Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel protein tyrosine kinase (PTK) was identified in Schistosoma mansoni and designated SmFes. SmFes exhibits the characteristic features of Fes/Fps/Fer (fes, feline sarcoma; fps, Fujinami poultry sarcoma; fer, fes related) PTKs, containing three coiled-coil regions, an SH2 (Src-homology-2) and a TK (tyrosine kinase catalytic) domain signature. SmFes is the first gene from the Fes/Fps/Fer family identified in S. mansoni, and is a single copy gene. Phylogenetic analyses revealed that SmFes is most closely related to its invertebrate orthologues. The assembly of the SmFes cDNA and genomic sequences indicated the presence of 18 introns in SmFes. Comparison of its genomic structure with those of human Fps/Fes and Drosophila Fps indicates that intron positions are conserved within the region encoding the kinase domain. Analysis of partial cDNA clones showed the presence of a 9 bp insertion at the 3' end of exon 10, producing two different cDNA populations, pointed as an alternative splicing event. In addition, an allele of SmFes containing a 15 bp insertion was observed in the genomic sequence. Quantitative RT-PCR indicated that the overall transcription level of SmFes is rather low in all parasite developmental stages. Moreover, SmFes mRNA levels decrease progressively after cercarial transformation, consistent with a role for the corresponding protein in the early stages of infection.
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PMID:Molecular analysis of SmFes, a tyrosine kinase of Schistosoma mansoni orthologous to the members of the Fes/Fps/Fer family. 1758 35

Gastrointestinal stromal tumors GIST are rare mesenchymal tumors of the gastrointestinal tract characterized by expression of a receptor that activates tyrosine kinase called C- kit. Since malignant GIST has an extremely poor prognosis even after surgical resection. The developement of a tyrosine kinase inhibitor, STI571/imatinib mesylate/Gleevec, Glivec which inhibits the BCR-ABL, PDGF-R alpha, and C-Kit receptors, has changed the management of unresectable malignant GIST and has improved the survival of patients with metastaic disease. We report a 32 year old male patient with subcardiale gastric GIST and massive gastrointestinale bleeding. The patient underwent total gastrectomy, D2 lymphadenestomy, distal pancreatectomy and splenectomy on 02.02. 2004. Histopathology examination of the primary tumor revealed a strong C-Kit expression and CD 34 +++, Ki67 20 and so called "Pure GIST" was approved Liver metastasis was detected on ultrasound and CT 12 months later and segmentectomy S7 was performed on 23.03.2005. Postoperative course was uneventfull. HP examination--malignant 35 x 30 mm sarcoma like tumor of mesenchymal origin. The patient received adjuvant imatinib-mesylate Gleevec Novartis Pharma Basel 400 mg a day. The initial complete response to treatment continued to 24 monts postoperatively Imatinib is a recent and very promising tretemenextirpation remains the only curative treatment of malignant GIST as evideneced by our patient.
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PMID:[Gastrointestinal gastric tumor (GIST) as a cause of massive hemorrhage from the upper digestive tract]. 1763 80

The common feature of gastrointestinal stromal tumors (GISTs) is the expression of KIT protein or acquisition of activating, constitutive mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes that are the early oncogenic events during GIST development. With these discoveries, GIST has emerged as a distinct sarcoma entity, enabling the introduction of targeted therapy using the inhibition of KIT/PDGFRA and their downstream signaling cascade. The introduction of a small-molecule tyrosine kinase inhibitor, imatinib mesylate, to clinical practice has revolutionized the treatment of patients with advanced GISTs and is currently approved as first-line treatment for patients with metastatic and/or inoperable GISTs. Mutation screening is currently a tool in GIST diagnosis, assessment of sensitivity to tyrosine kinase inhibitors, and prediction of achieving response to molecularly targeted therapy. This article discusses the histologic and molecular criteria for distinguishing GISTs from other types of sarcoma, and the molecular diagnostic tools that are currently available or in development to assist in therapy decisions.
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PMID:Gastrointestinal stromal tumors: key to diagnosis and choice of therapy. 1851 Mar 77

A 77-year-old woman presented with hoarseness and hemoptysis. Chest CT scan revealed a mediastinal tumor in the lumen of the left pulmonary artery. A definitive diagnosis could not be made based on mediastinoscopy and thoracotomy. Eight months later, multiple nodular shadows appeared in both lung fields.Video-assisted lung biopsy showed that these nodules were lung metastases of a spindle cell sarcoma. Based on the pathological and radiological findings, a pulmonary artery sarcoma was eventually diagnosed. Interestingly, on immunohistological staining, the tumor cells were diffusely positive for KIT, which is an immunohistochemical marker of gastrointestinal stromal tumors. The patient was treated with imatinib, a KIT tyrosine kinase inhibitor; however, the tumors progressed. The relationship between pulmonary artery sarcoma and KIT requires further study.
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PMID:[Diffuse expression of KIT in a pulmonary artery sarcoma]. 1851 91

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed.
Sarcoma 2002
PMID:Molecular approaches to sarcoma therapy. 1852 43

Soft-tissue sarcomas (STS) include a spectrum of histologically and clinically different tumors. Patients with these tumors are typically relatively young and the course of disease is characterized by early metastasis as well as limited response to chemotherapy. However, a few subtypes, such as small round-cell tumors and rhabdomyosarcoma (other than pleomorphic), are considered chemotherapy sensitive. In addition, reflecting successful translational research of recent years, gastrointestinal stromal tumor and dermatofibrosarcoma protuberans have become model diseases for targeted oncologic therapy. We summarize current treatment options for metastatic STS, including established first-line chemotherapy approaches, mainly with anthracyclines and/or ifosfamide and second-line treatment choices beyond anthracyclines. Until only a few years ago, treatment choices for metastatic STS were easy to review because of the very limited number of active compounds available. However, with the advent of novel therapeutic strategies such as the anti-angiogenic approach and a multitude of novel compounds available both outside and within clinical studies, it has potentially become more difficult to keep track of currently available treatment options for STS and their clinical safety and efficacy. In this practice-oriented article, we therefore review treatment goals in advanced STS and provide an overview of compounds with proven activity in this setting. Anthracyclines with or without ifosfamide are still considered standard of care for most STS subtypes, especially for high-grade tumors. There is no evidence-based recommendation regarding use of second-line treatment options. However, a number of established compounds, including dacarbazine/temozolomide, gemcitabine, taxanes, trofosfamide, DNA topoisomerase I inhibitors, DNA minor groove binders, and bendamustine have shown activity. Recently, trabectedin, a DNA minor groove binder initially isolated from a sea sponge, has proven effective and received European approval for use in treatment-refractory STS. In addition, novel compounds such as bevacizumab, multi-tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, imatinib, and the thrombospondin agonist ABT 510 represent attractive partners for the above-mentioned cytostatic agents, or may even be effective single agents in the clinically advanced setting. Novel combinations are being evaluated in clinical studies. In order to be successful, it may be necessary to combine not only different compounds but also different targets beyond the proliferation machinery of sarcoma cells such as tumor angiogenesis, the tumor stromal compartment, or tumor cell oncogene products.
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PMID:Potential combination chemotherapy approaches for advanced adult-type soft-tissue sarcoma. 1857 72

Sarcomas comprise a heterogeneous and biologically diverse group of malignant neoplasms having as a common denominator their origin from mesenchymal cells. Head and neck sarcomas account for 4 to less than 20% of total body sarcomas depending on the criteria, such as age of patients (pediatric vs adult population), type of sarcomas (soft-tissue vs bony sarcomas) and site of location. Although head and neck sarcomas occur infrequently in adults, in the pediatric population one in three sarcomas will occur in the head and neck region. Most head and neck sarcomas are of the soft-tissue type, with only 20% being of bony or cartilaginous origin. Sarcomas display a diverse array of histologies and a wide spectrum of clinical behavior, ranging from relatively slow growing lesions to aggressive locally and regionally destructive tumors with the potential for systemic metastases. Osteosarcomas, rhabdomyosarcomas, pleomorphic sarcomas (malignant fibrous histiocytomas), fibrosarcomas and angiosarcomas are among the most common histologic types of sarcoma found in the head and neck. Surgery has been the primary therapeutic approach for the management of head and neck sarcomas. Survival rates for head and neck sarcomas suggest worse outcomes than for their extremity counterparts. Lymph node metastasis only occurs in 3-10% of sarcomas of the head and neck. An improvement in local disease control has recently been suggested with the combined use of surgery and radiotherapy. Conflicting results have been reported on the benefit from the use of chemotherapy as an adjuvant or neoadjuvant regimen, especially for high-grade sarcomas in long-term survival or local disease control. Encouraging results have recently been reported with the use of molecular targeted therapies with tyrosine kinase inhibitors and antiangiogenetic agents.
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PMID:Sarcomas of the head and neck in adult patients: current concepts and future perspectives. 1869 65

Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors, including more than a hundred different entities attending to histological patterns. Sarcomas are quite resistant to conventional chemotherapy (anthracycline and ifosfamide) with the exception of some subtypes, such as Ewing's sarcoma (ES). New drugs with proved efficacy against sarcomas include taxanes, gemcitabine, and ET-743. Preclinical studies have also identified key molecular events leading to the progression and development of sarcomas which are good candidates to targeted therapy. Inhibitors of the tyrosine kinase receptors, such as IGF-1R, c-kit, PDGFR, VEGFR, or the mTOR signaling pathway, proteasome, angiogenesis, and stress response proteins are under clinical evaluation against sarcomas. ES, a tumor characterized by chromosomal translocations that originate gene fusions (EWS-FLI1, EWS-ERG), is an example of a good chemotherapy responder tumor whose survival rate shows a plateau in recent years. Preclinical studies have identified that new targets such as HSP90 are of relevance to ES. On the other hand, recent studies showed the role of cancer stem cells (CSCs) in sarcomas and the relevance of the identification of reliable molecular markers and possible therapeutic targets. New therapeutic approaches could be directed against CSCs. This review describes more recent targeted therapy in sarcomas, with special emphasis on ES and the role of CSCs. We also emphasize the role of high throughput proteomic techniques in identifying new therapeutic targets.
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PMID:Targeting sarcomas: therapeutic targets and their rational. 1901 96

The insulin-like growth factor 1 receptor (IGF-1R) and its associated signalling system has provoked considerable interest over recent years as a novel therapeutic target in cancer. A brief outline of the IGF-1R signalling system and the rationale for its use in cancer medicine is given. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417, NVP-AEW541, NVP-ADW742, AG1024, potent quinolinyl-derived imidazo (1,5-a)pyrazine PQIP, picropodophyllin PPP, Nordihydroguaiaretic acid Insm-18/NDGA). The following tumour types are specifically discussed: lung, breast, colorectal, pancreatic, NETs, sarcoma, prostate, leukaemia, multiple myeloma. Other tumour types are mentioned briefly: squamous cell carcinoma of the head and neck, melanoma, glioblastoma, ovary, gastric and mesothelioma. Results of early stage clinical trials, involving recently patented drugs. are included where appropriate. We then outline the current understanding of toxicity related to IGF-1R targeted therapy, and finally outline areas for further research.
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PMID:Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. 1914 88

This review describes the current multidisciplinary management of gastrointestinal stromal tumor (GIST), which is the most common sarcoma of the gastrointestinal tract. Before 2001, surgery was the only effective therapy for GIST. The discovery of the central role of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of specific inhibitors of KIT tyrosine kinase (TK) function, has changed the paradigm of treatment for GISTs. Imatinib and sunitinib are TK inhibitors with activity against GISTs. Their major established role in GIST is in the treatment of advanced disease. A growing body of literature and clinical experience support the potential perioperative use of these drugs. The adjuvant use of imatinib is based on retrospective series and limited prospective studies demonstrating that imatinib reduces the risk of recurrence. Ongoing studies are further defining the length of adjuvant therapy, as well as identifying the patients that could achieve the best results. Neoadjuvant treatment often decreases the tumor size, allowing a less morbid surgery, appears to be safe and beneficial for some patients, and therefore deserves further study.
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PMID:Perioperative treatment of gastrointestinal stromal tumors. 1928 24


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