Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors

2013 ◽  
Vol 21 (4) ◽  
pp. 288-295 ◽  
Author(s):  
Yoko Komori ◽  
Kazuhiro Yada ◽  
Masayuki Ohta ◽  
Hiroki Uchida ◽  
Yukio Iwashita ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Pancreatic Neuroendocrine Tumors ◽  
Activation Patterns ◽  
Signaling Activation

scholarly journals Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung

2010 ◽  
Vol 17 (4) ◽  
pp. 977-987 ◽  
Author(s):  
Luisella Righi ◽  
Marco Volante ◽  
Ida Rapa ◽  
Veronica Tavaglione ◽  
Frediano Inzani ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Differential Sensitivity ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Low Grade ◽  
Mtor Inhibition ◽  
Signaling Activation ◽  
Activation Status

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.

scholarly journals Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor‐Naïve Advanced Pancreatic Neuroendocrine Tumors

2017 ◽  
Vol 23 (7) ◽  
pp. 766 ◽  
Author(s):  
Ramon Salazar ◽  
Rocio Garcia‐Carbonero ◽  
Steven K. Libutti ◽  
Andrew E. Hendifar ◽  
Ana Custodio ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Pancreatic Neuroendocrine Tumors

Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors

2009 ◽  
Vol 65 (5) ◽  
pp. 889-893 ◽  
Author(s):  
Takashi Shida ◽  
Takashi Kishimoto ◽  
Mitsuko Furuya ◽  
Takashi Nikaido ◽  
Keiji Koda ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Gastroenteropancreatic Neuroendocrine Tumors

scholarly journals PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1902 ◽  
Author(s):  
Gabriel Mpilla ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Steve Kim ◽  
Rafic Beydoun ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neuroendocrine Tumors ◽  
Clinical Investigation ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Residual Tumor ◽  
Pancreatic Neuroendocrine Tumors ◽  
Nicotinamide Phosphoribosyltransferase

Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation.

scholarly journals Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer

2020 ◽  
Vol 111 (4) ◽  
pp. 1291-1302
Author(s):  
Hiroshi Shiratori ◽  
Kazushige Kawai ◽  
Masamichi Okada ◽  
Hiroaki Nozawa ◽  
Keisuke Hata ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Advanced Rectal Cancer ◽  
Target Of Rapamycin ◽  
Signaling Activation

Progesterone Receptor and PTEN Expression Predict Survival in Patients With Low- and Intermediate-Grade Pancreatic Neuroendocrine Tumors

2014 ◽  
Vol 138 (8) ◽  
pp. 1027-1036 ◽  
Author(s):  
Jeannelyn S. Estrella ◽  
Russell R. Broaddus ◽  
Amber Mathews ◽  
Denái R. Milton ◽  
James C. Yao ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Negative Regulator ◽  
Small Subset ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Tumors ◽  
Intermediate Grade ◽  
Low Profile ◽  
Phosphatase And Tensin Homologue

Context.—The PI3K-AKT-mTOR (phosphatidylinositol 3-kinase–AKT–mammalian target of rapamycin) pathway plays a crucial role in a subset of advanced pancreatic neuroendocrine tumors (PanNETs). In breast and endometrial carcinoma, activation of this pathway inhibits progesterone receptor (PR) expression. Objective.—To determine whether combined low expression of PR and phosphatase and tensin homologue (PTEN), a negative regulator of the PI3K-AKT-mTOR pathway, is a prognostic factor. Design.—A total of 160 resected PanNETs (89 low grade and 71 intermediate grade) were analyzed for PR and PTEN immunohistochemical positivity and staining was correlated with metastasis-free survival (MFS) and overall survival (OS). Progesterone receptor staining was scored as positive by using 1% or greater as cutoff. Weak/faint staining in greater than 90% of tumor cells was considered low PTEN positivity. Results.—Most PanNETs (110 cases, 69%) were both PR and PTEN positive, 45 (28%) were either PR or PTEN positive, and only 5 (3%) had a PR-negative and PTEN-low profile. Combined PR-PTEN positivity was significantly associated with MFS in patients with stage I and II disease (P &lt;.001) and OS in all patients (P &lt; .001) and remained a significant predictor of survival after adjusting for other factors. Patients with PR-negative–PTEN-low PanNETs had the shortest median MFS and OS, compared to those with tumors that were either PR or PTEN positive and with tumors positive for both PR and PTEN (P ≤ .001). Conclusion.—Combined immunohistochemical assessment of PR and PTEN may help identify a small subset of PanNETs with more aggressive behavior and may aid in risk stratification.

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