Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c-kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain-of-function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germline mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR-ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule-based diagnosis and treatment of solid tumors.
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PMID:Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. 1282 97

Imatinib mesylate, an orally administered 2-phenylaminopyrimidine derivative that inhibits BCR/ABL tyrosine kinase activity, has shown great promise in the treatment of chronic myelogenous leukemia (CML). This small molecule, tyrosine kinase inhibitor, has also been shown to be effective against metastatic gastrointestinal stromal tumors (GISTs) expressing the stem cell factor (SCF) receptor kit. However, the threat of resistance in patients has prompted investigators to uncover the mechanisms whereby malignant cells develop resistance to imatinib, and has also led to the establishment of strategies designed to over-ride imatinib resistance. Here, we provide a comprehensive overview of the effectiveness of imatinib in the treatment of chronic, accelerated and blast crisis-phase CML, Philadelphia chromosome-positive (Ph+) acute lymphoid leukemia (ALL) and metastatic GIST. Established mechanisms of resistance to imatinib are discussed, as are novel therapeutic approaches to improving drug responsiveness by reversing development of imatinib resistance in patients.
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PMID:Resistance to imatinib (Glivec): update on clinical mechanisms. 1464 93

A number of agents targeting components of pathways and processes critical to neoplastic transformation and progression are ongoing clinical development. Notable successes include imatinib mesylate (STI571, Gleevec) in Chronic Myelogenous Leukemia (CML), and Gastrointestinal Stromal Tumors (GIST) and trastuzumab (Herceptin) in HER2 amplified breast carcinoma. More recently, gefitinib (ZD1839, Iressa) and bortezomib (PS-341, Velcade) have been approved for refractory nonsmall cell lung carcinoma (NSCLC) and multiple myeloma (MM), respectively. In addition, promising results from randomized studies of bevacizumab (Avastin) and cetuximab (IMC-225, Erbitux) have been reported and shortly may lead to their approval for the treatment of colorectal carcinoma (CRC). To what degree the success or failure of these agents has been due to target, the agent, the dose or the selection of patients is uncertain. Certainly, further evaluation of these factors is required to optimize the therapeutic impact of targeted agents and imaging modalities may play a vital role in this process. The purpose of this review is to summarize recent results from trials of selected targeted agents and to suggest roles imaging may play in the further development of these and other targeted agents.
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PMID:Recent advances of molecular targeted agents: opportunities for imaging. 1468 62

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, is thought to originate from the interstitial cells of Cajal. The mutation of c-kit, cording KIT, is essential in the development of GIST. Imatinib mesylate (IM), an agent for chronic myeloid leukemia, was reported to inhibit tyrosine kinase activity of KIT and to be highly effective for GIST. We report, here, a case of huge gastric GIST who underwent neoadjuvant therapy followed by surgical resection. The patient was a 62-year-old man with GIST in cardia (KIT+, CD34+, mitotic rate 5/50 HPF), whose chief complaint was general fatigue. Because the huge tumor, 7.5 cm in size, directly invaded the pancreas, total gastrectomy with distal pancreatosplenectomy was necessary for curative resection. IM was administered (400 mg/body/day) as a neoadjuvant treatment for down-staging of the tumor. Leucopenia (grade 2) and diarrhea (grade 1) were observed as the adverse effects of IM. Partial response was obtained. He underwent proximal gastrectomy without pancreatosplenectomy since CT no longer showed direct invasion to the pancreas. Histological examination of the resected specimen revealed the extensive degeneration of the tumor, in which tumor cells containing condensed nuclei had decreased remarkably. Interestingly, mitotic rate decreased to 0/50 HPF in the effective area of the resected specimen, indicating that recurrent risk might be decreased. A part of the viable tumor cells, however, had the same feature to that in the biopsied specimen before treatment. The results suggest that the heterogeneity of GIST induces different sensitivity to IM. The postoperative course was uneventful and no sign of recurrence was observed 3 months after surgery. Neoadjuvant therapy with IM may become a useful strategy for GIST, as it reduces the tumor size and decreases the recurrence rate.
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PMID:[A case of gastric GIST treated preoperatively by imatinib mesylate]. 1533 47

The proto-oncogene c-kit is a receptor tyrosine kinase recognized to initiate essential signal transduction pathways that transmit biological signals for cellular proliferation, differentiation, and metastasis. Aberrant expression or mutation of c-kit has been shown to be involved in the pathogenesis of many cancers. Studies using imatinib mesylate (STI 571, Gleevec, Novartis, East Hannover, NJ, USA), an inhibitor of the tyrosine kinases brc-abl, c-kit, and PDGFR, have shown significant response 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 imatinib mesylate treatment, we looked at the expression of c-kit in medulloblastoma. Medulloblastoma, a highly invasive primitive neuroectodermal tumor of the cerebellum, is the most common, malignant central nervous system tumor of childhood. Histologic features of medulloblastoma have failed to provide an accurate prediction of the clinical-biological behavior of these tumors. Characterizing the genetic events that play a role in the biology of these tumors may allow for molecular sub-typing and could lead to the development of novel therapeutic strategies. This study evaluated c-kit expression and mutational status in 10 medulloblastoma tumor samples. All 10 medulloblastoma tumors expressed c-kit by reverse transcriptase-polymerase chain reaction and 9 by immunohistochemical analysis. All tumor samples were screened for mutations in exons 9, 11, and 13 of the c-kit gene by direct sequencing. No sequence abnormalities were detected in these exons. These experiments lead us to the conclusion that c-kit activation in medulloblastoma is independent of mutation.
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PMID:C-kit expression and mutational analysis in medulloblastoma. 1554 73

Among gynecologic malignancies, ovarian carcinoma is the most frequent cause of death, with the majority of patients presenting at advanced stage. There is a high rate of recurrence despite first-line chemotherapy. Sarcoma of the uterus, while accounting for a small percent of uterine cancers, is also associated with a high-recurrence rate and poor overall survival. Therefore, the development of novel treatment strategies is paramount. Imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a tyrosine kinase inhibitor with activity against abl, c-kit, and platelet derived growth factor receptor (PDGFR), and is approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor. Preclinical data provides evidence for c-kit and PDGFR expression in ovarian epithelial carcinomas and uterine sarcomas and have led to clinical trials evaluating the use of imatinib in these malignancies. Additionally, inhibition of PDGFR signaling has been proposed as an effective mechanism of chemotherapy by lowering tumor interstitial fluid pressure. Recent data have also suggested benefit with metronomic scheduling of cytotoxic agents at lower doses at more frequent dosing intervals, in combination with other targeted therapies. While activity of this agent remains to be established, further studies of imatinib in gynecologic malignancies are warranted, to demonstrate not only single-agent activity and the enhancement of cytotoxicity of other antineoplastic agents.
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PMID:Imatinib mesylate and its potential implications for gynecologic cancers. 1571 93

The term "targeted cancer therapies" refers to treatment strategies designed to inhibit the product of an oncogene involved in the process of neoplastic transformation. Different categories of targeted therapies can be identified: 1) Therapies directed at oncogenes that are directly involved in the initiation of neoplastic transformation: the use of imatinib for the treatment of CML or GIST is the classical model in this subgroup. Single agent targeted therapies generally produce high response rates in this situation. 2) Therapies directed at oncogenes involved at a later stage of neoplastic transformation. These oncogenes contribute to tumor progression but not necessarily to the onset of malignant transformation. The use of trastuzumab for HER2-amplified breast adenocarcinoma is the classical model in this subgroup. These treatments are associated with low response rates when used as single agent therapy, whereas generally displaying a synergistic or additive effect with classical chemotherapy in models currently available. In contrast, when these targeted therapies are applied to tumor models where the targeted gene is present but not directly involved in the process of malignant transformation, no antitumor efficacy is generally observed. Recently, the identification of HER1 mutations in subsets of lung carcinoma as a predictive factor for response to gefitinib and erlotinib provided an example of how the empiric use of a targeted treatment may enable to identify new nosological entities. The present paper reviews examples of targeted cancer therapies and their results.
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PMID:Targeted cancer therapies. 1574 38

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Pancreatic cancer (PanC) is an extremely lifethreatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well.
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PMID:Genomics of pancreatic cancer: does it make any improvement in diagnosis, prognosis and therapy? 1599 49

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Activating mutations of KIT or the platelet-derived growth factor receptor alpha gene (PDGFRA) have been identified in the vast majority of GISTs. The respective oncoproteins exhibit constitutive tyrosine kinase activity and promote cell growth. KIT and PDGFRA mutations are rarely found in GISTs in patients with neurofibromatosis type 1 (NF1) suggesting that the pathogenesis of GIST in NF1 patients is different from that in non-NF1 patients. Endoscopic diagnosis of GIST is usually difficult. Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNAB) is a useful method for the diagnosis of GIST and for the detection of KIT or PDGFRA mutations. Imatinib mesylate, a tyrosine kinase inhibitor known to inhibit the activities of BCR-ABL, KIT, and PDGFR, is currently being used for the treatment of both chronic myeloid leukemia and metastatic GIST. The clinical response to imatinib therapy correlates with the types of mutations of KIT and PDGFRA, and the determination of KIT and PDGFRA mutations is useful for predicting the effect of imatinib. Resistance to imatinib after an initial response has been reported; secondary point mutations in KIT or PDGFRA that confer imatinib resistance are the most common mechanisms responsible for acquired resistance to imatinib. The continued development of target-specific therapies should increase the probability of cure in most patients with GISTs.
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PMID:Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors. 1614 81


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