Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrointestinal stromal tumor (GIST) has emerged in the past year as a prototypical neoplasm that responds to therapy directed against a single target molecule-the KIT receptor tyrosine kinase protein. Although GIST seldom responds to conventional chemotherapeutic agents, early experience with the tyrosine kinase inhibitor, STI-571 (Gleevec; Novartis, Basel, Switzerland), has been extremely encouraging. Early results have appeared in a recent case report in the New England Journal of Medicine (April 5, 2001),(1) and in early clinical trials from the United States and Europe that were reported at the plenary session of the American Society of Clinical Oncology in San Francisco on May 14, 2001. STI-571 is one of the earliest examples of a nontoxic chemotherapeutic agent (an agent whose anti-cancer activity is not predicated on a cytotoxic mechanism). STI-571 has already shown clinical value in BCR-ABL-positive leukemias. Early clinical results in GIST are so encouraging that oncologists may soon be wrestling with the opportunity of referring every patient with malignant GIST into clinical trials with STI-571. To ensure appropriate treatment, pathologists need to understand the biology and treatment of this tumor and to have standard methods and criteria for providing diagnosis (GIST or not GIST) and consistent prognostic classification (high risk of metastasis or low risk of metastasis).
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PMID:Gastrointestinal stromal tumor workshop. 1143 11

The cytokine interferon-alfa (IFN-alpha) has substantial activity in chronic myeloid leukemia (CML) and is the nontransplant standard of care for chronic-phase disease. When used as front-line therapy, IFN-alpha induces a state of tumor dormancy and delays progression to advanced phase. Unfortunately, IFN-alpha is associated with substantial toxicity at therapeutic doses. The introduction of pegylated IFN-alpha (PEG-IFN-alpha), a modified form of the protein that permits weekly administration, may alleviate some of the problems observed with IFN-alpha. Combination regimens of IFN-alpha with other drugs such as cytarabine (Ara-C) appear to enhance efficacy and are currently under investigation. The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) also is efficacious in chronic-phase CML, with a low toxicity profile. However, its potential to cure CML remains unknown even though it achieves frequent cytogenetic responses. To enhance treatment outcome, a combination of IFN-alpha and imatinib mesylate therapies is proposed. Low-dose IFN-alpha may be given after imatinib mesylate-induced remission as a specific immune stimulant to consolidate the remission. Recent data showing a possible additive effect of imatinib mesylate and IFN-alpha suggest that concurrent use of these agents may also be more effective than single use, particularly in advanced stages of CML where imatinib mesylate has activity but resistance develops.
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PMID:Interferon-alfa-based treatment of chronic myeloid leukemia and implications of signal transduction inhibition. 1152 98

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.
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PMID:Tyrosine kinase inhibitors: from rational design to clinical trials. 1160 31

Platelet-derived growth factor (PDGF) was one of the first polypeptide growth factors identified that signals through a cell surface tyrosine kinase receptor (PDGF-R) to stimulate various cellular functions including growth, proliferation, and differentiation. Since then, several related genes have been identified constituting a family of ligands (primarily PDGF A and B) and their cognate receptors (PDGF-R alpha and beta). To date, PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and even angiogenesis. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein, and was recently approved for several indications in the treatment of chronic myeloid leukemia. Imatinib mesylate is also a potent inhibitor of the PDGF-R kinase and is currently being evaluated for the treatment of PDGF-responsive tumors such as prostate cancer. More clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that may describe the biologic significance of PDGF-R inhibition in vivo are needed to expand the applications that target the PDGF axis.
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PMID:Platelet-derived growth factor receptors: a therapeutic target in solid tumors. 1174 Aug 4

Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-gamma), IFN-alpha, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1beta transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself.
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PMID:New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents. 1183 73

The stem cell factor/c-kit tyrosine kinase receptor pathway has been shown to be important for tumor growth and progression in several cancers, including mast cell diseases, gastrointestinal stromal tumor, acute myeloid leukemia, small cell lung carcinoma, and Ewing sarcoma. Studies using the oral agent STI-571 (Gleevec, Novartis), an inhibitor of the tyrosine kinases bcr-abl, c-kit, and PDGFR, have shown significant responses in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. With the aim of identifying additional groups of tumors that may use the stem cell factor/c-kit pathway and secondarily may be responsive to STI-571 treatment, this study surveyed 151 primary tumors from patients treated at St. Jude Children's Research Hospital for immunohistochemical expression of c-kit. Formalin-fixed, paraffin-embedded sections were stained with rabbit polyclonal anti-human c-kit (CD117, Dako) using standard avidin-biotin-peroxidase complex technique, antigen retrieval, and an automated stainer. Strong, diffuse staining for c-kit was seen in a proportion of synovial sarcomas, osteosarcomas, and Ewing sarcomas. Strong, diffuse staining was less common in neuroblastomas, Wilms' tumors, and rhabdomyosarcomas and was negative in alveolar soft part sarcomas and desmoplastic small round cell tumors. Tumors with strong, diffuse staining for c-kit in a pattern similar to gastrointestinal stromal tumor may represent suitable targets for new therapeutic agents.
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PMID:C-kit expression in pediatric solid tumors: a comparative immunohistochemical study. 1191 27

This paper reviews data on the prognosis of gastrointestinal stromal tumors (GISTs). These tumors are specific KIT-expressing and KIT-signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. GISTs occur in the entire gastrointestinal (GI) tract and may also arise from the omentum, mesenteries, and retroperitoneum. They range from small benign tumors to sarcomas at all sites of occurrence. A KIT tyrosine kinase inhibitor, STI-571 (imatinib [Gleevec]; Novartis, Basel, Switzerland), has recently shown promise in the treatment of metastatic GISTs. Understanding the natural history of GIST before introduction of STI-571 will help assess the impact and position of this new treatment. The frequency of benign versus malignant GISTs varies between sites. Benign GISTs outnumber malignant GISTs in the stomach, whereas malignant GISTs are more common in the intestines. Tumors that have metastasized at presentation have a very poor prognosis. Traditionally, the 3 key prognostic factors have been mitotic rate, tumor size, and site. Tumors that are small (< or =2 cm) and show mitotic activity not exceeding 5 mitoses per 50 high-power fields (HPFs) have an excellent prognosis, probably independent of site, although this has not been shown specifically for all sites. In the stomach, most epithelioid GISTs are benign, provided that mitotic counts do not exceed 5/50 HPFs. However, a small proportion of tumors apparently lacking mitotic activity do metastasize. Tumors with a mitotic rate >5/50 HPFs usually have a malignant behavior. The Ki67 index may help identify tumors with malignant potential, but large site-specific series are not yet available. Genetic markers, including DNA-copy number changes, telomerase activity, and KIT mutation status, may be useful in more accurately identifying tumors with malignant potential.
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PMID:Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. 1209 72

This review examines how the identification of tumor-specific translocations and fusion proteins has advanced the basic scientific and clinical understanding of sarcomas. Recent genetic advances, including the ASPL-TFE3 fusion of alveolar soft part sarcoma, the JAZF1-JJAZ1 fusion of endometrial stromal sarcoma, and HMGIC fusions in liposarcoma, are discussed. Next, the review addresses the ways in which molecular genetic data have influenced diagnostic and prognostic paradigms. For example, recent studies describe the detection of occult tumor cells and the identification of primary renal neoplasms that are genetically related to alveolar soft part sarcoma. In addition, the review discusses potential therapies based on the targeting of sarcoma-specific fusion proteins. These reports describe the potential use of Gleevec (STI571) for dermatofibrosarcoma protuberans and the use of tumor-specific fusion proteins as potential targets for immunotherapy. Finally, basic scientific findings are reviewed that elucidate, for example, the aberrant functions of SYT-SSX in chromatin remodeling and of EWS-FLI1 in transcription and mRNA splicing. These and other emerging models of tumorigenesis will help identify new therapeutic targets.
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PMID:Chromosomal translocations and sarcomas. 1213 Sep 26

Over the past 15 years, numerous signal transduction pathways have been elucidated whose dysregulation may play an important role in the growth and survival of cancer cells. The success of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ), a small molecule that inhibits the activation of the BCR-Abl oncogene in the treatment of chronic myelogenous leukemia, has demonstrated how effective targeted strategies can be when properly applied. With the hope of selectively targeting other critical components of cancer growth and survival while minimizing toxicity to the host, numerous strategies have been developed to inhibit receptor tyrosine kinases for various growth factors commonly expressed by cancer cells. Success of targeted inhibitors is inherently dependent on the proper selection of patients whose tumors are dependent on these growth factor pathways. Unfortunately, in prostate cancer, such selection has been a difficult-to-impossible task to date. Because of the vast number of mutational events, it is difficult to demonstrate that any particular growth factor signaling pathway is critical. In addition, because of the type (mostly bone only) and nature (usually small foci) of metastases, limited access to tumor tissue in the advanced cancer population has hampered attempts to characterize patients by their molecular features or phenotype. This article will focus on defining alternative criteria for a rational drug target and novel study designs for testing these agents in prostate cancer. In particular, the neoadjuvant setting represents a unique opportunity for new drug development in prostate cancer. An example of a neoadjuvant study testing, imatinib mesylate, is presented to display the advantages and limitations of this study design.
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PMID:Receptor tyrosine kinases as rational targets for prostate cancer treatment: platelet-derived growth factor receptor and imatinib mesylate. 1223 Oct 66

Gastrointestinal stromal tumor (GIST) is a quite common gastrointestinal mesenchymal tumor entity that has been recently established by pathologists. The prediction of the biologic behavior of GISTs is relatively difficult. Recently, classifications of the biologic behavior of GISTs according to metastatic potential (low risk, intermediate, high risk) have been proposed. The gain-of function mutation of c-kit proto-oncogene has been detected in GISTs and its role in molecular pathogenesis of GIST has been established. Imatinib mesylate (formerly STI 571, Glivec, Novartis Pharmaceuticals Corp, Switzerland) inhibits the tyrosin-kinase activity of KIT receptor, and clinical trials for GIST are in progress. In the past, no effective drug was known for the treatment of GISTs. Recently, the effectiveness of Imatinib mesylate in patients bearing metastatic GISTs has been reported. The treatment and prognosis of GIST will change significantly in the coming few years, as the clinical application of Imatinib mesylate becomes more common. In the near future, the value of Imatinib mesylate as a post-operative adjuvant chemotherapy for patients with GISTs without metastasis should be studied, and the way to classify GISTs according to biologic behavior will become quite important.
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PMID:[Recent progress in gastrointestinal stromal tumor (GIST)]. 1235 34


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