Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heat-shock protein-90 (HSP90) inhibitors are currently being used in phase I clinical trials for treating patients with a variety of neoplasms including lymphomas. Using immunohistochemical methods, we assessed for HSP90 expression in 412 cases of non-Hodgkin's lymphoma. In B-cell lymphomas, HSP90 was moderately to strongly expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in subsets of follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). HSP90 was weakly expressed in six of 14 (43%) cases of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. In T-cell lymphomas, HSP90 was moderately to strongly expressed in subsets of anaplastic large-cell lymphoma (14/24, 58%; 9/12 ALK+ and 5/12 ALK-), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%) and angioimmunoblastic T-cell lymphoma (2/17, 12%). HSP90 was weakly expressed in seven of 58 (12%) cases of mycosis fungoides. We conclude that HSP90 is commonly expressed in a subset of many types of B- and T-cell lymphoma. These data suggest that many lymphoma types are suitable targets for modulation of HSP90 activity, and that HSP90 inhibitors are a potential investigational therapy for lymphoma patients.
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PMID:Expression of heat-shock protein-90 in non-Hodgkin's lymphomas. 1605 52

Recent evidence suggests that diffuse large B-cell lymphoma (DLBCL) with plasmablastic differentiation represents a clinically heterogeneous spectrum with different clinicopathologic characteristics representing distinct entities. Subtypes of DLBCL with plasmablastic features and terminal B-cell differentiation include plasmablastic lymphoma (PBL) of oral mucosa type; PBL with plasmacytic differentiation; primary effusion lymphoma (PEL); KSHV-positive solid lymphoma/extracavitary PEL/HHV-8 associated DLBCL; and DLBCL expressing ALK. In contrast, PBL associated with multicentric Castleman disease, DLBCL with secretory differentiation, pyothorax-associated lymphoma, and atypical Burkitt lymphoma with plasmacytoid differentiation have morphologic appearances of plasma cell differentiation but maintain a mature B-cell (CD20 positive) phenotype. These tumors as well as extramedullary plasmablastic tumors secondary to multiple myeloma or plasmacytomas are included in the differential diagnosis. In this review, we discuss recently described clinicopathologic insights, case observations, and recently reported molecules involved in terminal B-cell or plasma cell differentiation and their possible roles in disease pathogenesis.
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PMID:Diffuse large B-cell lymphomas with plasmablastic differentiation. 1609 Nov 96

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.
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PMID:Kinases as drug discovery targets in hematologic malignancies. 1630 89

Synchronous occurrence of lymphomatous proliferations of B and T lineage in the same patient is a very rare event and still poorly understood. All the cases reported in the English language literature are described as single case reports. We report a case of 49-year-old man, with 2-year history of multiple myeloma, presented with a raised, erythematous and ulcerated nodule in the anterior aspect of his right thigh. Histologic examination of biopsy specimen showed a dense dermic infiltrate made of large balastic cells displaying anaplastic morphology with no epidermotropism. Immunohistochemical study showed that tumor cells stained positive with CD30, EMA and CD4, and negative for CD3, CD8, CD5, CD20, CD79a, CD138 and anaplastic lymphoma kinase 1 (ALK or Ki-1).
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PMID:Multiple myeloma and cutaneous anaplastic large T-cell lymphoma in the same patient: is there a causal relation? 1989 57

Bortezomib, a reversible proteasome inhibitor, is used for the treatment of hematologic malignancies. Common adverse events with bortezomib include gastrointestinal symptoms, thrombocytopenia, and neuropathy, whereas severe pulmonary complications have been rarely described. Herein, we present a case of rapid fatal pulmonary complications in a patient with ALK-negative anaplastic large-cell lymphoma after receiving a treatment with bortezomib.
Clin Lymphoma Myeloma Leuk 2010 Apr
PMID:Rapid fatal pulmonary complications in a Chinese patient after bortezomib treatment for ALK-negative anaplastic large-cell lymphoma. 2037 51

The congress of Asco made the object of numerous summaries of congress made in the heat of the moment and the Bulletin du Cancer decided to ask to his editorial board, a digested summary, at distance of the congress, to try to sum up the data of the congress which are going to change practice. Of the considerable number of communications, editorial board chose 40 communications which appeared to answer these rules. Best understanding of biological mechanisms and new molecules to inhibit targets allow in certain case, to use therapeutic targeting in the true sense. The identification of the gene of fusion EML4-ALK in lung adenocarcinoma, and its inhibition by the crizotinib, constitute a considerable progress for 5% of patients with this disease. Molecular biology with the mutations of the exon 11 in GIST, allow to better define the population which is going to benefit from adjuvant imatinib. In Advanced non-small cell lung cancer, myeloma and advanced lymphoma, maintenance therapy by monoclonal anti-body or inhibitors of tyrosines kinases showed the proof of their effectiveness. In advanced melanoma, ipilimumab is a light of hope in a pathology in always prognostic is so dark. In metastatic adenocarcinoma of the pancreas, there is finally an alternative to gemcitabine with the Folfirinox regimen, with an improvement of overall survival. Biological personalization of cancer treatments is on the road run but the road is still long.
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PMID:[Following communications made at American Society of Clinical Oncology 2010, what will change our practice? The point of view of the editorial board of Bulletin du Cancer]. 2122 Feb 30

Plasmablastic differentiation can be found in a variety of large B-cell lymphomas, including plasmablastic lymphoma, ALK-positive large B-cell lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in human herpesvirus-8 (HHV-8)-associated multicentric Castleman disease and diffuse large B-cell lymphoma (DLBCL) with partial plasmablastic phenotype. These tumors are characterized by acquisition of the transcriptional profile of plasma cells (with overexpression of PRDM1/Blimp1 and XBP1s, in concert with extinction of the B-cell differentiation program) by proliferating immunoblasts. This particular biological entity, i.e. large B-cell lymphoma with plasmablastic differentiation, is almost always associated with an aggressive clinical behavior. This review summarizes the current knowledge of the biological basis of plasmablastic differentiation in large B-cell lymphomas, the diagnostic borders with DLBCL and multiple myeloma, the associated adverse molecular events (with concomitant MYC, p53 and ALK alterations) and the potential therapeutic targets so far identified (including the unfolded protein response pathway). The highly aggressive nature of these lymphomas and the relative paucity of molecular data available highlight the need for deeper insights into the molecular pathogenesis of large B-cell lymphomas with plasmablastic differentiation in order to identify new and effective alternative treatments.
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PMID:Large B-cell lymphomas with plasmablastic differentiation: a biological and therapeutic challenge. 2181 34

The hedgehog (HH) signaling pathway is a highly regulated signaling pathway that is important not only for embryonic development, tissue patterning, and organogenesis but also for tissue repair and the maintenance of stem cells in adult tissues. In the adult hematopoietic system, HH signaling regulates intrathymic T-cell development, and it is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in germinal center B cells. HH signaling is required for primitive hematopoiesis; however, conflicting data have been reported regarding the role of the HH pathway in adult hematopoiesis. Inappropriate activation of the HH signaling pathway occurs in several human cancers, including hematological neoplasms. Emerging data demonstrate abnormal HH pathway activation in chronic lymphocytic leukemia/small lymphocytic lymphoma, plasma cell myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, ALK-positive anaplastic large cell lymphoma, chronic myelogenous leukemia, and acute leukemias. In these neoplasms, HH signaling promotes proliferation and survival, contributes to the maintenance of cancer stem cells, and enhances tolerance or resistance to chemotherapeutic agents. Here, we review current understanding of HH signaling, its role in the pathobiology of hematological malignancies, and its potential as a therapeutic target to treat malignant hematological neoplasms.
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PMID:Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms. 2205 10

Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and it is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Investigators established Hsp90's druggability using the natural products geldanamycin and radicicol, which mimic the unusual ATP structure adopted in the chaperone's N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and show antitumor activity. Preclinical data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clinical activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Many optimized synthetic, small-molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. There has been significant learning from studies of the basic biology of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers that are addicted to particular driver oncogene products (e.g., HER2, ALK, EGFR, and BRAF) that are sensitive Hsp90 clients, as well as malignancies (especially multiple myeloma) in which buffering of proteotoxic stress is critical for survival. We discuss approaches for enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress-response pathway targets, including HSF1 and Hsp70.
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PMID:Hsp90 molecular chaperone inhibitors: are we there yet? 2221 7

We present a case of pediatric anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK-positive LBCL) with a cervical, mesentery, and pelvis cavity mass. Histologic examination of the cervical mass revealed that the lesion was composed of diffuse large immunoblastic-like or plasmablastic-like tumor cells with a sinusoidal growth pattern. The tumor cells were strongly immunoreactive for ALK; revealed a granular cytoplasmic distribution; and were diffusely positive for CD45, CD4, CD138, epithelial membrane antigen, and multiple myeloma oncogene-1 but negative for CD20 and CD79a. The patient underwent 5 courses of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposid and obtained a remarkable clinical response with regression of mesentery and pelvis cavity mass. We suggest that this distinct subtype of large B-cell lymphoma should belong to the spectrum of pediatric lymphomas and that radiologic examination should be performed to inspect the progression of disease even if the patients experienced complete remission at initial chemotherapy.
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PMID:Pediatric anaplastic lymphoma kinase-positive large B-cell lymphoma: a case report and review of the literature. 2239 91


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