Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids

Zatelli, Maria Chiara; Minoia, Mariella; Martini, Chiara; Tagliati, Federico; Ambrosio, Maria Rosaria; Schiavon, Marco; Buratto, Mattia; Calabrese, Fiorella; Gentilin, Erica; Cavallesco, Giorgio; Berdondini, Lisa; Rea, Federico; Uberti, Ettore C. degli

doi:10.1677/erc-10-0097

Cited by 61 publications

(48 citation statements)

References 37 publications

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“…In particular, the treatment of lung carcinoid cells with inhibitors of the PI3K/ AKT/mTOR pathway significantly reduced cellular growth and neuroendocrine marker expression in vitro (18,19). In Table III.…”

Section: Discussionmentioning

confidence: 98%

“…The AKT/mTOR signaling pathway is aberrantly activated in many tumor types (13,14,16,17). In particular, this pathway seems to play a role in tumor cell growth and proliferation in human pulmonary carcinoid cells (18,19), as well in small-cell lung cancer cells (12,20). Because of these functions, mTOR has been considered an attractive target for anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

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Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Alì

Boldrini

Capodanno

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Bronchopulmonary neuroendocrine tumors (BP-NETs) are separated into four subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC). The signaling pathway involving AKT/ mammalian target of rapamycin (mTOR) is crucial to the regulation of cell growth, proliferation and survival, and is frequently activated in human cancers. Consequently, mTOR is considered an attractive target for anticancer agents. The present study aimed to evaluate the expression of phosphorylated AKT and mTOR in a series of BP-NETs, and to analyze the correlations with clinicopathological parameters. p-AKT and p-mTOR levels were determined by immunohistochemistry in a series of 210 BP-NETs, including 85 SCLCs, 17 LCNECs, 26 ACs, 75 TCs and 7 tumorlets. Higher p-AKT and p-mTOR expression levels were identified in the majority of tumorlets and carcinoids in comparison to the LCNECs (P=0.0001) and SCLCs (P=0.0002). Furthermore, a significant association was observed between p-mTOR expression and tumor size (T) in SCLCs (P=0.04) and LCNECs (P=0.03): T3-T4 tumors exhibited significantly lower p-mTOR expression compared to T1-T2 tumors. In conclusion, most of the BP-NETs examined in this study expressed p-AKT and p-mTOR, suggesting that the AKT/mTOR pathway plays an important role in these tumors. Additionally, our results confirm that low-to intermediate-grade tumors are more closely associated to each other than to high-grade tumors, despite sharing common classification and a common origin from neuroendocrine cells. These findings improve our knowledge of the biological characterization of these tumors and indicate new therapeutic opportunities for the treatment of BP-NETs.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Alì

Boldrini

Capodanno

et al. 2011

Experimental and Therapeutic Medicine

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“…28 In 2010, Zatelli et al observed an anti-proliferative effect of everolimus in human BC tumour cells associated with a reduction in chromogranin A level, VEGF secretion and cell viability, probably mediated by a mechanism involving IGF1 signalling. 29 mTOR expression levels together with aggressive clinical features (i.e. AC, larger tumour size, higher number of mitoses) were found to be associated with an enhanced sensitivity to everolimus.…”

Section: Preclinical Studies Of Mtor Inhibitors In Bronchial Carcinoimentioning

confidence: 89%

Mammalian Target of Rapamycin (mTOR) Inhibition in Advanced Bronchial Carcinoids

Fazio

Frezza

2015

European Oncology &Amp; Haematology

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Bronchial carcinoids (BCs), comprising typical (TC) and atypical (AC) carcinoids, account for 1-2 % of all lung cancers and approximately 20-30 % of all neuroendocrine neoplasms (NENs). They represent the low-and intermediate-grade lung NENs, whereas small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) represent the high-grade entities. While the prognosis of BCs is favourable at early stages, it is poor when distant metastases are present. Unfortunately, there is a lack of therapeutic options as well as limited data to support the use of standard therapies and sequences of treatments. Some chemotherapeutic regimens have been reported to be active, but their efficacy has not been validated so far. Somatostatin analogues (SSAs) as single agents can be an option for very slow-growing disease, but their role in combination with other therapies has not been established. Among the new targeted agents, data from clinical trials showed that everolimus is a promising one. KeywordsLung NET, lung neuroendocrine tumour, bronchial carcinoid, carcinoid tumour, pulmonary neuroendocrine neoplasm, somatostatin analogue, small cell lung cancer, large cell neuroendocrine carcinoma, bronchopulmonary carcinoid, everolimus 2 Thoracic NENs, the majority of which are bronchial, are classified as carcinoids and carcinomas (see Table 1). 6 BCs can be associated with a hyper-secretion syndrome, although this is more commonly seen in GEP NENs. Carcinoid syndrome (fewer than 5 % of cases), related to serotonin, is the most common one, and it is usually atypical. Cushing syndrome is rarer, related to ectopic adrenocorticotropic hormone (ACTH) production.

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“…In addition, a recent preclinical study of the impact of the mTOR inhibitor, everolimus, found that it suppressed the viability of typical and atypical carcinoid lung cells in culture [20]. Thus, there is a theoretical rationale for the use of both Tyrosine-kinase inhibitor (TKIs) and mTOR inhibitors.…”

Section: Management Of Advanced/metastatic Diseasementioning

confidence: 99%

Update on Therapeutic Strategy in Lung Carcinoids

Pusceddu¹,

Vitali²,

Haspinger³

et al. 2013

JCT

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An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchial tree and into the lungs. Although lung NETs account for less than 1% of all pulmonary malignancies, the incidence of these neoplasms has risen precipitously since the mid 1970s. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Surgery is the treatment of choice for typical and atypical carcinoid lung NETs with loco-regional disease. At diagnosis up to 64% of patients with atypical carcinoid lung NETs present with lymph node metastases, and 5-year survival ranges from 61% to 88%. In contrast, lymph node metastases are present in fewer than 15% of typical carcinoid lung NETs, and 5-year survival exceeds 90%. To date, there is no recognized standard of treatment for advanced carcinoid lung NETs. In recent years only two trials reported intriguing results regarding lung NETs: a phase 2 retrospective study of dacarbazine derivative temozolomide and the phase 3, RADIANT-2 trial in advanced NETs. Successful management requires a multidisciplinary team management. This review is restricted to typical/atypical NETs.

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Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids

Cited by 61 publications

References 37 publications

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Mammalian Target of Rapamycin (mTOR) Inhibition in Advanced Bronchial Carcinoids

Update on Therapeutic Strategy in Lung Carcinoids

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