Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 37-year-old man was diagnosed with metastatic dermatofibrosarcoma. Dermatofibrosarcoma protuberans is a rare skin tumour with a strong tendency for infiltrative growth, resulting in a high rate of local recurrences; metastatic disease develops in approximately 5% of patients, especially in the lungs. On the basis of some recent publications about the use of imatinib in patients with dermatofibrosarcoma, the patient was prescribed this drug. The treatment resulted in a partial response. Imatinib is the first registered selective tyrosine-kinase inhibitor for treatment of chronic myeloid leukaemia. The inhibition of tyrosine kinase interrupts the proliferative signal transduction.
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PMID:[Good response to treatment with the selective tyrosine-kinase inhibitor imatinib in a patient with metastatic dermatofibrosarcoma protuberans]. 1460 47

Scientific knowledge on gastrointestinal stromal tumors (GIST) has dramatically progressed over the last 10 years. During this period, this distinct disease entity was identified under various acronyms (GIST remaining the most commonly used), the molecular basis of disease transformation (i.e. activating c-KIT mutations) was identified in sporadic and familial cases, and finally GIST was identified as the sarcoma subtype most resistant to chemotherapy in both retrospective and prospective studies. Until 2000, surgery was the only reported efficient treatment modality in this disease, both in the localized and metastatic phase. In 2000, the first GIST patient received Glivec, and in the last 3 years, more than 2,000 patients were included in prospective trials evaluating this compound in advanced phases. Disease control is initially achieved in 80-90% of patients, with only 10-15% of patients dying in the first year following the occurrence of metastases, while the median overall survival was less than 12 months with previous treatment options. However, there still remain several questions regarding long-term outcome, tolerance, cure, dose of Glivec, and alternative treatment upon relapse of GIST in patients receiving Glivec. Additional follow-up is necessary. Glivec treatment of GIST is the first example of an efficient targeted treatment in a solid tumor.
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PMID:Gastrointestinal stromal tumors: biology and treatment. 1465 91

Recent significant advances in understanding the biology of gastrointestinal stromal tumours (GIST) have led to the introduction of a new targeted therapy (imatinib mesylate, Glivec). Hopes of a new era of a specific cancer therapy, however, have been tempered by the recognition that a significant proportion of patients who initially respond to the drug eventually become resistant to it. Given the successful development of peptide receptor scintigraphy and radiotherapy for neuroendocrine tumours, we postulated that a similar approach could offer a valid alternative in the diagnosis and therapy of GIST. Using in vitro receptor autoradiography to measure peptide receptors, we found that 16/19 GIST expressed bombesin subtype 2 receptors, 16/19 expressed vasoactive intestinal peptide subtype 2 receptors (VPAC(2)) and 12/19 expressed cholecystokinin subtype 2 receptors, in most cases in extremely high densities. All GIST metastases were shown to express two or more of these peptide receptors in very high density. Receptors were also expressed in non-responders to Glivec or after chemo-embolisation. Conversely, somatostatin subtype 2, cholecystokinin subtype 1, bombesin subtype 1 and 3, and neuropeptide Y subtype Y(1) and Y(2) receptors were not or only rarely expressed. These data represent a strong molecular basis for the use of radiolabelled bombesin, vasoactive intestinal peptide and/or cholecystokinin analogues as targeting agents to localise GIST tumours in patients by in vivo scintigraphy and/or to perform targeted radiotherapy to destroy GIST primaries, metastases and recurrences, including those resistant to Glivec.
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PMID:High expression of peptide receptors as a novel target in gastrointestinal stromal tumours. 1498 69

The Kit receptor tyrosine kinase is a transmembrane receptor that is expressed in a variety of different tissues and mediates pleiotropic biological effects through its ligand stem cell factor (SCF). Sporadic mutations of Kit as well as autocrine/paracrine activation mechanisms of the SCF/Kit pathway have been implicated in a variety of malignancies, where its primary contribution to metastases is in enhancing tumor growth and reducing apoptosis. For example, Kit is frequently mutated and activated in gastrointestinal stromal tumors (GISTs) and there is ligand-mediated activation of Kit in some lung cancers. Kit is a convenient target in Kit-induced tumors and inhibition of this receptor with the small molecule drug Gleevec (imatinib mesylate, STI571) in GIST has shown dramatic efficacy. Unfortunately, past experience has demonstrated that chemotherapy of cancers with a single drug often leads to resistance of the cancer. Further understanding of the molecular mechanisms underlying Kit-mediated transformation is therefore important and may lead to the identification of further novel drug targets. These Kit-specific signaling pathways may then be targeted to overcome potential drug resistance. This review will focus on our understanding of the molecular mechanisms involved in transformation by Kit. The potential mechanisms by which Kit induces cellular transformation are described. We will also discuss the role and expression of Kit in various malignancies. Ultimately, the understanding of c-Kit biology, biochemistry, and mutational analysis will lead to better therapeutics.
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PMID:Targeting c-Kit mutations: basic science to novel therapies. 1503 37

Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST). With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (chi2=13.844, P=0.001). In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.
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PMID:Increased c-kit (CD117) expression in malignant mammary phyllodes tumors. 1504 24

The vast majority of mesenchymal tumors originating from the GI tract consists of gastrointestinal stromal tumors (GIST), an entity just recently defined. The incidence is estimated to be around 10 - 20/1000000, the median age at diagnosis has been reported to be 55 to 65 years. GISTs most commonly occur in the stomach or duodenum, followed by the small intestine. About half of the patients present with metastatic disease at first diagnosis, predominantly in the liver or periteneum. GISTs are strongly and uniformly positive for CD117 (c-kit), a type III receptor-tyrosine kinase. Kit mutations, mostly in exon 11, leading to ligand independent constitutive activation are supposed to play a major role in the pathogenesis of GIST. Until recently no active systemic treatment was available for advanced gastrointestinal stromal tumors. Imatinib (STI571 = Glivec) is a rationally designed, orally available phenylaminopyrimidin analogue. The mechanism of action consists of a competitive interaction with the ATP-binding pocket of specific tyrosine kinases. Early results from clinical trials with response rates around 60 % and progression arrest in more than 80 % of patients resulting in fast relief of symptoms, confirm the high activity of this novel treatment. The role of adjuvant treatment after potentially curative resection of GIST is currently evaluated in ongoing clinical trials. Patients with progressive disease while under treatment with Imatinib should be enrolled in studies testing novel treatment strategies as RAD001, PKC412 or SU11 248.
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PMID:[Gastrointestinal stromal tumors (GIST)]. 1509 24

Gastrointestinal stromal tumor (GIST) is a neoplasm of the gastrointestinal tract, mesentery, or omentum that expresses the protein-tyrosine kinase KIT (CD117) and is the most common mesenchymal tumor arising at these sites. Surgical resection is the first-line intervention for operable GISTs, particularly localized primary tumors, and it was historically the only effective treatment. However, more than half of all GIST patients present with locally advanced, recurrent, or metastatic disease. The 5-year survival rate ranges from 50% to 65% after complete resection of a localized primary GIST and decreases to approximately 35% for patients with advanced disease who undergo complete surgical resection. A total of 40% to 90% of all GIST surgical patients subsequently have postoperative recurrence or metastasis. Imatinib is a potent, specific inhibitor of KIT that has demonstrated significant activity and tolerability in the treatment of malignant unresectable or metastatic GIST, inducing tumor shrinkage of 50% or more or stabilizing disease in most patients. A key strategy for prolonging the survival of patients with GIST is to improve the outcome of surgery. It is possible that the adjuvant and neoadjuvant use of imatinib (e.g., rendering initially inoperable tumors resectable) in the overall management approach to advanced GIST may contribute to surgeons' success in attaining this objective.
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PMID:Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. 1512 59

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract characterized by the expression of a receptor that activates tyrosine kinase called c-kit. Since malignant GISTs are resistant to conventional radiation therapy and chemotherapy, recurrent or malignant GIST has an extremely poor prognosis even after surgical resection. The development of a tyrosine kinase inhibitor, STI571 (imatinib mesylate, Glivec, Gleevec), 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 metastatic disease. We report a patient with GIST and diffused peritoneal metastases, whose tumor initially responded to STI571 and eventually became resistant. A 45-year-old woman underwent partial jejunostomy on September 3, 1998, under a diagnosis of submucosal tumor of the jejunum. Pathological examination of the primary tumor revealed a strong c-kit expression and GIST was diagnosed. The patient underwent an excision of peritoneal recurrences on October 31, 2000; April 17, 2001; and August 28, 2001. A treatment with STI571 (400 mg/day) was initiated on October 15, 2001, and she was free from peritoneal masses for 8 months after the fourth operation. However, the patient herself suspended the STI571 therapy for one month and multiple peritoneal metastases developed. Although the treatment with STI571 was restarted at 400 mg/day, the peritoneal masses did not respond this time. She died of liver, lung, and peritoneal metastases after the seventh cytoreductive operation on February 11, 2004. Several mechanisms of the resistance to STI571 have been identified. Amplification or an overexpression of KIT has been proposed to be involved in the resistance development. Several mutations of KIT were also correlated with the clinical outcome. Her tumors showed mutations in exons 9 or 11 of KIT, which had longer event-free and overall survival times than those tumors that had mutations of exons 13 or 17. In this case, an exon 11 mutation of KIT was initially noted. After the interruption of the treatment, an additional point mutation arose in exon 13 that caused a resistance to STI571. Currently STI571 is the first-line therapy for non-resectable GISTs, but a single-agent therapy often leads to tumor resistance. It is our hope that we will be able to design an alternative treatment to overcome such resistance.
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PMID:[A case of metastatic gastrointestinal stromal tumor developing a resistance to STI571 (imatinib mesylate)]. 1555 17

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of gastrointestinal tract. The tumors express the cell surface transmembrane receptor KIT that has a tyrosine kinase activity and is a protein product of KIT protoeoncogene. These tumors occur in the whole of Gastrointestinal tract. Treatment includes surgical resection for localized tumors. For metastatic disease treatment options include systemic chemotherapy, radiation therapy, with a response rate of less than 10%. Presently Imatinib; a tyrosine kinase inhibitor has shown promising result with response rates upto 59-69% in phase II results in metastatic setting; and ongoing phase II & phase III trials in adjuvant setting will help to establish its role as an adjuvant to surgery. We have treated eleven patients of metastatic GIST with Imatinib and we hereby present these cases.
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PMID:Imatinib in gastrointestinal stromal tumors. 1565 32

Gastrointestinal stromal tumours (GIST), previously classified as smooth muscle tumours, are the most common mesenchymal tumours of the digestive tract. Since the discovery of KIT (CD 117) expression, these tumours can be diagnosed confidently by pathology. Until recently, surgery was the only treatment available because these tumours were not sensitive to chemotherapy nor radiation therapy. In the long run most of these tumours recurred in the abdominal cavity or in the liver. Recently a new drug STI 573 (Glivec) showed very promising results in metastatic disease with response rates of about 65%. In six patients treated at our center, surgery was indicated during STI therapy because of subobstruction, skin necrosis, abdominal distention, bleeding. Surgery proved to be safe and efficient, allowing continuation of STI therapy in much better circumstances.
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PMID:Surgical interventions during STI 571 treatment of metastatic GIST: experience in six patients. 1566 75


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