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

Patients with mantle cell lymphoma (MCL) have a poor prognosis; consequently, new therapeutic approaches, such as rapamycin and its derivates, mammalian target of rapamycin (mTOR) inhibitors, are warranted. Temsirolimus (also known as CCI-779), a dihydroester of rapamycin, in MCL cell lines inhibited mTOR, downregulated p21 and v-Raf, and induced autophagy. The first clinical trial in MCL patients was performed using 250 mg of temsirolimus weekly for 6-12 cycles. The overall response rate was 38%; the median time to progression was 6.5 months, median overall survival was 12 months, and the median duration of response was 6.9 months. At lower dose (25 mg/week), the overall response rate was 41%, median overall survival was 14 months, and time to progression was 6 months. In another trial, 162 patients were randomly assigned to receive temsirolimus at 2 different doses (175 mg/week for 3 weeks, then 75 mg or 25 mg/week) or a treatment chosen by the investigator among the most frequently adopted single agents for treatment of relapsed MCL. Patients treated with 175/75 mg of temsirolimus had significantly higher response rates and longer progression-free survival than those treated with investigator's choice therapy. These data support the use of mTOR inhibitors for the treatment of MCL, probably in combination with other agents, such as antiangiogenic drugs or histone acetylase inhibitors.
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PMID:Temsirolimus in the treatment of relapsed and/or refractory mantle cell lymphoma. 2118 9

mTOR-inhibitors are part of targeted agents and are already in use in the clinic, especially for treatment of metastatic renal cell carcinoma. Distinct from conventional chemotherapeutics, targeted agents imply chronic treatment, which has changed our perspective on the commerce of adverse events (AE). In principle, mTOR-inhibitors are associated with a broad number of AEs. The occurrence of stomatitis, infection, pneumonitis, hyperlipidemia and hyperglycemia are considered major class effects of mTOR-inhibitors. However, severe adverse events remain scarce among mTOR-inhibitors and support chronic use of these agents. Based on their good clinical tolerability mTOR-inhibitors are prone to be developed in combinational therapies. However, the hepatic metabolism of these agents may limit their use to partners with a distinct metabolism in order to avoid drug interaction. Meanwhile about 40 different trials use mTOR-inhibitors in different tumor entities. The use of mTOR-inhibitors in neuroendocine tumors of the intestine, mantle cell lymphoma and sarcomas has hereby shown to be very promising. The mainstay of therapy already incorporates the use of everolimus in second line and temsirolimus in first line treatment in patients with metastatic renal cell carcinoma.
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PMID:[Use of mTOR-inhibitors in solid tumors]. 2152 29

The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is vital for cell metabolism, growth, and proliferation. mTOR is frequently upregulated in many tumor types and hence has become an important target in cancer treatment. Sirolimus and its derivatives (rapalogs) interact with the intracellular receptor FK506 binding protein 12 (FKBP12), forming a complex with high affinity for mTOR and thus disrupting its activity. Rapalogs are being evaluated extensively in cancer patients with different formulations and schedules. Significant clinical activity has led to their approval for the treatment of kidney cancer, mantle cell lymphoma, and subependymal giant cell astrocytoma; however, despite increasing knowledge about cancer cell biology, their activity in other malignancies is unclear. Further research is needed to identify optimal dosage, administration and targeted combination as well as the subset of patients likely to respond to mTOR/PI3K inhibition. This review focuses on a discussion of the pathway, its implications in cancer biology and results of clinical trials of rapalogs alone or in combination, organizing them by common malignancy type.
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PMID:Clinical activity of mammalian target of rapamycin inhibitors in solid tumors. 2154 89

PI3K/AKT/mTOR pathway is an intracellular signalling pathway composed of different kinases. Many protein mutations are described in that pathway, and are responsible of dysregulation of cell growth, proliferation, survival and angiogenesis. Rapamycin is an antibiotic inhibiting mTOR. Different analogs of rapamycin are developed or being developed in antitumoral therapy, in which temsirolimus, everolimus and deforolimus, demonstrated antitumoral activity in renal cancer and mantle cell lymphoma, and many clinical trials are in progress in other tumors. In the future, predictive factors of response need to be identified; patient selection and associations with chemotherapy or with other targeted therapies should be explored.
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PMID:[PI3K-AKT-mTOR pathway and cancer]. 2174 93

Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in non-Hodgkin's lymphoma (NHL), prompting evaluation of the rapamycin-analog (rapalog) mTOR inhibitors in multiple clinical trials. The drugs show activity as single agents, and the rapalog temsirolimus is now accepted as a therapeutic option in relapsed/refractory mantle cell lymphoma. Response rates, however, are typically below 50%, resulting in remissions that are neither complete nor durable. Results of preclinical studies shed important new light on resistance mechanisms that may explain results. Looking ahead, it is likely PI3K/AKT/mTOR inhibition will find expanded roles in NHL therapy due to 1) assessments of the rapalogs in combination with other therapies and in less heavily pretreated patients, 2) the development and evaluation of multiple novel inhibitors of the pathway that may increase specificity and potency, 3) alternative treatment strategies able to bypass particular resistance mechanisms, and 4) increased efforts to identify biomarkers for better pretreatment patient stratification.
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PMID:Targeting the PI3K/AKT/mTOR pathway in non-Hodgkin's lymphoma: results, biology, and development strategies. 2175 75

Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by the translocation t(11;14) that leads to aberrant expression of cyclin D1. Response to first-line chemotherapy is good, but most patients relapse, resulting in a median survival of 5 to 7 years. The important PI3K/AKT/mTOR pathway can be targeted with small molecules. mTOR inhibitors have clinical activity and temsirolimus has been approved in Europe. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 offer additional means to target the pathway. Promising results with the BTK inhibitor PCI-32765 suggest that B-cell receptor signaling could play a role. For unknown reasons, MCL appears to be particularly sensitive to disruption of protein homeostasis. The proteasome inhibitor bortezomib achieves responses in up to 50% of relapsed patients. Much work has been done in elucidating the mechanism of its cytotoxicity, its incorporation into combination therapies, and the development of second-generation proteasome inhibitors. Deacetylase and HSP90 inhibitors are also promising classes of drugs that can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients an immediate chance to benefit from these advances and is essential to maintain the momentum of progress.
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PMID:Molecular targeted approaches in mantle cell lymphoma. 2178 64

Temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is a new targeted therapy used in advanced renal cell carcinoma and mantle cell lymphoma and is currently tested in several other human tumors. It induces several cutaneous and mucosal side effects, including painful, dose-limiting stomatitis. We report the unusual case of a 77-year-old man who developed severe mucosal, scrotal and perianal cutaneous aphthous-like ulcerations, 6 weeks after introduction of temsirolimus therapy for advanced-stage renal cell carcinoma. Other causes of aphthous-like ulcerations were ruled out. Topical corticosteroids remained ineffective. It led to the interruption of the treatment. Introduction of colchicine resulted in a dramatic improvement within 1 month. Reintroduction of temsirolimus with concomitant colchicine therapy was followed by a delayed recurrence of the lesions. We provide here a review of the potential cutaneous and mucosal side effects of mTOR inhibitors.
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PMID:Cutaneous and mucosal aphthosis during temsirolimus therapy for advanced renal cell carcinoma: review of cutaneous and mucosal side effects of mTOR inhibitors. 2184 63

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of up to 15% long-term survivors has been identified with a rather indolent clinical course. Advanced stage disease is usually apparent already at first clinical manifestation; in general, conventional chemotherapy is only palliative and median duration of remissions is only 1-2 years. In 2000, the European MCL Network ( http://www.european-mcl.net ) was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high-dose Ara-C to a rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Warsaw, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed.
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PMID:Update on the molecular pathogenesis and clinical treatment of mantle cell lymphoma: report of the 10th annual conference of the European Mantle Cell Lymphoma Network. 2185 Dec 18

PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.
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PMID:PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma. 2193 91

Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by aberrant expression of cyclin D1 due to the translocation t(11;14). Epigenomic and genomic lesions in pathways regulating B-cell activation, cell cycle progression, protein homeostasis, DNA damage response, cell proliferation and apoptosis contribute to its pathogenesis. While patients typically respond to first-line chemotherapy, relapse is the rule resulting in a median survival of 5-7 years. The PI3K/AKT/mTOR appears as a key pathway in the pathogenesis and can be targeted with small molecules. Most experience is with mTOR inhibitors of the rapamycin class. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 are novel options to more effectively target this pathway. Bruton's tyrosine kinase inhibition by PCI-32765 has promising activity and indicates immunoreceptor signaling as a novel therapeutic target. Up to 50% of relapsed patients respond to the proteasome inhibitor bortezomib suggesting that MCL may be particularly sensitive to disruption of protein homeostasis and/or induction of oxidative stress. Recent work has focused on elucidating the mechanism of bortezomib-induced cytotoxicity and the development of second-generation proteasome inhibitors. DNA hypomethylating agents and histone deacetylase inhibitors effect epigenetic de-repression of aberrantly silenced genes. These epigenetic pharmaceuticals and HSP90 inhibitors can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients a chance to benefit from these advances and is essential to maintain the momentum of progress. Innovative trial designs may be needed to expedite the clinical development of these targeted agents.
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PMID:New molecular targets in mantle cell lymphoma. 2194 17


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