Pasireotide (SOM230): Development, mechanism of action and potential applications

Schmid, Herbert

doi:10.1016/j.mce.2007.09.006

Cited by 267 publications

(181 citation statements)

References 31 publications

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“…In one-third of acromegalic patients, who do not respond to Octreotide, there is diminished expression of sst2A, but persistent sst5 expression (13). SOM230 (Pasireotide), a new multiligand SSA with binding to all sst except to sst4, is currently investigated in clinical trials (14,15,16,17,18,19). Nevertheless, its negative effects on glucose tolerance are even more pronounced than with Octreotide (14,20).…”

Section: Introductionmentioning

confidence: 99%

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

Plöckinger

Hoffmann²,

Geese³

et al. 2012

European Journal of Endocrinology

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Objective: Somatostatin analogues (SSA) reduce autonomous GH secretion by activating somatostatin receptors (sst) 2 and 5 in 50-60% of acromegalic patients. However, by inhibiting insulin secretion these SSA reduce glucose tolerance. DG3173 is a novel SSA with additional binding to sst4 and low insulin-suppressing activity. We investigated the effect of DG3173, including its relation to specific tumour characteristics, on GH secretion in human somatotroph adenoma cell cultures (hSA) in comparison with Octreotide. Methods: Twenty-seven hSA were characterised immunohistochemically for their hormone-and sstexpression, granularity and pre-surgical therapy with SSA. GH was determined in supernatants of hSA treated with DG3173 or Octreotide in time-(nZ6) and dose-response (nZ21) experiments. A positive response was defined as GH suppression to below 80% of baseline. Results: In the dose-response experiments DG3173 suppressed GH secretion in more adenomas than Octreotide (10/21 vs 5/21), including 38% (6/16) of Octreotide non-responders. In responders the extent of GH suppression and IC 50 were comparable for both SSA. The response-rate of both SSA was higher in monohormonal vs bihormonal adenomas, yet GH declined similarly in both groups. Neither pre-surgical SSA (nZ6) nor tumour morphology was related to the GH response. However, semiquantitative analysis indicated a small but significant negative correlation between the GH response to Octreotide and the immunoreactivity scores of sst2 expression. Conclusions: DG3173 equalled Octreotide in suppressing GH secretion in hSA. Since DG3173 suppressed GH in some Octreotide-non-responsive adenomas, its clinical effectiveness will be worth testing. Moreover, its reduced insulin-suppressive potency would make it a valuable alternative to Octreotide.

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Section: Introductionmentioning

confidence: 99%

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

Plöckinger

Hoffmann²,

Geese³

et al. 2012

European Journal of Endocrinology

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“…The novel developed SSTA (parieotide) which has high affinity to sstr1, sstr2, sstr3 and sstr5, has proved to be more effective than octreotide in treating acromegaly. (Schmid, 2008) Pasireotide may have the potential to be effective in patients unresponsive or refractory to octreotide and lanreotide, as well as in NETs expressing sstr other than SSTR2. (Modlin et al, 2010) Fourth, the release of bioactive mediators of NETs may operate via a different road besides the inhibitory pathways of SSTA.…”

Section: Discussionmentioning

confidence: 99%

Somatostatin Analogues Do Not Prevent Carcinoid Crisis

Guo

Tang²

2014

Asian Pacific Journal of Cancer Prevention

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Background: Carcinoid crisis is a life-threating syndrome of neuroendocrine tumors (NETs) characterized by dramatic blood pressure fluctuation, arrhythmias, and bronchospasm. In the era of booming anti-tumor therapeutics, this has become more important since associated stresses can trigger carcinoid crisis. Somatostatin analogues (SSTA) have been recommended for prophylactic administration before intervention procedures for functioning NETs. However, the efficacy is still controversial. The aim of this article is to review efficacy of SSTA for preventing carcinoid crisis. Materials and Methods: PubMed, Cochrane Controlled trials Register, and EMBASE were searched using 'carcinoid crisis' as a search term combining terms with 'somatostatin'; 'octreotide'; 'lanreotide' and 'pasireotide' until December 2013. Results: Twenty-eight articles were retrieved with a total of fifty-three unique patients identified for carcinoid crisis. The most common primary sites of NETs were the small intestine and respiratory tract. The triggering factors for carcinoid crisis included anesthesia/ surgery (63.5%), interventional therapy (11.5%), radionuclide therapy (9.6%), examination (7.7%), medication (3.8%), biopsy (2%) and spontaneous (2%). No randomized controlled trials (RCTs) were identified and two case-control studies were included to assess the efficacy of SSTA for preventing carcinoid crisis by meta-analysis. The overall pooled risk of perioperative carcinoid crisis was similar despite the prophylactic administration of SSTA (OR 0.44, 95% CI: 0.14 to 1.35, p=0.15). Conclusions: SSTA wasnot helpful for preventing carcinoid crisis based on a meta-analysis of retrospective studies. Attentive monitoring and careful intervention are essential. Future studies with better quality are needed to clarify any effect of SSTA for preventing carcinoid crisis.

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“…Moreover, symptom control disappears in about half of patients during the first year of treatment with SSAs. However, this symptomatic and proliferative control does not last forever and some mechanisms of resistance to treatment have been described, although the exact one is not yet known [32][33][34][35][44][45][46][47][48] (Table 1).…”

Section: Resistance To Somatostatin Analogsmentioning

confidence: 99%

“…internalization and desensitization with respect to the number of SSTRs at the cell surface, causing modification of the ratio expression between different cell surface receptors, altering the downstream signaling triggered by the receptor, causing up-or downregulation of the pre-existing intracellular pathways, and even creating new intracellular signaling pathways by the formation of homo-and heterodimers between different receptor subtypes or other receptor superfamily [33][34][35][44][45][46][47][48][49][50].…”

Section: Resistance To Somatostatin Analogsmentioning

confidence: 99%

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

et al. 2016

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The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being reduced by approximately 50% within the first year. The exact mechanisms of resistance to SSAs are not fully understood, but it is believed that serotonin might be involved. Patients with carcinoid syndrome present with a significant increase in serotonin plasma levels and, consequently, in the soluble urinary metabolite 5‐hydroxyindole acetic acid. Telotristat etiprate is a potent inhibitor of tryptophan hydroxylase, a rate‐limiting enzyme in the synthesis of serotonin, that has demonstrated in the phase III TELESTAR clinical trial a significant improvement in the control of bowel movements in patients with NETs who have carcinoid syndrome and who have progressed to an SSA. Based on these results, telotristat etiprate has emerged as a potential new option in the treatment algorithm of symptomatic control of functioning NETs. However, some issues need to be clarified, such as the safety profile of the drug outside clinical trials, the benefit in quality of life, and the possible impact on tumor growth, as well as its role within sequencing or combination treatment strategies with pre‐existing drugs effective in NET treatment. Implications for Practice: This article reviews the literature about carcinoid syndrome, which affects patients diagnosed with neuroendocrine tumors. Few articles have been published about this syndrome and its pathophysiology. Somatostatin analogs provide symptomatic relief; however, patients may become refractory to this strategy, usually within the first year of treatment. In this context, as an agent with an innovative mechanism of action, telotristat etiprate has demonstrated activity in a phase III trial, and findings may offer a path to an improve quality of life and prolonged survival for certain patients.

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Pasireotide (SOM230): Development, mechanism of action and potential applications

Cited by 267 publications

References 31 publications

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

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

Somatostatin Analogues Do Not Prevent Carcinoid Crisis

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

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