Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several epidemiologic studies support the emerging paradigm that current alcohol consumers have decreased risk of most types of non-Hodgkin lymphoma. The observed lower risk among people who drank alcohol does not seem to vary with beverage type. The mechanisms accounting for alcohol-induced decrease in the incidence of lymphomas remain largely unknown. We demonstrate that low-dose chronic exposure to ethanol inhibits mammalian target of rapamycin (mTOR) C1 complex formation, resulting in decreased phosphorylation events involved in mTOR pathway signaling in a lymphoid-tissue specific manner. These changes in mTOR signaling lead to a decrease in eIF4E associated with the translation initiation complex and a repression of global cap-dependent synthesis in both lymphoma cell lines and normal donor lymphocytes. We show that chronic exposure of ethanol at physiologically relevant concentrations in a xenograft model results in a striking inhibition of lymphoma growth. Our data support a paradigm in which chronic ethanol exposure inhibits mTOR signaling in lymphocytes with a significant repression of cap-dependent translation, reducing the tumorigenic capacity of non-Hodgkin lymphoma in a human xenograft model. The ethanol-mediated repression of mTOR signaling coupled with decreased in vivo lymphoma growth underscore the critical role of mTOR signaling and translation in lymphoma.
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PMID:Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction. 1929 24

Mutations in tuberous sclerosis complex (TSC) genes are associated with dysregulated mammalian target of rapamycin (mTOR)/Akt signaling and unusual neoplasms called perivascular epithelioid cell tumors (PEComas), including angiomyolipomas (AMLs) and lymphangioleiomyomatosis (LAM). Tools that quantify metabolic activity and total body burden of AML and LAM cells would be valuable for the assessment of disease progression and the response to therapy in patients with TSC and LAM. Our hypothesis was that constitutive activation of mTOR in LAM and AML cells would result in increased glucose uptake of [(18)F]2-fluoro-2-deoxyglucose (FDG) on PET scanning, as has been suggested by a single prior case report. After institutional review board approval, FDG-PET scanning was performed in six LAM patients. Six additional LAM patients underwent FDG-PET scanning for clinical evaluation of suspected malignancy. Pleural uptake related to prior therapy was identified in four individuals with a remote history of talc pleurodesis. Focal increased uptake was observed in a supraclavicular lymph node in a patient with Hodgkin lymphoma and in a lung nodule in a patient with a biopsy-documented primary lung adenocarcinoma. In one TSC-LAM patient with a biopsy-documented malignant uterine PEComa, robust uptake was noted in metastatic nodules in the lung but not in the LAM-involved lung parenchyma or the patient's massive abdominal lymphangioleiomyomas. No abnormal uptake was identified in the AMLs or LAM lesions in any patients. This pilot study suggests that FDG-PET scans are negative in patients with benign PEComas and therefore are not likely to be useful for estimating the burden of disease in patients with TSC or LAM, but that FDG-PET scans can be used to identify or exclude other neoplasms in these patients.
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PMID:Utility of [18F]2-fluoro-2-deoxyglucose-PET in sporadic and tuberous sclerosis-associated lymphangioleiomyomatosis. 1934 86

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.
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PMID:Drug development for recurrent and refractory classical Hodgkin lymphoma. 1937 50

Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)-driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets.
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PMID:The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways. 1953 56

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

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

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.
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PMID:Exploring mammalian target of rapamycin (mTOR) inhibition for treatment of mantle cell lymphoma and other hematologic malignancies. 1975 6

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has anti-tumor activity in patients with relapsed or refractory mantle cell lymphoma (MCL) and other mature lymphoid neoplasms. mTOR is an intracellular kinase that controls the mRNA translation of many proteins (eg, cyclin D1) that can act as oncogenes and contribute to lymphomagenesis. Characterized by overexpression of cyclin D1, MCL was identified as a disease that might be susceptible to mTOR inhibition. When single-agent temsirolimus was explored in two phase II studies for treatment of patients with relapsed or refractory MCL, it demonstrated anti-tumor activity, with overall response rates of 38% and 41%. Subsequently, a three-arm, randomized phase III trial was conducted to compare two dosing regimens of temsirolimus with investigator's choice of therapy for heavily pretreated patients with relapsed or refractory MCL (N = 162; randomized 1:1:1). Once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly (175/75) significantly improved progression-free survival (hazard ratio = 0.44; P = .0009) versus investigator's choice therapy. Median progression-free survival durations were 4.8 and 1.9 months, respectively. The objective response rates were 22% in the 175/75 group and 2% in the investigator's choice group (P = .0019). For patients receiving temsirolimus, the most frequent grade 3 or 4 adverse events were thrombocytopenia, anemia, neutropenia, and asthenia. The results of this trial established a recommended clinical dose for temsirolimus monotherapy in patients with relapsed or refractory MCL and validated the importance of mTOR in the pathogenesis of advanced MCL. Objective responses also have been reported for other mature B-cell neoplasms (eg, diffuse large B-cell lymphoma or follicular lymphoma) in the phase II setting. Temsirolimus as monotherapy or in combination with other active agents warrants further investigation for treatment of MCL and other non-Hodgkin lymphomas.
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PMID:Temsirolimus in mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. 1996 99

Activation of mammalian target of rapamycin (mTOR) signaling occurs in a wide variety of human tumors and can lead to increased susceptibility to mTOR inhibitors. Temsirolimus, a novel analog of rapamycin, has shown promising preclinical and early clinical anti-tumor activity in various solid and hematologic tumor types, either alone or in combination with chemotherapy or other targeted agents. Randomized phase III trials have already demonstrated significant clinical benefits of treatment with single-agent temsirolimus in advanced renal cell carcinoma and relapsed and/or refractory mantle cell lymphoma. Other malignancies studied in the phase I and II trial settings include glioblastoma, breast cancer, endometrial cancer, non-Hodgkin lymphomas, and multiple myeloma. This article reviews a comprehensive collection of the clinical trial results reported to date for temsirolimus in various solid and hematologic malignancies, as well as current strategies being tested in ongoing trials. The findings with temsirolimus in multiple tumors provide a valuable framework for future development of temsirolimus and other mTOR inhibitors.
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PMID:Evaluating temsirolimus activity in multiple tumors: a review of clinical trials. 1996

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphomas characterized by the chromosomal translocation t(11;14)(q13;q32) and nuclear cyclin D1 overexpression in the vast majority of cases. Most patients present with advanced stage disease, often with extranodal dissemination, and pursue an aggressive clinical course in the majority of cases. Recent improvement has been achieved by the successful introduction of monoclonal antibodies and dose-intensified approaches including autologous stem cell transplantation (ASCT) strategies. With the exception of allogeneic hematopoietic stem cell transplantation, current treatment approaches are non-curative and the corresponding survival curves are characterized by a delayed, but continuous decline and a median survival of 4 to 6 years. However, recently a subset (15%) of long-term survivors have been identified with a rather indolent clinical course even after conventional treatment strategies only. Emerging strategies such as proteasome inhibitors, IMIDs, mTOR inhibitors and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy of these compounds achieves efficacy comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in numerous trials; however, their introduction into clinical practice and current treatment algorithms remains a challenge.
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PMID:Current treatment standards and emerging strategies in mantle cell lymphoma. 2000 39


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