Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that is frequently associated with the t(2;5)(p23;q35), resulting in expression of a fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be detected by either monoclonal or polyclonal antibodies to the ALK protein. The clinical features of adults with ALCL are incompletely described, and the prognostic factors that are useful for predicting survival remain unclear. This report describes the clinical and laboratory findings in 70 adults with systemic ALCL who were treated with curative intent. We attempted to identify the clinical and pathological factors of prognostic importance, including the International Prognostic Index (IPI), immunophenotype, and expression of the ALK protein. The median age of the patients was 49 years (range, 15 to 75). There were 26 women and 44 men with a median follow-up of 50 months for living patients. Advanced stage was present in 56% and B symptoms were noted in 70% of the patients. Immunostains showed that 46% of the cases had a T-cell phenotype, 36% a null phenotype, and 18% a B-cell phenotype. The expression of ALK protein was found in 51% of the cases. The IPI factors were evenly distributed between the ALK+ and ALK- groups, except that the ALK+ patients were younger (median age, 30 v 61 years; P <.002). The ALK+ cohort included cases with null (44%), T-cell (42%), and B-cell (14%) phenotypes. All 10 cases with cytogenetic or molecular evidence of a t(2;5) were ALK+. The 5-year overall survival (OS) of the entire cohort was 65%. The 5-year OS of the ALK+ and ALK- cases was 79% and 46%, respectively (P <.0003). Analysis of only the T-cell/null cases (n = 57) showed a 5-year OS of 93% for the ALK+ cases and only 37% for the ALK- cases (P <.00001). Univariate analysis of the clinical features showed that age </=60 years (P <.007), a normal serum lactate dehydrogenase (LDH) (P <.00001), a good performance status (Eastern Cooperative Oncology Group [ECOG] <2) (P <.03), </=1 extranodal site of disease (P <.012), and an IPI score </=3 (P <.00001) were associated with improved OS. Although a younger age correlated with ALK positivity, multivariate analysis showed that only a normal serum LDH (P <. 00001), an IPI score of </=3 (P <.0005), and ALK protein expression (P <.005) predicted independently for an improved OS. We conclude that ALCL is a heterogeneous disorder. However, ALK protein expression is an independent predictor of survival and serves as a useful biologic marker of a specific disease entity within the spectrum of ALCL.
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PMID:Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. 1033

Large B-cell neoplasms represent one of the most frequent groups of non-Hodgkin-lymphomas (30-40%). They are characterized by an aggressive clinical course. These lymphomas may evolve either de novo or secondary during the course of a less aggressive lymphoma. In addition to primary nodal, a primary extranodal manifestation is rather common. The neoplastic cells, even within one given case, show a broad morphological spectrum. Several findings of the last two decades have revealed that the large B-cell lymphomas represent an inhomogeneous group. This fact has been taken into account by the new WHO classification of malignant lymphomas. There are two groups identified, that of the variants and that of the subtypes. The various variants (centroblastic, immunoblastic, anaplastic, T-cell/histiocyte-rich) correspond to lymphomas without reproducible discriminating criteria lacking characteristic clinical, immuno-phenotypical and genetic findings. In contrast, the primary mediastinal, the intravascular, the primary effusion and primary central nervous system lymphomas represent distinct disease entities. A number of recently described large cell lymphoma types, i.e. plasma-blastic, ALK-positive and primary gastric, are included in the classification, their designation as distinct entities is still under discussion.
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PMID:[Large B-cell lymphomas: variants and entities]. 1084 Aug 22

Patients with relapsed aggressive lymphoma after high dose chemotherapy have a very poor prognosis and long-term survival is rare. Most patients are not eligible for allogeneic stem cell transplantation in this setting and treatment, therefore, becomes palliative. A few studies have shown that trofosfamide, an oral alkylating agent, may be effective as palliative treatment in non-Hodgkin's lymphoma. Trofosfamide therapy is considered rather non-toxic with an overall response rate from 50 to 80%. Most responses are, however, partial and their duration is short. We report a patient with a very aggressive ALK + anaplastic large cell lymphoma (ALCL), relapsing shortly after high dose chemotherapy. Unrelated allogeneic transplantation was hot possible. After several radio/chemotherapy regimens trofosfamide was started as palliative treatment. This therapy resulted in a complete remission, still ongoing, 27 months after termination of intravenous cytotoxic therapy and 16 months after withdrawal of trofosfamide. Thus, in this particular case, trofosfamide turned out to be an unexpectedly effective salvage therapy for an otherwise very aggressive relapsing ALCL.
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PMID:Trofosfamide as salvage therapy for anaplastic large cell lymphoma relapsing after high-dose chemotherapy. 1261 23

Autologous transplantation (ASCT) is the standard of care for chemosensitive relapsed or primary refractory aggressive lymphoma, but little is known about its efficacy in the subset of patients with peripheral T-cell lymphoma (PTCL). We undertook a retrospective review of patients with PTCL who underwent ASCT for relapsed or refractory disease after responding to second-line therapy, excluding patients with indolent histologies and those with anaplastic lymphoma kinase (ALK) expressing anaplastic large cell lymphoma. The results of 24 patients with PTCL were compared with those of 86 consecutive patients with chemosensitive relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL). With a median follow-up time of 6 years for surviving patients with PTCL and DLBCL, the 5-year progression-free survival (PFS) rates for PTCL and DLBCL patients were 24% and 34% respectively (P = 0.14); the corresponding overall survival (OS) rates were 33% and 39% respectively. There were no significant differences between the two groups with respect to time to disease progression or survival after progression. The second-line age-adjusted international prognostic index was the only variable prognostic for PFS and OS in a multivariate analysis. The outcome of ASCT for patients with chemosensitive relapsed or primary refractory PTCL is similar to that for patients with DLBCL.
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PMID:Autologous transplantation for relapsed or primary refractory peripheral T-cell lymphoma. 1675 21

Anaplastic large cell lymphoma (ALCL) is a biologic and clinically heterogenous subtype of T-cell lymphoma. Clinically, ALCL may present as localized (primary) cutaneous disease or widespread systemic disease. These two forms of ALCL are distinct entities with different clinical and biologic features. Both types share similar histology, however, with cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) molecule. Primary cutaneous ALCL (C-ALCL) is part of the spectrum of CD30+ lymphoproliferative diseases of the skin including lymphomatoid papulosis. Using conservative measures, 5-year disease-free survival rates are > 90%. The systemic ALCL type is an aggressive lymphoma that may secondarily involve the skin, in addition to other extranodal sites. Further, systemic ALCL may be divided based on the expression of anaplastic lymphoma kinase (ALK) protein, which is activated most frequently through the nonrandom t(2;5) chromosome translocation, causing the fusion of the nucleophosmin (NPM) gene located at 5q35 to 2p23 encoding the receptor tyrosine kinase ALK. Systemic ALK+ ALCLs have improved prognosis compared with ALK-negative ALCL, although both subtypes warrant treatment with polychemotherapy. Allogeneic and, to a lesser extent, autologous stem cell transplantation play a role in relapsed disease, while the benefit of upfront transplant is not clearly defined. Treatment options for relapsed patients include agents such as pralatrexate (Folotyn) and vinblastine. In addition, a multitude of novel therapeutics are being studied, including anti-CD30 antibodies, histone deacetylase inhibitors, immunomodulatory drugs, proteasome inhibitors, and inhibitors of ALK and its downstream signaling pathways. Continued clinical trial involvement by oncologists and patients is imperative to improve the outcomes for this malignancy.
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PMID:Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic aspects and therapeutic options. 2066 96

The prognosis of relapsed or refractory aggressive lymphoma is poor. The huge variety of currently evolving targeted treatment approaches would benefit from tools for early prediction of response or resistance. We used various ALK-positive anaplastic large cell lymphoma (ALCL) cell lines to evaluate two inhibitors, the HSP90 inhibitor NVP-AUY922, and the mTOR inhibitor everolimus, both of which have shown to interfere with ALK-dependent oncogenic signal transduction. Their therapeutic effect was determined in vitro by MTT assay, [(18)F]fluorodeoxyglucose (FDG)- and [(18)F]fluorothymidine (FLT)-uptake, and by biochemical analysis of ALK-induced signaling. Micro-FDG- and FLT-positron emission tomography (PET) imaging studies in immunodeficient mice bearing ALCL xenotransplants were carried out with the cell lines SUDHL-1 and Karpas299 to assess early treatment response to NVP-AUY922 or everolimus in vivo. SUDHL-1 cells showed sensitivity to both inhibitors in vitro. Importantly, we detected a significant reduction of FLT-uptake in SUDHL-1 bearing animals using both inhibitors compared with baseline as early as 5 days after initiation of targeted therapy. Immunostaining showed a decrease in Ki-67 and an increase in cleaved caspase-3 staining. In contrast, FDG-uptake did not significantly decrease at early time points. Karpas299 xenotransplants, which are resistant to NVP-AUY922 and sensitive to everolimus treatment, showed an increase of mean FLT-uptake on day 2 after administration of NVP-AUY299, but a significant reduction in FLT-uptake upon everolimus treatment. In conclusion, we show that FLT-PET but not FDG-PET is able to predict response to treatment with specific inhibitors very early in the course of treatment and thus enables early prediction of treatment efficacy.
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PMID:FLT-PET is superior to FDG-PET for very early response prediction in NPM-ALK-positive lymphoma treated with targeted therapy. 2287 26

Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with dismal prognosis. New treatments are needed to improve outcome of relapsed/ refractory disease. Recently, several drugs targeting at least partially the process of angiogenesis have been successfully tested in the therapy of MCL. Molecular mechanisms that regulate MCL-induced angiogenesis and that might represent potential new druggable targets remain, however, incompletely understood. We established two mouse models of human MCL by subcutaneous xenotransplantation of JEKO-1 and HBL-2 cell lines into immunodeficient mice. Histological analyses of xenografts confirmed their neovascularization. The growth of xenografts was significantly suppressed by single-agent therapy with bevacizumab, monoclonal antibody targeting vascular endothelial growth factor (VEGF). Subsequently, we analysed expression of 94 angiogenesis related genes in ex vivo isolated JEKO-1 and HBL-2 cells compared to in vitro growing cells using TaqMan low-density arrays. The most up-regulated genes in both JEKO-1 and HBL-2 xenografts were genes encoding platelet/endothelial cell-adhesion molecule (CD31/PECAM1), VEGF receptor 1 (FLT1), hepatocyte growth factor (HGF), angiogenin (ANG) and transcription factor PROX1. The most downregulated genes in both JEKO-1 and HBL-2 xenografts were midkine (MDK) and ephrine B2 (EPHB2). In summary, our results demonstrate an important role of angiogenesis in the biology of MCL and provide preclinical evidence of potent anti-MCL activity of bevacizumab. In addition, gene expression profiling of 94 angiogenesis-related targets revealed several in vivo up-regulated and down-regulated transcripts. The most differentially expressed target in both MCL tumours was CD31/PECAM1. Whether any of these molecules might represent a potential druggable target in MCL patients remains to be elucidated.
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PMID:In vivo growth of mantle cell lymphoma xenografts in immunodeficient mice is positively regulated by VEGF and associated with significant up-regulation of CD31/PECAM1. 2353 25

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is aberrantly expressed in a subset of T cell lymphoma that commonly affects children and young adults. NPM-ALK possesses significant oncogenic potential that was previously documented using in vitro and in vivo experimental models. The exact mechanisms by which NPM-ALK induces its effects are poorly understood. We have recently demonstrated that NPM-ALK is physically associated with type I insulin-like growth factor receptor (IGF-IR). A positive feedback loop appears to exist between NPM-ALK and IGF-IR through which these two kinases interact to potentiate their effects. We have also found that a single mutation of the Tyr(644) or Tyr(664) residue of the C terminus of NPM-ALK to phenylalanine decreases significantly, but does not completely abolish, the association between NPM-ALK and IGF-IR. The purpose of this study was to determine whether the dual mutation of Tyr(644) and Tyr(664) abrogates the association and interactions between NPM-ALK and IGF-IR. We also examined the impact of this dual mutation on the oncogenic potential of NPM-ALK. Our results show that NPM-ALK(Y644,664F) completely lacks association with IGF-IR. Importantly, we found that the dual mutation of Tyr(644) and Tyr(664) diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration. Furthermore, the association between NPM-ALK and IGF-IR through Tyr(644) and Tyr(664) appears to contribute to maintaining the stability of NPM-ALK protein. Our results provide novel insights into the mechanisms by which NPM-ALK induces its oncogenic effects through interactions with IGF-IR in this aggressive lymphoma.
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PMID:Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma kinase and type I insulin-like growth factor receptor. 2373 Feb 15

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product with tyrosine kinase activity and is expressed in substantial subset of anaplastic large cell lymphomas (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3). Although NPM-ALK(+) ALCL overall shows a better prognosis, there is a sub-group of patients who relapses and is resistant to conventional chemotherapeutic regimens. NPM-ALK is a potential target for small molecule kinase inhibitors. Crizotinib (PF-2341066) is a small, orally bioavailable molecule that inhibits growth of tumors with ALK activity as shown in a subgroup of non-small lung cancer patients with EML4-ALK expression. In this study, we have investigated the in vitro effects of Crizotinib in ALCL cell line with NPM-ALK fusion. Crizotinib induced marked downregulation of STAT3 phosphorylation, which was associated with significant apoptotic cell death. Apoptosis induction was attributed to caspase-3 cleavage and marked downregulation of the Bcl-2 family of proteins including MCL-1. These findings implicate that Crizotinib has excellent potential to treat patients with NPM-ALK(+) ALCL through induction of apoptotic cell death and downregulation of major oncogenic proteins in this aggressive lymphoma.
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PMID:Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK(+) anaplastic large cell lymphoma. 2448 91

Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma seen in both adults and children. ALCL is associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in a NPM-ALK fusion protein, ALK over-expression and constitutive tyrosine kinase activity. This aggressive lymphoma is more prevalent in males and can present with extranodal involvement (lung, skin and marrow infiltration) and haemophagocytic lymphohistocytosis. The long-term overall survival is approximately 70-90% in children and over 70% in adults. Staging systems and prognostic risk factors are different in both childhood and adult ALCL. Treatment in adults is typically anthracycline-based, with autologous stem cell transplantation (ASCT) salvaging patients in relapsed disease. There is evidence for ALL-like therapy or intensive, pulsed anthracycline-based induction in children. ASCT, allogeneic SCT and vinblastine maintenance are all considered reasonable options in relapsed childhood disease. The anti-CD30 immunoconjugate Brentuximab Vedotin and the specific ALK inhibitor Crizotinib are changing the treatment paradigm in ALCL (ALK-positive or negative) and ALK-positive ALCL respectively. Both agents have shown encouraging responses in relapsed ALCL. It remains to be seen how these novel agents are used, but it is very possible that they may improve overall responses and survival in both children and adults. This review highlights the presentation, histopathological features, prognostic factors, and evidence-based treatment approaches in the first line and relapsed setting in ALK-positive ALCL. The review concludes by discussing the novel approaches using Brentuximab and Crizotinib which are being tested in clinical trials.
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PMID:Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease. 2495 81


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