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

Previous studies have documented that, in malignant B cells, rituximab elicits a complex and not yet totally understood signaling network contributing to its antitumor effect. In this context, we investigated the role of protein kinase C zeta (PKCzeta), an atypical PKC isoform, in the cellular response to rituximab. We found that follicular lymphoma cells displayed an increase in PKCzeta expression and activity levels, compared with nonmalignant B cells, and that this enzyme was a critical regulator of the classical MAPK module by stimulating Raf-1 kinase activity. PKCzeta appeared to be a significant contributor of abnormal mTOR regulation in follicular lymphoma cells through a MAPK-dependent mechanism. Rituximab was found to inhibit the PKCzeta/MAPK/mTOR module in these cells but not in other B-cell lymphomas. Importantly, the expression of a constitutively active form of PKCzeta resulted in an efficient protection of these cells toward rituximab. Altogether, our study describes a new regulatory component of mTOR pathway in follicular cell lymphoma and demonstrates that PKCzeta is a target for rituximab. Therefore, PKCzeta could represent an important parameter for rituximab efficacy and a promising target for future targeted therapy in follicular lymphoma.
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PMID:PKC zeta mTOR pathway: a new target for rituximab therapy in follicular lymphoma. 1785 29

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

Rituximab (RTX), a monoclonal antibody directed against the CD20 protein, is a drug commonly used in the treatment of B-cell-derived lymphoid neoplasias and of antibody-mediated autoimmune diseases. In addition to cell- and complement-mediated B-cell depletion, RTX is thought to inhibit B-cell survival and proliferation through negative regulation of canonical signaling pathways involving Akt, ERK, and mammalian target of rapamycin. However, surprisingly, although B-cell receptor (BCR) signaling has been considered critical for normal and more recently, for neoplastic B cells, the hypothesis that RTX could target BCR has never been investigated. Using follicular lymphoma cell lines as models, as well as normal B cells, we show here, for the first time, that pretreatment with RTX results in a time-dependent inhibition of the BCR-signaling cascade involving Lyn, Syk, PLC gamma 2, Akt, and ERK, and calcium mobilization. The inhibitory effect of RTX correlates with decrease of raft-associated cholesterol, complete inhibition of BCR relocalization into lipid raft microdomains, and down-regulation of BCR immunoglobulin expression. Thus, RTX-mediated alteration of BCR expression, dynamics, and signaling might contribute to the immunosuppressive activity of the drug.
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PMID:Rituximab inhibits B-cell receptor signaling. 1996 64

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL) with treatment outcomes that have historically been poorer than those observed with other NHL subtypes. Patients typically present with advanced-stage disease and frequent extranodal involvement; the median age at diagnosis is >60 years. Recent improvements in progression-free and overall survival have been observed with more dose-intensive strategies, although at least half of patients diagnosed with MCL are not eligible for such treatment approaches based on age and co-morbidities. In addition, therapy options for relapsed MCL are limited. Only bortezomib is approved for treatment of relapsed MCL in the US. Development of targeted therapy approaches to minimize toxicities while preserving anti-neoplastic properties is of particular importance in MCL. Multiple ongoing studies are attempting to build on the known efficacy of bortezomib by evaluating combination regimens with other targeted agents or cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has known activity in MCL, making this an attractive class of agents for further investigation in combination regimens. Rituximab and other monoclonal antibodies are being evaluated for novel roles in MCL treatment, including as maintenance therapy. Other classes of drugs being investigated in MCL are immunomodulatory agents, inhibitors of the phosphoinositide 3-kinase/Akt and B-cell receptor signalling pathways, and inhibitors of bcl-2 and histone deacetylase. Although many of the agents appear to have modest single-agent activity, the favourable toxicity profile of many agents will make them best suited for incorporation into combination regimens.
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PMID:Current status of targeted therapies for mantle cell lymphoma. 2208 87

Intravascular large B-cell lymphoma (IVLBCL) is a rare, aggressive and often fatal non-Hodgkin lymphoma characterized by preferential growth of malignant B-cells within the lumina of small vessels. Rituximab plus anthracycline-based chemotherapy is the current standard regimen for IVLBCL, however it has minimal efficacy in relapsed or refractory diseases. Recent clinical trials have shown a significant anti-lymphoma activity of mammalian target of rapamycin (mTOR) inhibitors in relapsed and refractory diffuse large B-cell lymphoma (DLBCL); however, the activation status of the mTOR pathway and the therapeutic potential of mTOR inhibitors in IVLBCL have not yet been studied. Here we described the clinicopathological features of 3 cases of IVLBCL diagnosed at our institutions, and evaluated the activation status of the mTOR signaling in these tumors. Our results showed that the mTOR complex 2 pathway was selectively upregulated in IVLBCL, as evidenced by a predominant nuclear localization of the activated form of mTOR (p-mTOR at Ser2448) with concomitant overexpression of nuclear p-Akt (Ser473) and vascular endothelial growth factor (VEGF)-A in the lymphoma cells. These data suggest that overactivation of mTOR pathway may play a role in lymphomagenesis of IVLBCL and mTORC2 inhibitors may be beneficial in treating IVLBCL.
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PMID:Intravascular large B-cell lymphoma: report of three cases and analysis of the mTOR pathway. 2213 26

OPINION STATEMENT: The standard front-line treatment of Diffuse Large B-Cell Lymphoma (DLBCL) remains Rituximab combined with multi-agent cytotoxic chemotherapy. In spite of high response rates to this therapy, relapsed/refractory disease is observed in up to 40% of patients. It is our opinion that additional chemoimmunotherapy, followed by high-dose therapy with autologous stem cell transplant (HDT-ASCT) for responsive disease, is the optimal therapy for these patients. However, many patients cannot tolerate HDT-ASCT, or have relapsed/refractory disease in spite of it. These patients have a poor overall prognosis, and there is no clear consensus as to how these patients should be treated. Over the past decade, significant advances have been made in the understanding of the molecular genesis and subtyping of DLBCL, leading to the identification of multiple pathways and molecules that can be targeted for clinical benefit. Examples include Bcl-2, Bcl-6, cell surface markers, and myriad molecules in both the B-Cell receptor and PI3K/Akt/mTOR pathways. As agents targeting these molecules and pathways progress from preclinical models to early clinical trials, more is learned about what might predict for response to these agents, such as cell of origin classification, and/or expression of relevant molecular markers, as measured by immunohistochemistry or gene expression profiling. Both the successes and failures of these novel targeted agents promise to dramatically refine, improve, and individualize the classification and treatment of DLBCL. Therefore, it is our opinion that patients with relapsed/refractory DLBCL are an ideal population for clinical trials due to both the lack of standardized treatment, and the recent advancements in pathobiology and early-phase treatment options.
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PMID:Emerging Therapeutic Targets in Diffuse Large B-Cell Lymphoma. 2229 43

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of potentially life-threatening complications that occur after solid organ and bone marrow transplantation. Risk factors for acquiring PTLD are type of organ transplanted, age, intensity of immunosuppression, viral infections such as Epstein-Barr virus (EBV) and time after transplantation. Due to a dearth of well designed prospective trials, treatment for PTLD is often empirical, with reduction in immunosuppression accepted as the first step. Rituximab, a monoclonal antibody directed against the CD20 antigen of immature B cells, is often used as monotherapy after reduction in immunosuppression, although this is associated with a high risk of relapse if patients have at least one of the following risk factors: age greater than 60 years, elevated lactate dehydrogenase levels and Eastern Cooperative Oncology Group Score between 2 and 4. For such patients, rituximab should be considered in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), particularly if high-grade PTLD is present. Although widely prescribed, the use of ganciclovir for PTLD remains controversial as EBV-transformed cells lack the thymidine kinase necessary for ganciclovir activation. Newer antivirals that combine ganciclovir with activators of cellular thymidine kinase have shown promising results in preclinical studies. In the absence of controlled trials, surgery may be indicated for localized disease and radiotherapy for patients with impending spinal cord compression or disease localized to the central nervous system or orbit. Future interventions may include adoptive immunotherapy, intravenous immunoglobulin, mammalian target of rapamycin inhibitors, monoclonal antibodies to interleukin-6 and galectin-1, and even EBV vaccination. Although several trials are in progress, it is necessary to wait for the long-term outcome of these studies on risk of PTLD relapse.
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PMID:Managing post-transplant lymphoproliferative disorders in solid-organ transplant recipients: a review of immunosuppressant regimens. 2286 44

Modern chemoimmunotherapies have produced higher response rates and improved survival in mantle cell lymphoma (MCL); however, disease relapse remains a challenge. The availability of various post-remission maintenance or consolidation strategies, have led some to question the role of upfront autologous hematopoietic cell transplantation (auto-HCT) consolidation for MCL, in the chemoimmunotherapy-era. A one size fits all approach is no longer appropriate for MCL in first remission, and the choice of preferred post-remission (observation, maintenance or consolidation) strategy is increasingly becoming a factor of patient age, comorbidities and disease risk stratification. In select low-risk patients (based on Mantle cell lymphoma International Prognostic Index (MIPI)), observation following rituximab plus Hyper-CVAD-like inductions seems appropriate. Rituximab maintenance after anthracycline-based chemoimmunotherapies in elderly transplant ineligible patients has shown survival benefit and should be considered a valid option. Limited studies suggest feasibility of radioimmunotherapy consolidation in first remission; however, in the absence of randomized data, this modality remains investigational. In younger, transplant-eligible patients receiving cytarabine-containing inductions, upfront consolidation with auto-HCT has shown survival benefit, and remains a standard-of-care option in the modern-era. Hyper-CVAD associated stem cell mobilization failure is an increasingly recognized problem, underscoring the need for alternative inductions, or consideration for early stem cell collection, when this induction regimen is used. Outcomes of high-risk MIPI patients remain suboptimal with currently available induction and post-remission strategies and represents an area where adoptive immunotherapy in the form of allogeneic-HCT warrants investigation. Incorporation of novel MoAbs and targeted agents (PI3K inhibitors, mTOR inhibitors, BTK inhibitors and so on.) in maintenance and consolidation strategies will build on the significant therapeutic gains of last decade, in coming years.
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PMID:Is hematopoietic cell transplantation still a valid option for mantle cell lymphoma in first remission in the chemoimmunotherapy-era? 2358 38

Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma and accounts for approximately 30% of newly diagnosed lymphoid neoplasms in Western countries, and 40-50% in China. A better understanding of the biology of DLBCL is needed for the development of potential therapeutic agents that target specific intracellular pathways. In this study, expression of the important components of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and their clinical significance were investigated in 73 DLBCL cases. The effect of rituximab alone or combined with the PI3K/AKT/mTOR pathway inhibitor rapamycin was further evaluated in the DLBCL cell lines. A total of 73 patients were identified, including 45 men and 28 women aged 18 to 78 years (median age 50 years). Of these patients, p-AKT was positive in 40 cases (54.8%), p-p70S6K in 34 cases (46.6%), and p-4E-BP1 in 33 cases (45.2%). Activation of the PI3K/AKT/mTOR pathway was related to poor disease outcome in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) but not in those treated with rituximab-CHOP. Rituximab combined with rapamycin synergically downregulated the PI3K/AKT/mTOR signaling pathway. Western blot analysis revealed a baseline activation status of the PI3K/AKT/mTOR pathway in DLBCL cell lines, with high levels of p-AKT, p-mTOR, in addition to downstream molecules p-p70S6K and p-4E-BP1. The results indicate that the PI3K/AKT/mTOR pathway is a potentially important signaling route and an unfavorable prognostic factor for DLBCL. Patients with PI3K/AKT/mTOR activation experience a more rapidly deteriorating clinical course with poor treatment response and decreased survival time. Addition of rituximab could downregulate PI3K/AKT/mTOR activation, reversing its negative effect on chemotherapy-treated patients. In addition, our results indicate that the combination of rituximab and inhibition of the activated PI3K/AKT/mTOR pathway could be a promising target for DLBCL therapeutic intervention in the future.
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PMID:Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: clinical significance and inhibitory effect of rituximab. 2363 13

Hodgkin lymphoma (HL) relapsing after an autologous hematopoietic cell transplant (HCT) poses a therapeutic challenge. In this setting, salvage chemotherapy (for example, gemcitabine-based, ifosfamide-containing and others) or immunotherapy (for example, brentuximab vedotin) is essential as a bridging-cytoreduction strategy to an allogeneic HCT. Myeloablative allogeneic hematopoietic cell transplantation in relapsed HL is associated with high rates of non-relapse mortality. In carefully selected patients with chemosensitive disease, allografting following lower-intensity conditioning regimens can provide durable disease control rates of about 25-35%. Promising early results with haploidentical and umbilical cord transplantation are noteworthy and are expanding this procedure to patients for whom HLA-matched related or unrelated donors are not available. Unfortunately, a significant number of HL patients relapsing after an autologous HCT are not candidates for allografting because of the presence of resistant disease, donor unavailability or comorbidities. Brentuximab vedotin is approved for HL relapsing after a prior autograft. Rituximab and bendamustine are also active in this setting, albeit with short durations of remission. Histone deacetylase inhibitors (for example, panobinostat, mocetinostat), mTOR inhibitors (for example, everolimus) and immunomodulatory agents (lenalidomide) have shown activity in phase II trials, but currently are not approved for this indication. Second autologous HCT are rarely performed but this approach should not be considered standard practice at this time. The need for effective agents for post autograft failures of HL largely remains unmet. Continuous efforts to ensure early referral of such patients for allogeneic HCT or investigational therapies are the key to improving outcomes of this not-so-good lymphoma.
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PMID:Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good cancer after all! 2444 46


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