mTOR, AKT, p70S6K and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Gagliano, Teresa; Bellio, Mariaenrica; Gentilin, Erica; Molè, Daniela; Tagliati, Federico; Schiavon, Marco; Cavallesco, Narciso Giorgio; Calabrese, Fiorella; Ambrosio, Maria Rosaria; Rea, Federico; Uberti, Ettore Degli; Zatelli, Maria Chiara

doi:10.1530/endoabs.32.p519

Cited by 11 publications

(13 citation statements)

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“…In randomized controlled trials, everolimus obtained a 65% decrease in the risk for tumor progression in pNETs [7] and a 23% decrease in patients with nonpancreatic NETs (non-pNETs) [9]. In addition, promising preclinical findings suggested that everolimus might be effective in aggressive endocrine neoplasms [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Real-World Study of Everolimus in Advanced Progressive Neuroendocrine Tumors

et al. 2014

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Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT andchemotherapy, a12-foldincreased riskforseveretoxicitywas observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS,and OS werereported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs. The Oncologist 2014;19:966-974 Implications for Practice: Data reported outside regulatory trial settings are useful for physicians dealing with neuroendocrine tumors (NETs) and provide understanding of whether the findings obtained in those trials are consistent with clinical practice. In this real-world study of everolimus in advanced, progressive NETs, significantly higher severe toxicity was observed in patients with long-duration disease and in those previously treated with systemic chemotherapy and/or peptide receptor radionuclide therapy. These findings may help physicians to plan an optimal therapeutic strategy for these patients to avoid predictable severe toxicity that may also result in limitations for further treatments.

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Section: Introductionmentioning

confidence: 99%

Real-World Study of Everolimus in Advanced Progressive Neuroendocrine Tumors

et al. 2014

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“…In addition, the expression of some of the above molecules (in particular p-mTOR and GLUT-1, as well as of the aminoacid transporter LAT-1, were strongly associated with SSTR2A expression, suggesting that somatostatin receptor inhibitor effects may result from mTOR pathway control, and that synergies can be obtained by combined treatments, as suggested in intestinal NETs [47]. Indeed, in in vitro models, bronchial carcinoid cells of patients responding to mTOR inhibitors were shown to have higher levels of phosphorylated mTOR [48].…”

Section: Prognostic and Predictive Molecular Markersmentioning

confidence: 97%

Therapeutic Biomarkers in Lung Neuroendocrine Neoplasia

et al. 2014

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The well known classification of neuroendocrine neoplasms of the lung into four major subtypes (including typical and atypical carcinoids and small and large cell neuroendocrine carcinomas) has a proven prognostic validity, but only partially helps to predict the response to specific therapies.Therapeutic biomarkers are incompletely known and include morphological, immunophenotypic and molecular markers. Morphology alone has no specific predictive role, nor has any immunophenotypic marker been proven to bear predictive implications. Ki67 is a relevant prognostic marker and can indirectly predict response to chemotherapy, when levels are extremely high in high-grade NE carcinomas. The expression of somatostatin receptors especially of the type 2A, has been shown to predict response to somatostatin analog treatments, paralleling the information derived from octreotide scintigraphy. mTOR pathway is targeted by specific inhibitors, but the exact cellular molecules predicting response are still to be defined. It seems that high levels of phosphorylated forms of mTOR and of its downstream factor S6K are associated to a better response to rapalogs in experimental models. Data from gene expression profiling and mutational analyses are currently emerging, providing a more detailed map of different molecular activation pathways, potentially leading to a more accurate molecular classification of lung NE tumors as well as to the discovery of new therapeutic targets. The combination of mutational profiles with those of up-or down-regulated genes also by gene gains or losses may ultimately provide a better characterization of NE tumor histological types in terms of response to specific chemo-or bio-therapies.

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“…Potential markers predicting sensitivity to mTOR inhibitors have been also suggested, such as total mTOR level, AKT, p70S6K (RPS6KB2), and mitogen-activated protein/extracellular signal-regulated kinases (MAPK/ERK) levels in patients with pulmonary carcinoids (20). In SCLC cells, high expression of eukaryotic translation initiation factor 4E (elF4E) was associated with increased resistance to everolimus treatment.…”

Section: Abstract Primary Lung Neuroendocrine Tumors (Nets) Consist mentioning

confidence: 99%

Insights into Novel Prognostic and Possible Predictive Biomarkers of Lung Neuroendocrine Tumors

2018

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mTOR, AKT, p70S6K and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Cited by 11 publications

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Real-World Study of Everolimus in Advanced Progressive Neuroendocrine Tumors

Real-World Study of Everolimus in Advanced Progressive Neuroendocrine Tumors

Therapeutic Biomarkers in Lung Neuroendocrine Neoplasia

Insights into Novel Prognostic and Possible Predictive Biomarkers of Lung Neuroendocrine Tumors

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