Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours

Colao, Annamaria; Filippella, Mariagiovanna; Pivonello, Rosario; Somma, Carolina Di; Faggiano, Antongiulio; Lombardi, Gaetano

doi:10.1530/eje.1.02348

Cited by 50 publications

(28 citation statements)

References 58 publications

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“…Radiotherapy remains the only post-operative option, but it is not curative. Chemotherapy is only used as salvage treatment, but usually with disappointing results (6,7). Therefore, novel therapeutic approaches are required.…”

Section: Introductionmentioning

confidence: 99%

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

Lee

Wiedemann

Groß

et al. 2015

Clinical Cancer Research

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Purpose: Novel therapeutic approaches are needed to improve the postoperative management of residual nonfunctioning pituitary adenomas (NFPA), given their high relapse rate. Here, we evaluated the antitumor efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in the only available model of spontaneous NFPAs (MENX rats).Experimental Design: Organotypic cultures of rat primary NFPAs were incubated with NVP-BEZ235 and assessed for cell viability, proliferation, apoptosis, and PI3K/mTOR inhibition. NVP-BEZ235, or placebo, was administered to MENX rats and tumor response was monitored noninvasively by diffusion weighted-magnetic resonance imaging (DW-MRI). Following treatment, tumor tissues were investigated for cell proliferation, apoptosis, and PI3K/mTOR inhibition. Genes mediating the cytotoxic activity of NVP-BEZ235 were identified by gene-expression profiling. Among them, Defb1, encoding beta-defensin 1, was further studied for its role in pituitary cells and in human pancreatic neuroendocrine tumor (NET) cells.Results: NVP-BEZ235 showed antiproliferative and pro-cell death activities against NFPAs both in vitro and in vivo, and the response to the drug correlated with inhibition of the PI3K pathway. DW-MRI identified early functional changes (decreased cellularity) in the adenomas before their size was affected and emerged as a useful modality to assess therapy response. The cytotoxic effect of PI3K/mTOR blockade in NFPA was mediated by several genes, including Defb1. NVP-BEZ235 treatment induced Defb1 expression in NFPAs in vitro and in vivo, and in pancreatic NET cells. High Defb1 levels sensitized NET cells to PI3K/mTOR inhibition.Conclusions: Our findings provide rationale for clinical investigation of PI3K/mTOR inhibition in NFPAs and identify novel effectors of PI3K-mediated neuroendocrine cell survival.

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Section: Introductionmentioning

confidence: 99%

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

Lee

Wiedemann

Groß

et al. 2015

Clinical Cancer Research

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“…The long-acting ergot-derived D2-selective dopamine agonist cabergoline is frequently prescribed in this condition because of superiority in terms of both tolerability and efficacy compared with various other agents (1,2). Cabergoline is also used in acromegaly as an adjunctive agent for lowering GH levels (3).…”

Section: Introductionmentioning

confidence: 99%

Absence of major fibrotic adverse events in hyperprolactinemic patients treated with cabergoline

Lafeber

Stades²,

Valk³

et al. 2010

European Journal of Endocrinology

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Background: Cabergoline, a dopamine agonist used to treat hyperprolactinemia, is associated with an increased risk of fibrotic adverse reactions, e.g. cardiac valvular fibrosis, pleuropulmonary, and retroperitoneal fibrosis. Objective: This study evaluated the prevalence and risk of fibrotic adverse reactions during cabergoline therapy in hyperprolactinemic and acromegalic patients. Design: A cross-sectional study was conducted in a University Hospital. Patients: A total of 119 patients with hyperprolactinemia and acromegaly who were on cabergoline therapy participated in the study. Methods: All patients were requested to undergo a cardiac assessment, pulmonary function test, chest X-ray, and blood tests as recommended by the European Medicine Agency. Matched controls were recruited to compare the prevalence of valvular regurgitation. Cardiac valvular fibrosis was evaluated by assessing valvular regurgitation and the mitral valve tenting area (MVTa). The risk of pleuropulmonary fibrosis was assessed by a pulmonary function test, a chest X-ray, and if indicated, by additional imaging studies. Results: The prevalence of clinically relevant valvular regurgitation was not significantly different between cases (11.3%) and controls (6.1%; PZ0.16). The mean MVTa was 1.27G0.17 and 1.24G0.21 cm 2 respectively (PZ0.54). Both valvular regurgitation and the MVTa were not related to the cumulative dose of cabergoline. A significantly decreased pulmonary function required additional imaging in seven patients. In one patient, possible early interstitial fibrotic changes were seen. Lung function impairment was not related to the cumulative cabergoline dose. Conclusion: Cabergoline, typically dosed for the long-term treatment of hyperprolactinemia or acromegaly, appears not to be associated with an increased risk of fibrotic adverse events.

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“…NFAs contain dopamine (D2) and somatostatin receptors, but the effect of dopamine receptor agonist (DA) and somatostatin analogues (SSA) are limited when used separately (4). Recent data indicate that a combination of DA and SSA could be effective (5,6). GH-secreting adenomas are usually treated with transsphenoidal surgery, which reduce hormone levels to acceptable levels in about 85% of microadenomas and in !60% of macroadenomas (7,8).…”

Section: Introductionmentioning

confidence: 99%

Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy

Schroeder¹,

Hansen

Hagen³

et al. 2009

European Journal of Endocrinology

112

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Objective: Aggressive pituitary tumours may be difficult to treat. Temozolomide (TMZ) is an alkylating cytostaticum. In a small number of cases, TMZ therapy has been reported to reduce pituitary tumour size and hormone hypersecretion. Design: We present three patients with pituitary tumours treated with TMZ. One tumour was initially a macroprolactinoma that developed into a mixed GH-and prolactin-secreting carcinoma (patient A). To our knowledge, this is the first published in English literature. Two adenomas, a macroprolactinoma (patient B) and a clinically non-functioning pituitary adenoma (patient C), were highly invasive. The three patients suffered from extensive tumour mass effects, and all tumours were resistant to conventional treatment. Method: TMZ, 150-200 mg/m 2 of body surface area was administered orally for 5 days during each 28-day cycle. Result: During TMZ therapy, tumour sizes were significantly reduced, hormone levels normalized and symptoms of mass effects decreased in all three cases. The carcinoma was treated from 2004 to 2006 (23 months). Three years after the terminating treatment, the tumour has not regrown and hormone levels are normalized. Immunohistochemical staining for methylguanine DNA methyltransferase (MGMT) was negative in two patients (A and B), and in one patient (C) a few nuclei stained positive. Conclusion: TMZ therapy significantly decreased tumour volume, hormone hypersecretion and symptoms in all three patients, corresponding to the pathological findings regarding MGMT. TMZ therapy may be a new option for the treatment of resistant pituitary adenomas.

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Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours

Cited by 50 publications

References 58 publications

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

Absence of major fibrotic adverse events in hyperprolactinemic patients treated with cabergoline

Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy

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