><p>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].</p><p>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].</p><p>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</p><p>Table 1. Investigational drugs targeting somatostatin receptor in acromegaly.</p><p>Agent Route of</p><p>administration</p><p>Pharmaceutical</p><p>company</p><p>Trials Binding</p><p>profile</p><p>Pasireotide Subcutaneous dailyintramuscular LAR</p><p>Novartis NCT00171730NCT01137682NCT00600886NCT01995734</p><p>SSTR1,2,3,5</p><p>Somatoprim Subcutaneous Aspireo N.A. SSTR2,4,5ITF 2984 Subcutaneous Italfarmaco NCT02111044</p><p>NCT01871844SSTR1,2,3,5</p><p>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</p><p>Oral formulation Aegis Therapeutics N.A. SSTR2,SSTR5</p><p>Octreotide Hydrogel Transdermal Indevus NCT01295060NCT00765323</p><p>SSTR2,SSTR5</p><p>OctreotideGP02</p><p>Transdermal Glide N.A. SSTR2,SSTR5</p><p>LAR: Long-acting release; N.A.: Not available; SSTR: Somatostatin receptors.</p><p>Investigational drugs targeting somatostatin receptors for treatment of acromegaly and NETs</p><p>Expert Opin. Investig. Drugs (2014) 23(12) 3</p><p>Exp</p><p>ert O</p><p>pin.</p><p> Inv</p><p>estig</p><p>. Dru</p><p>gs D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y C</p><p>olor</p><p>ado </p><p>Stat</p><p>e U</p><p>nive</p><p>rsity</p><p> on </p><p>08/2</p><p>3/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p><p></p></li><li><p>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.Lanreotid...</p></li></ul>