Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.
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PMID:Deregulation of mTOR signaling is involved in thymic lymphoma development in Atm-/- mice. 1936 3

Classical Hodgkin lymphoma (cHL) is highly treatable with chemotherapy alone or combined modality therapy. High dose therapy and autologous stem cell transplant is considered standard of care for patients who relapse. For patients who relapse following transplant or who are not candidates for high dose therapy, prognosis is poor, and new treatment strategies are needed. Targeted therapies for relapsed Hodgkin lymphoma include monoclonal antibodies directed at cell surface antigens, immunoconjugates, bispecific constructs created to recruit host effector cells and radioimmunotherapy. In Epstein-Barr virus (EBV)-associated Hodgkin lymphoma, cytotoxic T lymphocytes directed at EBV antigens have been utilised in clinical trials with some success. Additionally, the immunomodulatory agents thalidomide and lenalidomide, and new classes of drugs such as the mammalian target of rapamycin inhibitors and histone deacetylase inhibitors hold promise in relapsed Hodgkin lymphoma.
Leuk Lymphoma 2009 Apr
PMID:Drug development for recurrent and refractory classical Hodgkin lymphoma. 1937 50

The availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms. New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies. The aim of this review is to identify and discuss non-monoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide, mammalian target of rapamycin inhibitors, antisense oligonucleotides, heat shock protein inhibitors, protein kinase C inhibitors, antiangiogenic agents, and new cytotoxics are reviewed.
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PMID:Beyond monoclonal antibodies: new therapeutic agents in non-Hodgkin's lymphomas. 1941 16

Previous studies have shown that rapamycin can inhibit the growth of several different types of human tumor cells in vitro. In certain cases, it can reverse the phenotype of multidrug resistant (MDR) cells. However, there is limited information concerning its effect on P-glycoprotein (P-gp), a pump that is responsible for chemoresistance in many MDR cells. We investigated the effect of rapamycin on both P-gp function and the MDR phenotype in four cell lines. One cell line was also xenografted into SCID mice to determine whether rapamycin would chemosensitize the cells in vivo. Because rapamycin targets the mammalian target of rapamycin (mTOR) pathway, we also used our cells to confirm that rapamycin modified the expression of mTOR and effectively suppressed the phosphorylation of two downstream effector molecules in the mTOR pathway, S6K1, and 4E-BP1. We demonstrated that it inhibited the growth of the three cell lines in vitro and one in vivo showing that it modulated both the expression and function of P-gp and chemosensitized the three cell lines as effectively as verapamil.
Leuk Lymphoma 2009 Jul
PMID:Targeting mammalian target of rapamycin to both downregulate and disable the P-glycoprotein pump in multidrug-resistant B-cell lymphoma cell lines. 1955 25

Using immunohistochemistry with antibodies against the phosphoserine residues in both S6rp and 4E binding protein 1, we identified the activation of the mammalian target of rapamycin (mTORC)1 pathway in 29 cases of AIDS-related lymphoma. These cases represented a diverse spectrum of histological types of non-Hodgkin lymphoma (24 cases) and classic Hodgkin lymphoma (five cases). mTORC1 was also activated in the hyperplastic but not involuted follicles of HIV-associated lymphadenopathy in eight cases, supporting the notion that mTORC1 activation is a common feature of transformed lymphocytes irrespective of either their reactive or malignant phenotype. We also found that in B-cell lines that represent diffuse large B-cell lymphoma, Burkitt lymphoma, Epstein-Barr virus-infected lymphocytes, and human herpesvirus 8-positive primary effusion lymphoma, inhibitors of Syk, MEK, and, seemingly, phosphoinositide 3 kinases suppressed mTORC1 activation, in particular when these inhibitors were used in combination. These findings indicate that AIDS-related lymphoma and other histologically similar types of lymphomas that are derived from transformed B lymphocytes may display clinical responses to inhibitors that directly target mTORC1 or, possibly, upstream activators of the mTORC1 pathway.
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PMID:Activation of mTORC1 signaling pathway in AIDS-related lymphomas. 1960 73

The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic target for diffuse large B-cell lymphoma (DLBCL), as recent studies have demonstrated that 30% of relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we demonstrated that rapamycin inhibits mTORC1 in DLBCL lines and primary tumors but is minimally cytotoxic. Subsequent investigations revealed that rapamycin also activated eIF4E and the mTORC2 target Akt, suggesting a potential mechanism of rapamycin resistance. Furthermore, knockdown of the mTORC2 component rictor, but not the mTORC1 component raptor, inhibited rapamycin-induced Akt phosphorylation in lymphoma cells. Addition of the histone deacetylase inhibitor (HDI) LBH589 (LBH) overcame rapamycin resistance by blocking mTOR, thus preventing Akt activation. Further studies support the involvement of the protein phosphatase PP1 in LBH-mediated Akt dephosphorylation, which could be mimicked by knockdown of HDAC3. This is the first demonstration that a HDI such as LBH can overcome rapamycin resistance through a phosphatase that antagonizes mTORC2 activation. These results provide a mechanistic rationale for a clinical trial of a combination of HDI and mTOR inhibitors for DLBCL.
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PMID:Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. 1964 Nov 86

Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma that remains incurable, and is associated with a median survival of approximately 5 years. Management of patients with relapsed or refractory disease is challenging. The major therapeutic goal in MCL management is to improve survival and quality of life whenever possible. Progress has been made in MCL therapy in the past decade based on clinical experimentation with novel agents and combinations. There is a growing list of conventional and novel agents in our armamentarium, consisting of not only additional chemotherapy combinations including high-dose approaches, but also biologically targeted reagents such as the monoclonal antibody rituximab, the proteasome inhibitor bortezomib, the mTOR inhibitor temsirolimus, immunomodulatory and antiangiogenic agents including thalidomide and lenalidomide, and cyclin-dependent kinase inhibitors, as well as a renewed interest in older compounds such as bendamustine and metronomic regimens. Efficacy evaluations for individual agents and rational combinations are in various stages of development, while treatment selection based on molecular and clinical prognostic scores is yet to be tested. In the absence of evidence demonstrating relative survival advantages of various second-line options, management of relapsed and refractory disease should be individualized. Involvement of a lymphoma center participating in clinical trials of novel MCL treatments is encouraged.
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PMID:Management of relapsed mantle cell lymphoma: still a treatment challenge. 1971 84

Posttransplantation B-lymphoproliferative (PTBL) disease is a severe complication of organ transplantation, which requires reduction of immunosuppressive treatment. The use of the anti-CD20 monoclonal antibody, Rituximab, improves the survival of these patients. In this setting, maintenance immunosuppressive therapy may represent a challenge. The mammalian target of rapamycin (m-TOR) inhibitor Rapamycin has antiproliferative effects that makes it a safe, efficient option to avoid graft rejection and reduce the malignancy risk. We studied 6 renal recipients (4 men and 2 women) of overall mean age of 50.66 +/- 15.89 years who were diagnosed with lymphoma at a mean time of graft function of 137.0 +/- 68.00 months. All of the patients were Epstein-Barr-negative. Four received a combination of Rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and 2 received Rituximab only. In all cases complete remission persisted during follow-up of 21.83 +/- 8.34 months. The immunosuppressive treatment was switched to the m-TOR inhibitor Rapamycin at therapeutic trough blood levels of 5-8 ng/dL. The mean time of Rapamycin treatment was 15.5 +/- 8.96 months. Notably, we observed neither acute rejection nor relapse episodes. Renal function remained stable with no significant proteinuria. The serum creatinine level before switching to Rapamycin was 1.06 +/- 0.16 mg/dL and 0.9 +/- 0.14 mg/dL 12 months later. However, 1 patient had to stop Rapamycin treatment due to pneumonitis. Our study suggests that immunosuppressant monotherapy with Rapamycin is safe and efficient for renal recipients who develop lymphoma because of its antitumor effects without nephrotoxicity.
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PMID:Monotherapy rapamycin in renal transplant recipients with lymphoma successfully treated with rituximab. 1971 44

The mammalian target of rapamycin (mTOR) pathway regulates translation of key proteins that contribute to the pathogenesis of advanced hematologic malignancies. Inhibitors of mTOR (temsirolimus, everolimus, and deforolimus) constitute a new class of antitumor agents, with potential for treatment of relapsed and/or refractory hematologic malignancies. Mantle cell lymphoma (MCL) was the first hematologic malignancy in which mTOR inhibition was explored as a treatment strategy, owing to its characteristic overexpression of cyclin D1, a G1 cyclin regulated by mTOR signaling. Temsirolimus and everolimus exhibited antitumor activity against relapsed, refractory disease in phase II studies. In a randomized phase III trial, once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly was recently shown to improve progression-free survival (p=0.0009) and objective response rate (p=0.0019) versus investigator's choice of therapy in relapsed or refractory MCL. Evidence of antitumor activity seen in early clinical trials for other non-Hodgkin lymphoma subtypes, multiple myeloma, and myeloid leukemias supports further studies of mTOR inhibitors, alone or in combination strategies, in these diseases. Overall, the clinical findings to date strengthen mTOR inhibition as a novel and promising strategy for the treatment of certain hematologic malignancies, particularly for MCL.
Leuk Lymphoma 2009 Dec
PMID:Exploring mammalian target of rapamycin (mTOR) inhibition for treatment of mantle cell lymphoma and other hematologic malignancies. 1975 6

The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.
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PMID:Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. 1986 Sep 3


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