Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors

Caplin, Martyn; Pavel, Marianne; Ćwikła, Jarosław B.; Phan, Alexandria T.; Raderer, Markus; Sedláčková, Eva; Cadiot, Guillaume; Wolin, Edward M.; Capdevila, Jaume; Wall, Lucy; Rindi, Guido; Langley, Alison; Martinez, Séverine; Blumberg, Joëlle; Ruszniewski, Philippe

doi:10.1056/nejmoa1316158

Cited by 1,515 publications

(1,299 citation statements)

References 22 publications

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“…formulation (Modlin et al 2010). In two placebo-controlled trials (PROMID and CLARINET), the antiproliferative activity has been demonstrated by the prolongation of time to progression (TTP) and PFS, respectively for octreotide in low-grade (G1) midgut NET (TTP 14.3 months vs 6 months on placebo) and for lanreotide in entero-pancreatic NET (PFS >27 months vs 18 months on placebo) of low to intermediate grade (G1 and G2 ≤10% Ki-67) (Rinke et al 2009, Caplin et al 2014. Although objective remissions are rare with SSA (<2%), disease stabilization is observed in two-thirds of the patients.…”

Section: :11mentioning

confidence: 99%

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

Pavel¹,

Sers²

2016

Endocrine-Related Cancer

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Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms. Evidencebased treatment options for antiproliferative therapy include somatostatin analogues, the mTOR inhibitor everolimus, the multiple tyrosine kinase inhibitor sunitinib and peptide receptor radionuclide therapy with 177-Lu-octreotate. In the absence of definite predictive markers, therapeutic decision making follows clinical and pathological criteria. As objective response rates with targeted drugs are rather low, and response duration is limited in most patients, numerous combination therapies targeting multiple pathways have been explored in the field. Upfront combination of drugs, however, is associated with increasing toxicity and has shown little benefit. Major advancements in the molecular understanding of NET based on genomic, epigenomic and transcriptomic analysis have been achieved with prognostic and therapeutic impact. New insight into molecular alterations has paved the way to biomarker-driven clinical trials and may facilitate treatment stratification toward personalized medicine in the near future. However, an improved understanding of the complexity of pathway interactions is required for successful treatment. A systems biology approach is one of the tools that may help to achieve this endeavor.

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Section: :11mentioning

confidence: 99%

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

Pavel¹,

Sers²

2016

Endocrine-Related Cancer

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“…In particular, octreotide LAR and lanreotide SR (with a preferential binding affinity for SST2) have been demonstrated to control both the symptoms and hormone secretion in 50-60% of patients with functioning NET. Moreover, SS analogues have been found to stabilise tumour mass in 30-50% of patients, with a significant reduction in tumour mass being observed in a minority of them (Rinke et al 2009, Ö berg 2012, Caplin et al 2014, but the mechanisms involved in the resistance in non-responders patients being still unknown.…”

Section: Introductionmentioning

confidence: 99%

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Vitali

Cambiaghi

Zerbi

et al. 2016

Endocrine-Related Cancer

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Somatostatin receptor type 2 (SST2) is the main pharmacological target of somatostatin (SS) analogues widely used in patients with pancreatic neuroendocrine tumours (P-NETs), this treatment being ineffective in a subset of patients. Since it has been demonstrated that Filamin A (FLNA) is involved in mediating GPCR expression, membrane anchoring and signalling, we investigated the role of this cytoskeleton protein in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in human P-NETs and in QGP1 cell line. We demonstrated that FLNA silencing was not able to affect SST2 expression in P-NET cells in basal conditions. Conversely, a significant reduction in SST2 expression (K43G21%, P!0.05 vs untreated cells) was observed in FLNA silenced QGP1 cells after long term SST2 activation with BIM23120. Moreover, the inhibitory effect of BIM23120 on cyclin D1 expression (K46G18%, P!0.05 vs untreated cells), P-ERK1/2 levels (K42G14%; P!0.05 vs untreated cells), cAMP accumulation (K24G3%, P!0.05 vs untreated cells), VEGF expression (K31G5%, P!0.01 vs untreated cells) and in vitro release (K40G24%, P!0.05 vs untreated cells) was completely lost after FLNA silencing. Interestingly, BIM23120 promoted cell adhesion (C86G45%, P!0.05 vs untreated cells) and inhibited cell migration (K24G2%, P!0.00001 vs untreated cells) in P-NETs cells and these effects were abolished in FLNA silenced cells. In conclusion, we demonstrated that FLNA plays a crucial role in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in P-NETs and in QGP1 cell line, suggesting a possible role of FLNA in determining the different responsiveness to SS analogues observed in P-NET patients.

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“…14 Nevertheless, most patients with widespread metastatic PNET disease ultimately succumb to the disease despite the availability of multiple palliative interventions. 1,2,[15][16][17][18][19][20][21][22] Somatostatin analog therapy is usually the first non-surgical therapy used in patients with slowly progressive disease because it is generally well tolerated. Octreotide has not been studied in PNET patients specifically but the PROMID trial in widely metastatic small bowel carcinoid tumors was the first to show tumor stabilization in a randomized clinical setting and this has become the de facto first line treatment for many patients.…”

Section: Discussionmentioning

confidence: 99%

“…15 The CLARINET trial, which evaluated the impact of another somatostatin analog, lanreotide, in a double-blind, randomized trial of metastatic patients with both alimentary tract carcinoids as well as PNETs, was just recently published with a positive result, further cementing the value of using somatostatin analog therapy in these patients. 16 However, somatostatin analogs only produce tumor stabilization and this only persists for a finite period of time.…”

Section: Discussionmentioning

confidence: 99%

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target

Gurung

Hua

Runske

et al. 2014

Cancer Biology & Therapy

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Pancreatic neuroendocrine tumors (PNETs) are rare, indolent tumors that may occur sporadically or develop in association with well-recognized hereditary syndromes, particularly multiple endocrine neoplasia type 1 (MEN-1). We previously demonstrated that the hedgehog (HH) signaling pathway was aberrantly up-regulated in a mouse model that phenocopies the human MEN-1 syndrome, Men1l/l;RipCre, and that inhibition of this pathway suppresses MEN-1 tumor cell proliferation. We hypothesized that the HH signaling pathway is similarly upregulated in human PNETs. We performed immunohistochemical (IHC) staining for PTCH1 in human fresh and archival PNET specimens to examine whether human sporadic and MEN-1-associated PNETs revealed similar abnormalities as in our mouse model and correlated the results with clinical and demographic factors of the study cohort. PTCH1 staining was positive in 12 of 22 PNET patients (55%). Four of 5 MEN-1 patients stained for PTCH1 (p D 0.32 as compared with sporadic disease patients). Nine of 16 patients with metastatic disease stained for PTCH1 as compared with zero of 3 with localized disease only (p D 0.21). No demographic or clinical features appeared to be predictive of PTCH 1 positivity and PTCH 1 positivity per se was not predictive of clinical outcome. PTCH1, a marker of HH pathway up regulation, is detectable in both primary and metastatic tumors in more than 50% of PNET patients. Although no clinical or demographic factors predict PTCH1 positivity and PTCH1 positivity does not predict clinical outcome, the frequency of expression alone indicates that perturbation of this pathway with agents such as Vismodegib, an inhibitor of Smoothened (SMO), should be examined in future clinical trials.

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Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors

Abstract: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

Cited by 1,515 publications

References 22 publications

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target

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