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

Sirolimus, and its antiproliferative capacity, was studied in vivo in three different syngenic rat tumours in the liver. Sirolimus is an inhibitor of the cytosolic mTOR-kinase, associated with the phosphoinositide-3-kinase/Akt pathway. After one week of daily sirolimus treatment, initiated on the day of tumour-cell inoculation, a dose-response relationship was shown at doses between 0.01 mg/kg/day and 1 mg/kg/day, decreasing tumour weight from 0.5+/-0.1 g in control rats (n=9) to 0.09+/-0.04 g for sirolimus 1 mg/kg (n=9). Treating established liver adenocarcinoma (n=15), sirolimus halved the tumour weight (1.4+/-0.2 g vs 0.7+/-0.1 g, p=0.005). Trough concentration in blood was 6.4+/-0.2 ng/ml after five days of daily treatment with 1 mg/kg sirolimus intraperitoneally. At this dose, there was no decrease in food consumption or rat weight, but decrease in weight of spleen, and increase in weight of liver (p<0.01). The three tumours studied, an nitrosoguanidin-induced adenocarcinoma, a Leydig cell sarcoma and a hepatoma, all responded, establishing sirolimus as a promising anticancer drug.
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PMID:Inhibition of mTOR suppresses experimental liver tumours. 1586 10

Rhabdomyosarcoma is the most common pediatric soft-tissue sarcoma, which includes two major subtypes, alveolar and embryonal rhabdomyosarcoma. The mechanism of its oncogenesis is largely unknown. However, the oncogenic process of rhabdomyosarcoma involves multi-stages of signaling protein dysregulation characterized by prolonged activation of tyrosine and serine/threonine kinases. To better understand this protein dysregulation, we evaluated the phosphorylation profiles of multiple tyrosine and serine/threonine kinases to identify whether these protein kinases are activated in rhabdomyosarcoma. We applied immunohistochemistry with phospho-specific antibodies to examine phosphorylation levels of selected receptor and non-receptor tyrosine kinases, mammalian target of rapamycin (mTOR), p70S6K, and protein kinase C (PKC) isozymes on alveolar and embryonal rhabdomyosarcoma tissue microarray slides. Our results showed that the phosphorylation levels of these kinases are elevated in some rhabdomyosarcoma tissues compared to normal tissues. Phosphorylation levels of receptor and non-receptor tyrosine kinases are elevated between 26 and 68% in alveolar rhabdomyosarcoma and between 24 and 71% in embryonal rhabdomyosarcoma, respectively, compared to normal tissues. In addition, phosphorylation levels of mTOR and its downstream targets, p70S6K, S6, and 4EBP1, are increased between 50 and 72% in both subtypes of rhabdomyosarcoma. Further, phosphorylation levels of PKCalpha, PKCdelta, PKCtheta, and PKCzeta/lambda are upregulated between 57 and 69% in alveolar rhabdomyosarcoma and between 43 and 72% in embryonal rhabdomyosarcoma. This is the first report to create a phosphorylation profile of tyrosine and serine/threonine kinases involved in the mTOR and PKC pathways of alveolar and embryonal rhabdomyosarcoma. These protein kinases may play roles in the development or tumor progression of rhabdomyosarcomas and thus may serve as novel targets for therapeutic intervention.
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PMID:Phosphorylation profiles of protein kinases in alveolar and embryonal rhabdomyosarcoma. 1758 18

Bone and soft tissue sarcomas represent rare tumors that can be cured by local treatment at early stages of disease. However, advanced or metastatic disease is rarely cured, and very few drugs have shown efficacy in this setting. Early studies with mTOR inhibitors have demonstrated antitumor activity in patients with metastatic sarcoma who failed previous chemotherapies. The response rate and durable stable disease in early studies, as well as the tolerability profile, recommend these drugs as promising candidates for further clinical studies. This article discusses preliminary results from clinical trials in patients with advanced or metastatic sarcoma as well as future perspectives.
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PMID:The role of mTOR inhibitors for treatment of sarcomas. 1758 57

The mammalian target of rapamycin (mTOR) is a protein kinase that plays a pivotal role in the control of cell growth and development. A part of the PI3K/Akt pathway, mTOR responds to growth factor stimuli as well as nutrient availability by variations in downstream phosphorylation. Increasing knowledge of the upstream regulators and downstream targets of mTOR has led to the development of anticancer drugs that suppress protein synthesis and metabolism. Rapamycin (sirolimus) and three rapamycin analogues are currently being evaluated in clinical trials: temsirolimus (CCI-779, Wyeth), everolimus (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals Inc.). This review will highlight the role of these inhibitors in the treatment of sarcoma.
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PMID:Mechanisms of mammalian target of rapamycin inhibition in sarcoma: present and future. 1802 23

Lung cancer is a genetically heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling cascades. These pathways intersect at various points, rendering this network highly redundant and suggesting that combined mitogen-activated protein/extracellular signal-regulated kinase (MEK) and mammalian target of rapamycin (mTOR) inhibition may be a promising drug combination that can overcome its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor, rapamycin, or its analogue AP23573, exhibited dose-dependent synergism in human lung cancer cell lines that was associated with suppression of proliferation rather than enhancement of cell death. Concurrent suppression of MEK and mTOR inhibited ribosomal biogenesis by 40% within 24 h and was associated with a decreased polysome/monosome ratio that is indicative of reduced protein translation efficiency. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone or PD0325901 at the maximum tolerated dose in nude mice bearing human lung tumor xenografts or heterotransplants. Except for a PTEN mutant, all tumor models had sustained tumor regressions and minimal toxicity. These data (a) provide evidence that both pathways converge on factors that regulate translation initiation and (b) support therapeutic strategies in lung cancer that simultaneously suppress the RAS and AKT signaling network.
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PMID:Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. 1805 56

Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n=6) or tumor recurrence/metastasis (n=14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (> or =20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The high-expression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (P< or =0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.
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PMID:Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy. 1815 89

Tuberous sclerosis (TS), neurological disorder manifesting with the formation of tumors in numerous organ systems, is a disease associated with the upregulation of mammalian target of rapamycin (mTOR) pathway. It has been found that in healthy individuals two tumor suppressor genes, TSC1 and TSC2, encoding proteins called hamartin and tuberin, respectively, are responsible for the control over mTOR kinase. Loss of one of these genes constitutes the genetic background of TS. In the current study, we aimed at evaluating the fitness of the only TS-associated sarcoma cell line deposited in American Tissue Culture Collection, TSC2ang1, for the in vitro studies on TS. We found that the line shows a stable chromosome pattern with typical Robertsonian translocations. Similarly to primary tumors from TS patients, TSC2ang1 cells respond to rapamycin-induced mTOR inhibition. The cells demonstrate activation of both Akt and Erk pathways, but inhibition of neither of them is as effective as mTOR suppression when considering proliferation potential. Based on these results we propose TSC2ang1 as a good and stable model for pathophysiological and pharmacological studies on skin lesions in TS.
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PMID:Tuberin-heterozygous cell line TSC2ang1 as a model for tuberous sclerosis-associated skin lesions. 1820 92

Soft tissue sarcomas are a heterogeneous group of tumours arising predominantly from the embryonic mesoderm. They account for less than 1% of all adult malignancies. The prognosis of patients with advanced metastatic soft tissue sarcoma remains poor with a disease-free survival at 5 years less than 10%. Despite improvements in local tumour control due to surgery and radiotherapy, distant metastasis and death remain a significant problem in 50% of patients. Complete resection remains the major factor in providing cure with limited benefits in local tumour control by radiotherapy and only minimal benefit of systemic therapy for metastatic disease. Only few chemotherapeutic agents have been identified to be active with reported response rates for doxorubicin and ifosfamide around 20%. New strategies are urgently needed to improve patients' outcome. Progress in the molecular characteristics, the understanding of biology and pathogenesis of these tumours has been made and should in the near future translate into molecularly based therapies. We describe current treatment strategies and existing standards. Moreover, we give an overview on the emerging compounds for patients with soft tissue sarcoma including recent developments of targeted therapy focusing on antiangiogenic and immunomodulatory drugs, Bcl-2 antisense therapy, raf kinase and mTOR inhibition, minor groove binders, and other agents being developed.
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PMID:Standards and novel therapeutic options in the treatment of patients with soft tissue sarcoma. 1847 6

A 66-year old female with HIV-negative classic Kaposi's sarcoma responded to mTOR targeting by rapamycin. The response was well documented by PET-CT. This case provides supporting evidence that the mTOR pathway may be important in the tumorigenesis of KS and that rapamycin may have activity in this disease.
Sarcoma 2008
PMID:Targeting mTOR in HIV-Negative Classic Kaposi's Sarcoma. 1850 82

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


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