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

Bone metastases in prostate cancer are predominantly osteoblastic. To study regulatory mechanisms underlying the establishment of prostate cancer within an osteoblastic microenvironment, human androgen-sensitive prostate carcinoma cells (LNCaP) were treated with culture medium conditioned by human osteoblast-derived sarcoma cells (OHS), and activated signalling pathways in the carcinoma cells were analyzed using microarrays with tyrosine kinase substrates. Network interaction analysis of substrates with significantly increased phosphorylation levels revealed that signalling pathways mediated by EGFR and ERBB2 were activated in LNCaP cells under OHS influence but also by androgen treatment. Activation of EGFR/ERBB2 signalling was also found in LNCaP cells in cocultures with OHS cells or osteoblastic cells that had been differentiated from human mesenchymal stem cells. Our experimental data suggests osteoblast-directed induction of signalling activity via EGFR and ERBB2 in prostate carcinoma cells and may provide a rationale for the use of EGFR or ERBB2 inhibition in systemic prevention or treatment of metastatic prostate cancer in the androgen-sensitive stage of the disease.
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PMID:Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling. 1929 21

Dermatofibrosarcoma protuberans (DFSP) is a soft tissue tumor with tendency to recur locally and only rarely metastasizes to vital organs. Surgery with wide margins remains the standard treatment. DFSP is characterized by specific chromosomal abnormalities involving the platelet derived growth factor B locus (PDGFB). In the majority of cases a supernumerary ring chromosome containing amplified t(17; 22) translocation or a linear unbalanced t(17; 22) containing the COL1A1 -PDGFB fusion gene is present. This molecular event causes aberrant expression of a functional PDGFB leading to activation of PDGFR. Imatinib mesylate is a tyrosine kinase inhibitor with activity against activated PDGFR, and has significant activity against DFSP. Clinical evidence suggests that it has a role in locally advanced and metastatic disease and clinical trials are ongoing examining its role in this rare but potentially fatal sarcoma.
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PMID:Imatinib in the treatment of dermatofibrosarcoma protuberans. 1970 5

Prognostic factors in patients with chronic myeloid leukaemia (CML) treated with conventional treatment include age, spleen size, platelet count, blood percentage of blasts, basophils and eosinophils, and cytogenetic abnormalities besides the Philadelphia chromosome. The value of traditional clinical and laboratory features to identify patients at increased risk of imatinib failure has not been established yet. Biological markers such as gene expression profile, v-crk sarcoma virus CT10 oncogene homologue (avian)-like (Crkl) phosphorylation or expression of imatinib transporter proteins have been shown to be useful to predict the response to imatinib. In practice, the response obtained at different time points from the initiation of imatinib is employed to predict the patient's outcome, with this especially applying to cytogenetic response. The prognostic relevance of early molecular response to imatinib has also been pointed out. Prognostic factors for response to second-generation tyrosine kinase inhibitors (TKI) after imatinib failure are currently being investigated.
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PMID:Prognostic factors in chronic myeloid leukaemia. 1995 85

Epithelioid sarcoma is a rare, malignant, soft tissue neoplasm that can be classified into proximal, distal and fibroma-like subtypes. Regardless of subtype, epithelioid sarcoma often shows morphologic and immunophenotypic evidence of epithelial differentiation. Current therapeutic strategies include surgical resection, amputation, radiation or chemotherapy, although the overall prognosis remains poor. The epidermal growth factor receptor (EGFR) is a novel therapeutic target in carcinomas. In some carcinomas, EGFR kinase domain mutations or gene amplification may correlate with response to specific inhibitors. EGFR expression has been reported in some sarcoma types, but expression, amplification and mutations have not been studied in epithelioid sarcoma. We evaluated 15 cases of epithelioid sarcoma from 14 patients for EGFR expression using immunohistochemistry, EGFR copy number aberration using fluorescence in situ hybridization and screened for mutations in the tyrosine kinase domain of the EGFR gene using direct sequencing. In all, 14 of the 15 epithelioid sarcomas (93%) showed expression of EGFR by immunohistochemistry. A majority of the cases (n=11, 73%) showed strong (2+ to 3+) and homogeneous (>75% of cells) membrane staining. No amplification or polysomy of the EGFR gene or mutations of the tyrosine kinase domain of EGFR (exons 18-21) were detected. These results imply that although EGFR is expressed in most epithelioid sarcomas regardless of subtype, gene amplification and activating mutations in the tyrosine kinase domain appear to be rare or absent. Thus, the benefit of targeted therapy against EGFR in patients with epithelioid sarcoma remains to be determined.
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PMID:Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare. 2011 13

The Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of <30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869 is a multitargeted small-molecule inhibitor that targets Fms-like tyrosine kinase-3, c-KIT, vascular endothelial growth receptors, and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models. ABT-869 inhibited the proliferation of two EWS cell lines, A4573 and TC71, at an IC(50) of 1.25 and 2 mumol/L after 72 h of treatment, respectively. The phosphorylation of PDGFRbeta, c-KIT, and extracellular signal-regulated kinases was also inhibited. To examine the effects of ABT-869 in vivo, the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Therefore, our in vitro and in vivo studies show that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRbeta and c-KIT pathways.
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PMID:ABT-869 inhibits the proliferation of Ewing Sarcoma cells and suppresses platelet-derived growth factor receptor beta and c-KIT signaling pathways. 2019 94

The 8p11 myeloproliferative syndrome is an aggressive neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 tyrosine kinase gene on chromosome 8p11-12. By our count, 65 cases are currently reported in the literature. This neoplasm affects patients of all ages, with a slight male predominance. Patients often present with peripheral blood eosinophilia without basophilia. Bone marrow examination commonly is hypercellular, with or without eosinophilia, which usually leads to the initial diagnosis of a myeloproliferative neoplasm. Many patients also present with or develop lymphadenopathy. Lymph node biopsy in these patients has commonly shown lymphoblastic leukemia/lymphoma, most often reported as being of T-cell lineage, but bilineal myeloid/T-cell lymphomas and less often a myeloid sarcoma are also reported. The natural history of this neoplasm is to evolve into acute leukemia, usually of myeloid or mixed lineage, and less frequently of T- or B-lymphoid lineage. The prognosis is poor despite aggressive chemotherapy, with a few patients achieving long clinical remission after stem cell transplantation. At the molecular level, all cases carry a chromosomal abnormality involving the fibroblast growth factor receptor 1 (FGFR1) gene at chromosome 8p11, where 10 translocations and 1 insertion have been identified. These abnormalities disrupt the FGFR1 and various partner genes, and result in the creation of novel fusion genes and chimeric proteins. The latter include the N-terminal portion of the partner genes and the C-terminal portion of FGFR1. The most common partner is ZNF198 on chromosome 13q12. In the current World Health Organization classification, the 8p11 myeloproliferative syndrome is designated as "myeloid and lymphoid neoplasms with FGFR1 abnormalities."
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PMID:8p11 myeloproliferative syndrome: a review. 2022 62

Gastrointestinal stromal tumors (GISTs) are rare tumors of mesenchymal origin that develop along the gastrointestinal tract. Over ten years ago, their management dramatically changed following the discovery of an activating mutation of the KIT oncogene, which led to the use of small molecule inhibitors to therapeutically target these mutant kinases. Patients with advanced GIST, who were once a subset of sarcoma with poor prognosis due to their lack of chemosensitivity, may now survive more than 5 years following treatment with tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) and sunitinib malate (SU). After ten years of active clinical and preclinical research, it has become clear that, although relatively homogeneous compared to other solid malignancies, there is still some heterogeneity in GISTs and most notably in regard to response to therapy. Here, we review the current data regarding molecular prediction of response in this disease.
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PMID:Molecular response prediction in gastrointestinal stromal tumors. 2036 Dec 66

Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor (TKI) that binds to the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and several other key proteins responsible for angiogenesis, tumor growth and cell survival. Pazopanib exhibited in vivo and in vitro activity against tumor growth and, in early clinical trials, was well tolerated with the main side effects being hypertension, fatigue and gastrointestinal disorders. Pazopanib showed clinical activity in several tumors including renal cell cancer (RCC), breast cancer, soft tissue sarcoma, thyroid cancer, hepatocellular cancer and cervical cancer. A phase III clinical trial in metastatic RCC patients showed a significant improvement in progression-free survival, leading to its approval in the US. In metastatic breast cancer, the combination of pazopanib with lapatinib was more effective than lapatinib alone. At the time of the current publication, pazopanib is being evaluated in more than 35 phase II and III trials.
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PMID:Pazopanib: Clinical development of a potent anti-angiogenic drug. 2045 72

Soft tissue sarcomas (STS) are rare diseases, with an estimated 10,390 new cases in the United States in 2008. Unfortunately, only 50% are cured with surgical resection. The standard cytotoxic chemotherapeutic agents have not been successful in the treatment of metastatic disease. The standard single-agent chemotherapy for metastatic disease is doxorubicin, with only 20% to 25% response rates. The combination of doxorubicin with other agents, such as ifosfamide, has improved response rates, without any improvement in overall survival. New targeted therapies have shown some activity in STS; however, disease stabilization is seen more often than a true radiographic response. The combination of cytotoxic chemotherapy with more targeted and novel agents may be appropriate to improve outcome in these patients. The agents of interest in sarcomas at this time are multi-tyrosine kinase inhibitors, antiangiogenesis agents, inhibitors of mammalian target of rapamycin, hypoxia-activating prodrugs, insulin growth factor monoclonal antibodies, and tumor necrosis factor-related apoptosis-inducing ligand agonists.
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PMID:New developments in targeted therapy for soft tissue sarcoma. 2046 42

Pazopanib is a recently approved, novel tyrosine kinase inhibitor specifically designed to impair angiogenesis by abrogating vascular endothelial growth factor receptor 2 (VEGFR-2) to exert its function. Pazopanib inhibits VEGF-induced endothelial cell proliferation in vitro and angiogenesis in vivo and demonstrates antitumor activity in mouse models. Furthermore, the pazopanib concentration resulting in maximal inhibition of VEGFR-2 phosphorylation in vivo was in line with the steady-state concentration required to inhibit growth of tumor xenografts, suggesting that pazopanib's mechanism of action is indeed through VEGFR-2 inhibition. In a phase I trial, a generally well-tolerated dose was identified at which the majority of patients achieved pazopanib plasma concentrations above the concentration required for maximal in vivo inhibition of VEGFR-2 phosphorylation in preclinical models. Administered as monotherapy, evidence of antitumor activity was observed in phase II studies in several tumor types, including soft tissue sarcoma, renal cell cancer (RCC), ovarian cancer, and non-small cell lung cancer. Recently, the U.S. Food and Drug Administration granted approval for treatment with pazopanib in patients with RCC based on the longer progression-free survival time observed with this agent in a placebo-controlled, randomized trial. This review summarizes the preclinical and clinical pharmacokinetics and pharmacodynamics of pazopanib, as well as data on clinical activity, that ultimately resulted in its recent approval.
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PMID:(Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. 2051 20


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