Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian target of rapamycin (mTOR) is thought to play a critical role in regulating cell growth, cell cycle progression, and tumorigenesis. Because the AKT-mTOR pathway is frequently hyperactivated in ovarian cancer, we hypothesized that the mTOR inhibitor RAD001 (Everolimus) would inhibit ovarian tumorigenesis in transgenic mice that spontaneously develop ovarian carcinomas. We used TgMISIIR-TAg transgenic mice, which develop bilateral ovarian serous adenocarcinomas accompanied by ascites and peritoneal dissemination. Fifty-eight female TgMISIIR-TAg mice were treated with 5 mg/kg RAD001 or placebo twice weekly from 5 to 20 weeks of age. To monitor tumor development, mice were examined biweekly using magnetic resonance microimaging. In vivo effects of RAD001 on Akt-mTOR signaling, tumor cell proliferation, and blood vessel area were analyzed by immunohistochemistry and Western blot analysis. RAD001 treatment markedly delayed tumor development. Tumor burden was reduced by approximately 84%. In addition, ascites formation, together with peritoneal dissemination, was detected in only 21% of RAD001-treated mice compared with 74% in placebo-treated animals. Approximately 30% of RAD001-treated mice developed early ovarian carcinoma confined within the ovary, whereas all placebo-treated mice developed advanced ovarian carcinoma. Treatment with RAD001 diminished the expression of vascular endothelial growth factor in tumor-derived cell lines and inhibited angiogenesis in vivo. RAD001 also attenuated the expression of matrix metalloproteinase-2 and inhibited the invasiveness of tumor-derived cells. Taken together, these preclinical findings suggest that mTOR inhibition, alone or in combination with other molecularly targeted drugs, could represent a promising chemopreventive strategy in women at high familial risk of ovarian cancer.
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PMID:RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. 1736 57

Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with RAD001.
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PMID:Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. 1848 11

Phosphorylated (pi-) protein kinase B (AKT) is commonly expressed in nasopharyngeal carcinoma (NPC) cell lines and tissues, suggesting the involvement of AKT-mammalian target of rapamycin (mTOR) signaling in NPC carcinogenesis. This study evaluated the activity of an mTOR inhibitor, RAD001 (Everolimus, Novartis Pharma AG, Switzerland), in 5 NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1), 2 cisplatin-resistant NPC cell lines and their respective parental cell lines (HK1-LMP1, HONE-1-EBV). RAD001 inhibited cell growth in a dose-dependent manner at nanomolar concentrations in all cell lines. HONE-1 was most sensitive to RAD001 (IC(50) = 0.63 nM, 60% maximal inhibition), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant. No consistent relationship between sensitivity to RAD001 and basal expression of pi-mTOR and pi-p70S6 Kinase-1 (p70S6K) was found. Exposure to RAD001 at picomolar concentrations for 48 h resulted in reduction of pi-mTOR and pi-p70S6K1 expression, but increase in pi-AKT (Ser473) expression in HONE-1 and CNE-1 cell lines. RAD001 significantly induced apoptosis in HONE-1 cells, but has no effect on cell cycle progression. RAD001 exerted an additive to synergistic effect on cisplatin-induced growth inhibition in CNE-1 and HONE-1 cells, and could inhibit the growth of both cisplatin-resistant and cisplatin-sensitive NPC cell lines. In summary, combination of RAD001 and cisplatin maybe a useful therapeutic strategy in NPC. AKT upregulation following RAD001 treatment suggests the presence of a feedback loop on AKT signaling in NPC which warrants further investigation.
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PMID:The activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell lines. 1947 57

The mammalian target of rapamycin(mTOR)and its molecular pathways are supposed to be activated frequently in human renal cell carcinoma as well as other cancers. It has a kinase activity for 40S ribosomal protein kinase and eukaryotic translation initiation factor 4E-binding protein 1. These proteins, when phosphorylated, promote protein translation and RNA transcription in the nutrient-rich condition. mTOR inhibitors such as Temsirolimus (CCI779) and Everolimus (RAD001) are effective for suppressing cell growth with inhibiting mTOR kinase activity. Rapamycin and its related analogs such as Temsirolimus and Everolimus are less toxic for humans compared with other anti-VEGFR inhibitors and has been used as an immunosuppressive agent. These agents have an inhibitory activity against the mTORC1 complex. Since they do not have inhibitory activity against mTORC2 complex, the ability of mTOR inhibition by Temsirolimus is supposed to be 40 to 50% of full inhibition in mTOR kinase. Temsirolimus has modest anticancer activity against advanced clinical RCC patients with poor risk. The objective response rate was only 7%, 26% of patients experienced minor responses and another 17% of patients had stable disease that lasted 6 months. The median time to tumor progression and median survival for the study patients were 5.8 and 15.0 months, respectively. The overall survival of patients treated with Temsirolimus alone was statistically longer than in those treated with IFN alone in the 626 cases in phase II study. Combinations of mTOR with other anti- VEGFR agents were not effective. Vertical therapies of mTOR inhibitor in combination with AKT inhibitors, or newly development of stronger mTOR kinase which can suppress both mTORC1 and mTORC2 are planned at present.
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PMID:[Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]. 1962 Jul 95

Bronchial carcinoids (BCs) are rare tumors originating from endocrine cells dispersed in the respiratory epithelium. It has been previously demonstrated that everolimus, or RAD001, an mTOR inhibitor, has potent antiproliferative effects in human endocrine tumors. Our aim was to evaluate the possible antiproliferative effects of everolimus in human BCs in primary culture. We collected 24 BCs that were dispersed in primary cultures, treated without or with 1 nM-1 muM everolimus, 10 nM SOM230 (pasireotide, a somatostatin receptor multiligand), and/or 50 nM IGF1. Cell viability was evaluated after 48 h, and chromogranin A (CgA) as well as vascular endothelial growth factor (VEGF) secretion was assessed after 8 h incubation. Somatostatin receptors, mTOR, and AKT expression were investigated by quantitative PCR. We found that in 15 cultures (67.5%), everolimus significantly reduced cell viability (by approximately 30%; P<0.05 versus control), inhibited p70S6K activity (-30%), and blocked IGF1 proliferative effects. Everolimus also significantly reduced CgA (by approximately 20%) and VEGF (by approximately 15%) secretion. Cotreatment with SOM230 did not exert additive effects on cell viability and secretory activity. AKT expression was similar in responder and nonresponder tissues, while mTOR expression was significantly higher in the responder group, which was characterized by higher CgA plasma levels and bigger tumors with higher mitotic index and angiogenesis. Our data demonstrate that everolimus reduces VEGF secretion and cell viability in BCs with a mechanism likely involving IGF1 signaling, suggesting that it might represent a possible medical treatment for BCs.
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PMID:Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids. 2055 86

Inhibitors of the mammalian target of rapamycin (mTOR) have entered the landscape of treatment for advanced RCC. Their development has been based on their unique biology and their potential to simultaneously inhibit both tumor cell proliferation and angiogenesis. Despite the solid biologic rationale for their development, existing clinical data is somewhat mixed. Although Temsirolimus is capable of improving overall survival it does so only in a minority of selected mRCC patients and its effects on tumor burden reduction and PFS are minimal. Similarly the activity and clinical utility of Everolimus in the refractory setting is questionable. First, because it is unknown if mTOR becomes the major driver or cancer growth after developing progressive disease on a VEGF inhibitor and secondly because existing sequential VEGF data in same setting appears to be the same if not a bit more robust to that reported with Everolimus. Combination of mTOR and VEGF inhibitors has been disappointing due to the excessive toxicities encountered in early trials without a noticeable difference in efficacy. Efforts are now placed in a series of novel compounds capable of inhibiting mTOR and the upstream signaling pathway of PI3K/AKT.
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PMID:Therapeutic rationale for mTOR inhibition in advanced renal cell carcinoma. 2182 95

Recent evidence has suggested that breast cancer contains a rare population of cells called cancer stem cells (CSCs), which have an extensive self-renewal ability and contribute to metastasis and therapeutic resistance. This study evaluated the in vitro and in vivo effects of RAD001 (Everolimus) alone or in combination with docetaxel on stem cells from primary breast cancer cells and two breast cancer cell lines (MCF-7 and MDA-MB-231). In In vitro studies, we sorted ESA(+)CD44(+)CD24(-/low) cells as stem cells using flow cytometry from primary breast cancer cells, MCF-7 and MDA-MB-231 cell lines. MTT assays were used to quantify the inhibitory effect of the drugs on total cells and stem cells. Apoptosis and the cell cycle distributions of stem cells were examined by flow cytometry. The tumourigenicity of stem cells after treatment was investigated by soft agar colony formation assays. In In vivo studies, the BALB/c mice were injected with MDA-MB-231 stem cells and the different treatments were administered. After necropsy, the expression of Ki67, CD31, AKT1, and phospho-AKT (Thr308) was analysed by immunohistochemistry. In In vitro studies, all three populations of stem cells were resistant to the standard treatment doses of docetaxel compared with total cells treated with the same drug. Treatment with RAD001 resulted in growth inhibition of all stem cells in a dose-dependent manner. An additive growth inhibitory effect of the combination treatment on the three stem cells was observed in in vitro compared with treatment with RAD001 alone (P<0.001). In addition, an increase in G2/M cell cycle arrest and an increased population of cells in early apoptosis were seen in the combination treatment group compared with either single-agent group (P<0.01). In vivo, the volumes of the xenograft tumours significantly decreased in RAD001 alone group compared to control group (P=0.008), and RAD001 plus docetaxel therapy was much more effective at reducing tumour volume in mice compared with either single-agent alone (P<0.05). Compared with RAD001 alone, the combination of RAD001 and docetaxel reduced the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308) (P<0.05). We conclude that the combination treatment of RAD001 and docetaxel can inhibit the growth of stem cells in vitro and in vivo by inhibiting cell proliferation, inducing apoptosis, cell cycle arrest and reducing the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308). These data indicate that combination treatment with RAD001 and docetaxel may represent an effective therapy for breast cancer. However, further studies are required to evaluate the drug interaction between RAD001 and docetaxel in the clinical setting.
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PMID:Effects of the combination of RAD001 and docetaxel on breast cancer stem cells. 2242 Sep 43

This study evaluated the effects of a mammalian target of mTOR inhibitor everolimus alone or in combination with trastuzumab on stem cells from HER2-overexpressing primary breast cancer cells and the BT474 breast cancer cell line in vitro and in vivo. For the in vitro studies, we sorted ESA(+)CD44(+)CD24(-/low) cells as stem cells from primary breast cancer cells and BT474 cells using flow cytometry. The MTT assay was used to quantify the inhibitory effect of the drugs on total cells and stem cells specifically. Stem cell apoptosis, cell cycle distributions, and their tumorigenicity after treatment were investigated by flow cytometry or soft agar colony formation assays. For the in vivo studies, BALB/c mice were injected with BT474 stem cells, and the different treatments were administered. After necropsy, the expression of Ki67, CD31, AKT1, and phospho-AKT (Thr308) was analyzed by immunohistochemistry. For the in vitro studies, Treatment with everolimus resulted in stem cell growth inhibition in a dose-dependent manner. The combination of everolimus with trastuzumab was more effective at inhibiting cell growth (P < 0.001) and tumorigenicity (P < 0.001) compared with single-agent therapy. In addition, an increase in G1 cell cycle arrest and an increased population of cells in early apoptosis were seen in the combination treatment group compared with either of the single-agent groups (P < 0.01). For the in vivo studies, everolimus plus trastuzumab therapy was much more effective at reducing tumor volume in mice compared with either single agent alone (P < 0.05). Compared with everolimus alone, the combination of everolimus and trastuzumab reduced the expression of Ki67, AKT1, and phospho-AKT (Thr308) (P < 0.05). We conclude that everolimus has effective inhibitory effects on HER2-overexpressing stem cells in vitro and vivo. Everolimus plus trastuzumab is a rational combination treatment that may be promising in human clinical trials.
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PMID:Antitumor effect of the mTOR inhibitor everolimus in combination with trastuzumab on human breast cancer stem cells in vitro and in vivo. 2249 37

Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal-dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions.
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PMID:Molecular therapies for tuberous sclerosis and neurofibromatosis. 2254 7

Carcinoid tumors are relatively indolent, but the treatment of advanced disease remains a challenge. Liver-directed therapies are a consideration in patients with liver-dominant disease. Somatostatin analogs (SSTa) are routinely used to control hormone-mediated symptoms (carcinoid syndrome), but the identification of systemic agents with antitumor efficacy has proven difficult. Aside from octreotide for small bowel carcinoid (which is associated with delayed progression), no treatment has proven antitumor activity. Chemotherapy seems to be of limited value. The role of interferon is also controversial; it is typically used after failure of octreotide. Peptide receptor radionuclide therapy may have activity in patients with SST receptor-expressing tumors, but randomized controlled trials are lacking. Advances in the understanding of the mechanisms underlying tumor progression have led to the identification of several potential therapeutic targets (including the vascular endothelial growth factor [VEGF] and mammalian target of rapamycin [mTOR] signaling pathways), but none has been definitively validated in carcinoid. Everolimus is associated with a trend toward improved progression-free survival in patients with progressive carcinoid, but is not approved for this indication. Therefore, a serious unmet need remains for additional therapeutic strategies for patients with advanced disease. Several avenues are under study, including the use of novel SSTa; VEGF and mTOR inhibitors; and agents that interfere with insulin growth factor 1 receptor and AKT signaling. Moving forward, optimizing patient selection based on clinical features or biomarkers holds promise for identifying individuals most likely to benefit from therapy.
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PMID:Systemic therapy for advanced carcinoid tumors: where do we go from here? 2267 20


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