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)

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in at least 50% of sporadic clear-cell renal cell carcinoma (RCC). This leads to a pseudohypoxic state in which the pVHL complex does not degrade hypoxia-inducible factor. Subsequent intracellular hypoxia-inducible factor accumulation results in increased production of growth factors such as VEGF, responsible for angiogenesis, tumor proliferation and mitogenesis. Recently, a number of strategies have been designed to specifically target these pathways. The VEGF, its related receptor and the mammalian target of rapamycin (mTOR) signal transduction pathway, in particular, have been utilized as therapeutic targets. Clinical trials have demonstrated the survival benefit of these agents, particularly in clear-cell RCC. Today, sunitinib is recommended as first-line therapy for intermediate- or low-risk patients with metastatic RCC. Sorafenib is advised as second-line therapy, whereas temsirolimus is generally recommended as first-line treatment in high-risk patients. Everolimus is the new standard following sunitinib. High-risk patients appeared to benefit less than low-risk patients from bevacizumab plus IFN-alpha therapy. High-dose IL-2 has been proven effective in prolonging progression-free survival or overall survival, depending on risk group selection criteria. Although novel agents show a consistent effect as measured by objective response, no currently available data demonstrate that these agents will cure any patient.
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PMID:Systemic therapy of kidney cancer: tyrosine kinase inhibitors, antiangiogenesis or IL-2? 1966 36

The past 5 years were marked by fundamental changes in the systemic therapy of metastatic renal cell carcinoma. Up to the end of the last decade cytokine-based chemotherapy was the only, even if only moderately effective systemic therapy for metastatic renal cell carcinoma. Currently there are five new approved drug releases of so-called targeted substances, which function on a molecular based therapeutic mechanism. Sunitinib (Sutent) and sorafenib (Nexavar) as multikinase inhibitors, everolimus (Afinitor) and temsirolimus (Torisel) as mTOR inhibitors, and bevacizumab as an antibody against VEGF in combination with interferon-alpha (IFN-alpha). The following article will give an overview of the currently available substances and critically discuss therapy plans and future trends.
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PMID:[Current state of systemic therapy of metastatic renal cell carcinoma]. 1966 18

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignant tumors predominantly arising from the embryonic mesoderm. The mainstay of curative therapy is the complete surgical resection of all tumor manifestations with negative histological margins. However, up to 50% of patients will develop distant metastases during the course of their disease. The prognosis for those patients is grim with a 5-year overall survival of less than 10%. First-line systemic therapy with ifosfamide and doxorubicin results in overall response rates of only 20% by conventional response evaluation criteria in solid tumors (RECIST). However, stabilization of disease can be seen in a greater proportion. Therefore, the role of the RECIST criteria has been questioned and the implementation of new imaging studies (e.g., FDG-PET) has shown promising results in assessing early tumor response to therapy. Furthermore, a broader insight into the molecular pathways of sarcomagenesis has been gained in recent years, revealing intriguing targets for new therapeutic approaches (e.g., VEGF, VEGF receptor, IGF receptor, EGF receptor, mTOR and cyclin-dependent kinases). In addition, a growing body of evidence is linking specific genetic aberrations with clinical outcome (e.g., SYT-SXX translocation in synovial sarcoma). With further insight into the biology of STS and the combination of new treatment options with modern imaging techniques, we will most certainly be able to improve clinical outcome in patients with STS in the upcoming years.
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PMID:New medical treatment options and strategies to assess clinical outcome in soft-tissue sarcoma. 1967 Oct 35

Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia, while the inhibition of NOR-1 increased cell apoptosis. Hypoxia upregulated NOR-1 mRNA levels in a time- and dose-dependent manner. Blocking antibodies against VEGF or SU5614 (a VEGF receptor 2 inhibitor) did not prevent hypoxia-induced NOR-1 expression, suggesting that NOR-1 is not induced by the autocrine secretion of VEGF in response to hypoxia. The reduction of HIF-1 alpha protein levels by small interfering RNAs, or by inhibitors of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 upregulation. Intracellular Ca(2+) was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 upregulation. A hypoxia response element mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, the attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 overexpression upregulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia.
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PMID:The hypoxia-inducible factor 1/NOR-1 axis regulates the survival response of endothelial cells to hypoxia. 1972 Jul 40

The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC). Everolimus (RAD 001) is an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1) conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P </= 0 0.001). Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.
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PMID:Role of everolimus in the treatment of renal cell carcinoma. 1977 11

Breast cancer is a heterogeneous disease characterised by a dysregulation of multiple pathways related to cell differentiation, cell cycle control, apoptosis, angiogenesis and development of metastasis. Acting against these pathways provides therapeutic targets for new targeted biologic therapies, which, in the future, might constitute a key for fighting cancer. The development of molecular technology in recent years has allowed a further comprehension of these mutations and dysregulated pathways leading to oncogenesis. New targeted biologic therapies will block essential functions of cancer cells and tumour stroma. A growing number of therapy options, alone or in combination with background treatments (chemotherapy, hormone therapy, radiotherapy), will allow oncologists a better adaptation of treatment to patients and disease characteristics. Examples of approved targeted agents in breast cancer include agents targeting the human epidermal growth factor receptor 2 (HER2), such as trastuzumab, lapatinib and the anti-VEGF bevacizumab. In addition, there are other therapy classes under evaluation, including novel antiEGFR or antiHER2 therapies; agents fighting other tyrosine kinases, including the Src and the insulinlike growth factor receptor; agents interfering critically relevant pathways, such as PI3K/AKT/mTOR inhibitors; and agents promoting apoptosis, such as PARP inhibitors (for particular breast cancer subtypes, such as basal-like, or breast cancer with BRCA mutations) and others. The better selectivity against malignant cells of these therapies, when compared to conventional chemotherapy, gives, a priori, at least two advantages to biologic treatments: fewer side effects and a more individualised treatment of cancer depending on the tumour's molecular characteristics. The ability to identify patients' subgroups and response predicting factors will be crucial in obtaining the greatest benefit with minimal toxicity levels. Unsolved questions remain, such as appropriate patient selection based on the expression of the therapeutic target in the tumour, the study of the efficacy of the drug in not so extensively pretreated populations and with a greater chance of response, the use of new pharmacodynamic models to help to define new response predicting factors for a specific new biologic therapy, the combined and rational use of different biologic therapies having different molecular targets and fighting the same target through a complementary mechanism of action that might improve clinical efficacy.
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PMID:Targeted therapy of metastatic breast cancer. 1982 6

The prefrontal cortex has been implicated in schizophrenia (SZ) and affective disorders by gene expression studies. Owing to reciprocal connectivity, the thalamic nuclei and their cortical fields act as functional units. Altered thalamic gene expression would be expected to occur in association with cortical dysfunction. We screened the expression of the entire human genome of neurons harvested by laser-capture microdissection (LCM) from the thalamic primary relay to dorsolateral prefrontal cortex in three psychiatric disease states as compared with controls. Microarray analysis of gene expression showed the largest number of dysregulated genes was in SZ, followed by major depression (MD) and bipolar mood bipolar (BP) (1152, 385 and 288, respectively). Significantly, IGF1-mTOR-, AKT-, RAS-, VEGF-, Wnt- and immune-related signaling, eIF2- and proteasome-related genes were unique to SZ. Vitamin D receptor and calcium signaling pathway were unique to BP. AKAP95 pathway and pantothenate and CoA biosynthesis were unique to MD. There are significant differences among the three psychiatric disorders in MDNp cells. These findings offer new insights into the transcriptional dysregulation in the thalamus of SZ/BP/MD subjects.
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PMID:Thalamic transcriptome screening in three psychiatric states. 1983

Sarcomas are a group of heterogeneous tumors that arise from mesenchymal tissue and account for approximately 1% of all adult solid malignancies diagnosed, although its incidence approaches 20% in pediatric cancers. Characterization of molecular abnormalities in patients with sarcomas, in particular the up-regulation of the receptor tyrosine kinase and the PI3K-AKT-mTOR pathway, loss or deletions of retinoblastoma (Rb) and p53 gene, increased VEGF expression and angiogenesis, dysregulation of apoptosis through Bcl-2 overexpression, along with oncogene mutations and activations, such as c-KIT in Gastrointestinal stromal tumors (GISTs), makes treatment with novel biological therapies a promising option. This review focuses on the molecular heterogeneity of soft tissue and bone sarcomas, novel biological therapies currently in clinical trials to target the various molecular pathways, and the potential biological agents in pre-clinical and early clinical development.
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PMID:Targeting sarcomas: novel biological agents and future perspectives. 1986 Jun 42

Sunitinib demonstrating efficacy in pancreatic islet cell carcinomas will pave the way for further trials in other neuroendocrine tumor types such as carcinoid, poorly differentiated neuroendocrine disease, and several other endocrine tumors that are dependent on VEGF/VEGFR for angiogenesis. In addition, other drugs with distinct mechanisms of action, such as mTOR inhibitors, currently investigated in phase III trials, may also supply novel options in those diseases to control tumor growth and metastasis.
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PMID:Sunitinib paves the way for targeted therapies in neuroendocrine tumors. 1991 Nov 11

Ovarian cancers are the leading cause of death from gynaecological malignancies in Western countries. Despite optimal treatment combining surgery and chemotherapy, relapse is observed in the majority of patients. This review aims to present the results of trials having evaluated new drugs in ovarian cancers. Advances in the understanding of cancer biology and more specifically of cell signalling pathways have led to the identification of several potential molecular targets and to the development of new agents directed against these targets. The assessment of targeted therapies is relatively recent in this field. So far, only the results of phase II trials have been published, but many phase III trials are underway. Some targets (HER-2, EGFR) initially regarded as promising have already been abandoned due to the lack of results. The most advanced molecular therapies target angiogenesis (VEGF, VEFGR). PARP and mTOR inhibitors may also represent a significant therapeutic improvement. It remains to confirm the interest of these new approaches by assessing the benefit on overall survival. The goal remains to individualize and to tailor the drugs to the tumour biology, in order to provide personalized treatment to each patient.
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PMID:[New drugs and targeted therapeutic agents in ovarian cancer]. 1991 16


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