Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrointestinal stromal tumors (GISTs) are rare tumors of the wall of the stomach and small bowel, and also occasionally arise in the mesentery, omentum, or retroperitoneum. The incidence of GIST in the United States is approximately 500 to 750 patients per 100,000 people. GISTs often present late in their clinical course unless they are the cause of gastrointestinal bleeding or perforation. Surgical resection is the standard of care for primary GIST. However, there is a high risk of recurrence in the peritoneum and liver. For metastatic GIST, imatinib mesylate is the standard of care. Two phase III studies presented in 2003 in abstract form show slightly different results. In the US study, 400 mg/d was found to be equivalent to 800 mg/d with respect to response, progression-free survival, and overall survival at 12 months. In the European/Australasian study, the response rate was the same with either dosage, but progression-free survival was better with 800 mg/d compared with 400 mg/d. Overall survival data for the latter study were too immature for analysis as of May 2003. Adjuvant or neoadjuvant therapy with imatinib is the topic of at least three studies through the American College of Surgeons Oncology Group and Radiation Therapy Oncology Group and the American College of Radiology Imaging Network. Every effort to enroll eligible patients on these studies should be made. New treatments for metastatic disease under investigation include a tyrosine kinase inhibitor with an expanded panel of targets compared with imatinib (SU011248), and the addition of a mammalian target of rapamycin (mTOR) inhibitor and the rapamycin derivative RAD001 to imatinib. Given the finding of a specific molecular defect to exploit, GISTs have gone from an orphan disease to a proving ground for tyrosine kinase-targeted therapy.
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PMID:Gastrointestinal Stromal Tumors Respond to Tyrosine Kinase-targeted Therapy. 1472 34

ZD6474 (Zactima, AstraZeneca, Macclesfield, UK) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases, with additional activity versus rearranged during transfection (RET). This study explored the effect of ZD6474 in gastrointestinal stromal tumor-T1 (GIST-T1) cells that possess a gain of function mutation in exon 11 of the c-KIT gene. ZD6474 induced growth arrest and apoptosis of GIST-T1 cells in association with blockade of c-Kit and its downstream effectors, including Akt and extracellular signal-regulated kinase (ERK). ZD6474 treatment also blocked the mammalian target of rapamycin (mTOR), which lies downstream of Akt and ERK. Interestingly, when ZD6474 was combined with sunitinib (SU11248; Sutent, Pfizer, Kalamazoo, MI, USA), a class III and V receptor tyrosine kinase inhibitor, the ZD6474-mediated growth inhibition was potentiated in association with further down-regulation of the mTOR targets p-p70S6K and p-4E-BP-1. The combination of ZD6474 and sunitinib should be investigated further.
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PMID:ZD6474 induces growth arrest and apoptosis of GIST-T1 cells, which is enhanced by concomitant use of sunitinib. 1699 74

Most gastrointestinal stromal tumor (GIST) patients respond to KIT inhibition with imatinib, yet will eventually exhibit resistance. Imatinib-resistance mechanisms are heterogeneous, and little is known about KIT functional roles in imatinib-resistant GIST. Biological consequences of biochemical inhibition of KIT, phosphatidyl-inositol-3-kinase (PI3-K), PLCgamma, MAPK/ERK kinase/mitogen-activated protein kinase (MEK/MAPK), mammalian target of rapamycin (mTOR) and JAK were determined by immunoblotting for protein activation, and by cell proliferation and apoptosis assays in GIST cell lines from imatinib-sensitive GIST (GIST882), imatinib-resistant GISTs (GIST430 and GIST48) and KIT-negative GIST (GIST62). KIT activation was 3- to 6-fold higher in GIST430 and GIST48 than in GIST882, whereas total KIT expression was comparable in these three GIST lines. In addition to the higher set point for KIT activation, GIST430 and GIST48 had intrinsic imatinib resistance. After treatment with 1 muM imatinib, residual KIT activation was 6- and 2.8-fold higher in GIST430 and GIST48, respectively, compared to GIST882. In all GIST lines, cell growth arrest resulted from PI3-K inhibition, and - to a lesser extent - from MEK/MAPK and mTOR inhibition. Inhibition of JAK/STAT or PLCgamma did not affect cell proliferation. Similarly, only PI3-K inhibition resulted in substantial apoptosis in the imatinib-resistant GISTs. We conclude that GIST secondary KIT mutations can be associated with KIT hyperactivation and imatinib resistance. Targeting critical downstream signaling proteins, such as PI3-K, is a promising therapeutic strategy in imatinib-resistant GISTs.
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PMID:KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. 1754 49

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, and it is characterized by the occurrence, in > 90 % of cases, of a gain of function mutation in the c-kit proto-oncogene. STI-571 (imatinib mesylate), a selective KIT tyrosine kinase inhibitor, has changed the natural history of this disease, since it has shown high effectiveness in metastatic GIST, and it is currently under investigation also in the adjuvant and neoadjuvant setting. Mechanisms of resistance to imatinib mesylate include both de novo, and, more frequently, acquired resistance, which may occur after several months of drug administration and possibly depends, in most cases, upon an acquired second mutation. In order to overcome imatinib mesylate resistance, the addition of other drugs may be considered in patients who have less than an optimal response to imatinib mesylate monotherapy. Investigational agents that are being studied in this setting include the mammalian target of rapamycin (mTOR) inhibitor RAD 001 and the protein kinase C inhibitor PKC412. In addition, other KIT tyrosine kinase inhibitors with anti-VEGF receptor inhibitory activity, such as SU11248, PTK787/ZK787 and AMG 706, are currently being explored as second line monotherapy for imatinib mesylate-resistant GIST. Finally, another new drug, ecteinascidin (ET-743), that blocks cell cycle progression in G2/M phase through a p53-independent apoptotic mechanism, has shown important preclinical and clinical activity against a number of human solid tumors, including GIST.
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PMID:Medical treatment of gastrointestinal stromal tumors: state of the art and future perspectives. 1839 78

Gastrointestinal stromal tumors (GISTs) comprise a recently defined entity of the most common mesenchymal neoplasms of the gastrointestinal tract. Advances in the understanding of the molecular mechanisms of GIST pathogenesis have resulted in the development of a treatment approach which has become a model of targeted therapy in oncology. The introduction of imatinib mesylate (inhibiting KIT/PDGFRA (platelet-derived growth factor receptor-alpha) and their downstream signaling cascade) has revolutionized the therapy of advanced (inoperable and/or metastatic) GISTs. Imatinib has now become the standard of care in the treatment of patients with advanced GIST. However, a majority of patients eventually develop clinical resistance to imatinib. Over the last few years major progress has been made in elucidating the mechanism of disease progression (as secondary mutations in KIT and/or PDGFRA kinase domains) and resistance to imatinib. Currently, the sole approved second-line drug is sunitinib--a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET). However, a number of new generation tyrosine kinase inhibitors, alone or in combination, are being evaluated at present alongside treatment options alternative to inhibiting the KIT signaling pathway (as heat shock protein 90 or mammalian target of rapamycin). This article discusses the factors relating to imatinib resistance as well as upcoming potentially effective treatment options for patients with progressive disease available in 2008 and those under investigation with more individualized treatment methods, which has been recently patented. This review focuses on the current achievements in targeted therapy of advanced GISTs, and how the insight into the resistance mechanisms may allow in the near future to treat patients with advanced GISTs.
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PMID:Developments in targeted therapy of advanced gastrointestinal stromal tumors. 1853 51

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

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract and is associated with mutations of the KIT or PDGFRA gene. In addition, other genetic events are believed to be involved in GIST tumorigenesis. Cytogenetic aberrations associated with these tumors thus far described include loss of 1p, 13q, 14q, or 15q, loss of heterozygosity of 22q, numeric chromosomal imbalances, and nuclear/mitochondrial microsatellite instability. Molecular genetic aberrations include loss of heterozygosity of p16(INK4A) and p14(ARF), methylation of p15(INK4B), homozygous loss of the Hox11L1 gene, and amplification of C-MYC, MDM2, EGFR1, and CCND1. GISTs in patients with neurofibromatosis type 1 appear to lack the KIT and PDGFRA mutations characteristic of GISTs and may have a different pathogenetic mechanism. Gene mutations of KIT or PDGFRA are critical in GISTs, because the aberrant versions not only are correlated with the specific cell morphology, histologic phenotype, metastasis, and prognosis, but also are the targets of therapy with imatinib and other agents. Furthermore, specific mutations in KIT and PDGFR appear to lead to differential drug sensitivity and may in the future guide selection of tyrosine kinase inhibitors. Activation of the receptor tyrosine kinases involves a signal transduction pathway whose components (mitogen-activated protein kinase, AKT, phosphoinositide 3-kinase, mammalian target of rapamycin, and RAS) are also possible targets of inhibition. A new paradigm of classification, integrating the standard clinical and pathological criteria with molecular aberrations, may permit personalized prognosis and treatment.
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PMID:Genetic aberrations of gastrointestinal stromal tumors. 1867 Dec 47

Gastrointestinal stromal tumors (GISTs) generally arise from primary activating mutations in the KIT or PDGFRA genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib provides targeted therapy for GIST by inhibiting the KIT and PDGFR-alpha tyrosine kinases. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease, with a median progression-free survival of 20 to 24 months. The mechanisms of acquired resistance to imatinib are heterogeneous, with most involving the emergence of secondary mutations in KIT exons 13, 14, or 17. In patients failing or intolerant to imatinib, the multitargeted agent sunitinib achieves durable disease control in approximately 50% of cases. Experimental treatment options beyond those currently available consist of other KIT-targeting tyrosine kinase inhibitors, such as nilotinib, or agents targeting alternative pathways, such as antiangiogenic agents, mammalian target of rapamycin, RAF kinase, and chaperone inhibitors.
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PMID:Novel approaches to imatinib- and sunitinib-resistant GIST. 1877 61

Treatment of patients affected by advanced or inoperable GIST was revolutionized by the use of the tyrosine kinase inhibitors. Despite the fact that most patients have a good durable response of disease, they develop a resistance to treatments after a median time of 24 months. The acquired resistance is an emerging aspect in medical oncology especially in the era of target therapies. The aim of this review is to report all known mechanisms of secondary resistance to tyrosine kinase inhibitors and to highlight their clinical implications. In general, they may be divided in mechanisms related to the acquisition of new molecular abnormalities associated to KIT and PDGFRA receptor signalling pathway, such as the loss of KIT expression, the genomic amplification of KIT, the activation of an alternative downstream signalling pathways such as AKT/mTOR and the acquisition of new receptor mutations, and other mechanisms different to KIT/PDGFRA receptors. Future research perspectives on target therapy and early resistance evaluation are also discussed.
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PMID:Mechanisms of secondary resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumours (Review). 1942 10

The recent progress of the biology of the locally aggressive sarcomas of soft tissues and related connective tissue tumors enabled to reclassify molecular and histological entities of the disease. Six subgroups of sarcomas are identified with specific molecular alterations, the targeted treatments of which are the object of this article: 1) sarcomas with specific translocations with fusion oncogenes (DFSP, PVNS); 2) sarcomas with tyrosine kinase mutations (KIT in GIST); 3) tumors with deletion of tumor suppressor genes (TSC in the PEComes, NF1 involved in type 1 neurofibromatosis; 4) sarcomas with MDM2/CDK4 amplification in the 12q13-15 amplicon, i.e. well differentiated or dedifferentiated liposarcomas; 5) sarcomas with complex genetics present more unrefined genetic changes (leiomyosarcomas, osteosarcomas). On top these 5 groups, desmoids tumors characterized by alterations of the Wnt, beta catenin, APC, and giant cell tumors of the bone, in which RANK/RANKL operates a complex interaction between the cellular stroma and giant tumor cells. The identification of these abnormal ways of road marking to licence the development of effective targeted therapeutic agents against certain rare histological connective subcategories of sarcomas and tumors with local aggressiveness, in particular DFSP, PVNS, GCST, PEComes, endometrial stromal sarcomas, Ewing sarcomas, etc. Imatinib is used in the treatment of DFSP, characterized by a translocation of the gene PDGF, or in pigmented villonodular synovitis (PVNS), a tumor of soft part also locally aggressive, caused by an abnormality of the gene coding for the M-CSF. Several clinical trials of phase I and II trials demonstrated the antitumor activity of anti-IGF1R antibodies in Ewing, whose fusion gene downregulates IGFBP3. Inhibitors of MDM2 are in the course of clinical evaluation in liposarcomas. Inhibitors of mTOR (sirolimus, temsirolimus) demonstrated an antitumoral activity in the PEComas. The molecular characterization of sarcomas allowed to develop therapeutic targeted to correct the responsible abnormalities. Translational research is and will be an essential tool for the development of new treatments and the identification of the mechanisms of answer and resistance set up by these tumors.
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PMID:[Targeted treatment of rare connective tissue tumors and sarcomas]. 2049 11


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