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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian target of rapamycin (mTOR) inhibitors represent a new class of potential anticancer agents. The mTOR inhibitor, rapamycin, inhibited proliferation in three mantle cell lymphoma (MCL) cell lines and reduced cyclin D3 expression while cyclin D1 levels remained unchanged. This finding was confirmed in cells from a MCL patient.
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PMID:Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. 1621 81

To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12 of 12 aggressive blastoid MCL variants and in 4 of 4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5 of 16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27(kip1), FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27(kip1), FRKHL-1, MDM2, Bad, mTOR, GSK-3beta, IkappaB, and led to cell-cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and 1 with inactive Akt) and 3 of 4 cell lines showed loss of PTEN expression. PIK3CA mutations were not detected. We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. These data suggest that PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL.
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PMID:Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. 1664 63

The mammalian target of rapamycin (mTOR) is emerging as a promising target for antitumor therapy. However, the mechanism that contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active because the cells displayed rapamycin-sensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from patients with FL revealed that, in most cases, p70S6 kinase was highly phosphorylated compared to normal tonsillar tissue. In FL cells, mTOR was under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation because we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidence that Syk operates through PLD- and PI3K-independent pathways. Finally, Syk inhibition by piceatannol or by siRNA plasmids resulted in a potent inhibition of mTOR activity in FL cells, as well as in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma. These findings suggest that the Syk-mTOR pathway has a critical function in FL survival, and therefore, that Syk could be a promising new target for B-lymphoma therapy.
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PMID:Syk-dependent mTOR activation in follicular lymphoma cells. 1691 21

The phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Key components of the pathway are the lipid kinase PI3-K, the small guanosine triphosphate-binding protein Rheb, and the protein kinases Akt and mTOR. Important natural inhibitors of the pathway include the lipid phosphatase PTEN and the tuberous sclerosis complex. Several components of this pathway are targeted by investigational antineoplastic agents. Rapamycin (sirolimus), the prototypic mTOR inhibitor, exhibits activity in acute myeloid leukemia. Three rapamycin analogs, temsirolimus, everolimus, and AP23573, are in clinical trials for various hematologic malignancies. Temsirolimus has produced a 38% overall response rate in relapsed mantle cell lymphoma, and AP23573 has demonstrated activity in acute leukemia. Everolimus is undergoing clinical testing in lymphoma (Hodgkin and non-Hodgkin) and multiple myeloma. In addition, perifosine, an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models, is being examined in relapsed multiple myeloma. Based on results obtained to date, it appears that inhibitors of the PI3-K/mTOR pathway hold promise as single agents and in combination for hematologic malignancies.
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PMID:Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. 1691 89

Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma, with a mean survival of only 3-5 years and suboptimal therapeutic options. MCL is characterized by a balanced translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1, a G(1) cyclin regulated by the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. As improved therapy for MCL is required and the mTOR pathway may be involved in its pathophysiology, the antiproliferative effects of RAD001 (everolimus), an mTOR inhibitor, against three MCL cell lines were investigated. As a single agent, RAD001 inhibited proliferation in MCL cell lines (Jeko1, SP49 and NCEB1) approximately 40-65% compared to diluent control cells. This was associated with G(1) cell-cycle arrest and reduced phosphorylation of the mTOR downstream target, 4E-BP1. Furthermore, combination drug studies revealed predominantly synergistic cytotoxicity with RAD001 and several secondary agents, including doxorubicin, vincristine or rituximab (components of the standard MCL regimen), as well as paclitaxel, vorinostat and bortezomib. These data indicate that single agent RAD001 is effective in inhibiting growth of MCL cells in vitro and combination studies with secondary agents further demonstrate synergistic cytotoxicity. Thus, these findings support future clinical studies of RAD001 in the treatment of MCL.
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PMID:Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. 1713 16

Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.
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PMID:Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. 1714 79

The mammalian target of rapamycin (mTOR) is a large and highly conserved kinase that integrates growth factor stimulation, energy and nutrient availability to modulate translation of proteins responsible for cellular growth and proliferation. Its importance in malignant cells provides strong rationale for the development of mTOR inhibitors (mTORi) in a broad variety of solid tumors and hematological malignancies. However several questions regarding mTOR biology and its interaction with pharmacological inhibitors remain unanswered and are relevant for further development of this novel family of cancer drugs. Nevertheless, mTORi have demonstrated activity in lymphoma cells either alone or in combination with cytotoxic agents. The most promising results have been seen in mantle cell lymphoma (MCL), likely because of its dependence on Cyclin D, the translation of which is largely regulated by mTOR activity. The currently knowledge of mTOR biology will here be reviewed along with the status of clinical development of mTORi in non-Hodgkin's lymphomas.
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PMID:Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin's lymphoma. 1716 12

Mantle cell lymphoma (MCL) represents only 6% of non-Hodgkin's lymphoma but is one of the most active fields of clinical investigation. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and rituximab. Unfortunately, no standard therapy has been defined, and most patients eventually relapse. An impressive number of novel agents are currently being tested, the bulk of which are biologic agents or targeted therapies. Bortezomib is the first in class of proteasome inhibitors and the first new agent to be approved in relapsed/refractory MCL. Other small molecules have shown encouraging activity, including mTOR and Bcl-2 inhibitors, novel antibodies, and new cytotoxic agents. Future trials will also benefit from new molecular approaches through pharmacogenomics.
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PMID:Mantle cell lymphoma: evolving novel options. 1770 68

Mantle cell lymphoma (MCL) still carries a poor prognosis. Chemoimmunotherapy (combination with rituximab) is the routine first-line therapy, although data strongly suggest a benefit from intensification through high-dose therapy with stem cell transplantation consolidation or dose-intense chemotherapy with HyperCVAD (fractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone)/rituximab. Unfortunately, most patients still experience relapse, and a multitude of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and first Food and Drug Administration-approved drug in MCL), mammalian target of rapamycin inhibitors, Bcl-2 inhibitors, and antiangiogenesis agents, among others. Because of the relative rarity of the disease-MCL represents 6% of non-Hodgkin lymphoma-an obvious effort is needed to enroll patients on clinical trials. Not surprisingly, as in other non-Hodgkin lymphomas, MCL appears more and more as a heterogeneous disease, which might impact future clinical trial design through pharmacogenomics and hopefully help us develop smaller "molecular" relevant trials.
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PMID:Expanding therapeutic options in mantle cell lymphoma. 1787 43

There is no consensus treatment for newly diagnosed mantle cell lymphoma. The CHOP + rituximab and hyperCVAD + rituximab regimens are most commonly used. The former is limited by relatively lower rates of complete remission (CR) and frequent relapses. The latter is limited by toxicities, especially in older patients, and relapses that occur later than those usually seen with CHOP + rituximab. Thus, improved therapies are needed. The purine analog cladribine (2-cda) + rituximab has been studied as an alternative frontline regimen in MCL and is quite active with minimal toxicity. Cladribine has epigenetic activity in that it inhibits DNA methylation. Cladribine + rituximab should be further studied in newly diagnosed mantle cell lymphoma in combination with new agents such as inhibitors of histone deacetylation, the mTOR pathway, and the proteasome.
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PMID:The epigenetics of mantle cell lymphoma. 1821 89


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