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 prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials.
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PMID:Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells. 1950 44

Highly tumorigenic cancer cell (HTC) populations have been identified for a variety of solid tumors and assigned stem cell properties. Strategies for identifying HTCs in solid tumors have been primarily empirical rather than rational, particularly in epithelial tumors, which are responsible for 80% of cancer deaths. We report evidence for a spatially restricted bladder epithelial (urothelial) differentiation program in primary urothelial cancers (UCs) and in UC xenografts. We identified a highly tumorigenic UC cell compartment that resembles benign urothelial stem cells (basal cells), co-expresses the 67-kDa laminin receptor and the basal cell-specific cytokeratin CK17, and lacks the carcinoembryonic antigen family member CEACAM6 (CD66c). This multipotent compartment resides at the tumor-stroma interface, is easily identified on histologic sections, and possesses most, if not all, of the engraftable tumor-forming ability in the parental xenograft. We analyzed differential expression of genes and pathways in basal-like cells versus more differentiated cells. Among these, we found significant enrichment of pathways comprising "hallmarks" of cancer, and pharmacologically targetable signaling pathways, including Janus kinase-signal transducer and activator of transcription, Notch, focal adhesion, mammalian target of rapamycin, epidermal growth factor receptor (erythroblastic leukemia viral oncogene homolog [ErbB]), and wingless-type MMTV integration site family (Wnt). The basal/HTC gene expression signature was essentially invisible within the context of nontumorigenic cell gene expression and overlapped significantly with genes driving progression and death in primary human UC. The spatially restricted epithelial differentiation program described here represents a conceptual advance in understanding cellular heterogeneity of carcinomas and identifies basal-like HTCs as attractive targets for cancer therapy.
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PMID:Differentiation of a highly tumorigenic basal cell compartment in urothelial carcinoma. 1954 56

Several selected targeted agents are being investigated in combination with endocrine therapy for patients with breast cancer in an attempt to overcome or prevent endocrine resistance. The role of type I growth factor receptors epidermal growth factor receptor (EGFR) and HER2 in cross-talk with estrogen receptor (ER) signaling has been confirmed in preclinical studies in which various inhibitors have yielded additive or synergistic effects when combined with endocrine agents. Recently, several results from clinical trials investigating this concept have been reported. In ER-positive/HER-positive advanced breast cancer, the addition of trastuzumab to the aromatase inhibitor anastrozole, or the tyrosine kinase inhibitor (TKI) lapatinib to letrozole, both have significantly improved progression-free survival (PFS). The EGFR TKI gefitinib combined with tamoxifen as first-line therapy for ER-positive metastatic disease improved PFS (but not objective response rate) for patients with no previous endocrine therapy or completion of previous adjuvant therapy. A second study in a similar setting showed significant improvement in PFS for gefitinib plus anastrozole. Although it is encouraging that this approach could delay resistance, only a small proportion of patients benefit. Attempts to identify likely responders have been made in the neoadjuvant setting, with pre- and post-treatment biopsies being used to study biomarker changes. A recent preoperative study of letrozole with or without the mammalian target of rapamycin (mTOR) inhibitor everolimus reported greater tumor shrinkage for the combination, with changes in proliferation being predictive for response together with strong expression of protein S6 kinase, a downstream marker of activated mTOR. Key aspects that need to be addressed in future trials include understanding the mechanisms of action for each novel agent, designing the best trial and endpoints to demonstrate added benefit, and ensuring appropriately stratified populations based on previous endocrine exposure and/or sensitivity.
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PMID:Enhancing the efficacy of hormonal agents with selected targeted agents. 1956 Oct 4

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).
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PMID:Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. 1956 54

The epidermal growth factor receptor (EGFR) is dysregulated in various tumour types such as glioblastoma multiforme (GBM), breast cancer, ovarian carcinoma, non-small cell lung cancer and other cancers. As the intracellular tyrosine kinase of the EGFR activates signalling cascades leading to cell proliferation, angiogenesis and inhibition of apoptosis, the EGFR represents an attractive target in cancer therapy. In GBM which is the most common primary central nervous system tumour in adults, the EGFR is overexpressed in about 40 to 50% of cases, and almost half of these co-express the mutant receptor subtype EGFRvIII. This EGFR variant is constitutively activated, and thereby may contribute to the aggressive and refractory course of GBM which is associated with a median survival of only 40 to 60 weeks from diagnosis. Various trials are ongoing focusing on EGFR and EGFRvIII as new therapeutic targets in GBM. Anti-EGFR monoclonal antibodies (MAbs), e.g. cetuximab, and tyrosine kinase inhibitors (TKIs), e.g. erlotinib and gefitinib, are the most advanced in clinical development. Several trials are investigating MAbs or TKIs in combination with other agents such as inhibitors of the mammalian target of rapamycin. Other still preliminary approaches targeting the EGFR are small interfering RNA, antisense RNA and ribozymes, which lead to degradation of EGFR mRNA. Further studies are needed to define their clinical potential, to identify biological predictors of response and thus to characterize subgroups of patients who will benefit from treatment with these new agents.
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PMID:The epidermal growth factor receptor as a therapeutic target in glioblastoma multiforme and other malignant neoplasms. 1960 50

To gain the insight into the involvement of signaling mediated by the mammalian target of rapamycin (mTOR) in the phenotype and biological profiles of tumors and tumor-like lesions of the bone and soft tissue, we analyzed the expression and phosphorylation (activation) of mTOR and its correlation with the status of upstream and downstream modulator proteins Akt, p70S6-kinase (S6K), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), which we refer to collectively as mTOR cassette proteins. Immunohistochemical analysis of 140 cases showed activation of Akt in 55% (61% in malignant and 27% in benign), and mTOR expression in 61% (66% in malignant and 39% in benign). The preponderance of mTOR activation was found in tumors of peripheral nerve sheath (malignant peripheral nerve sheath tumor and schwannoma), skeletal muscle origin (rhabdomyosarcoma), and in those exhibiting epithelial nature (chordoma and synovial sarcoma). Together with the result of immunoblotting analysis, it was shown that many of those particular tumors with mTOR activation exhibited activation of Akt, S6K, and 4E-BP1, suggesting the constitutive activation of the Akt/mTOR pathway. In addition, although activation of the Akt/mTOR pathway was largely independent of activation of epidermal growth factor receptor (EGFR), mutation of EGFR was frequently accompanied by constitutive activation of Akt-mTOR-S6K/4E-BP1. By clinicopathological analysis, activation of Akt correlates with statistically higher probability of metastasis. We conclude that mTOR-mediated signaling proteins function not only in the proliferation of the tumor cells, but also in the differentiation and/or maintenance of morphological phenotypes in tumors of rhabdomyoblastic and nerve sheath cell origin. Furthermore, mTOR signaling may also modulate morphogenesis of tumors exhibiting epithelial nature. Additionally, activated Akt may have a function in metastasis. Overall, these results suggest that inhibitors of mTOR cassette may be useful as novel components of combined chemotherapy for a defined subset of bone and soft tissue sarcomas.
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PMID:EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors. 1964 84

The anti-epidermal growth factor receptor monoclonal antibodies cetuximab and panitumumab have established efficacy as single agent and in combination with chemotherapy in advanced colorectal cancer. However, only a small percentage of unselected patients (around 10%) are responsive to these costly agents. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab and account for approximately 30% to 40% of resistant patients. Nevertheless, having an intact KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Further, positive predictive markers that are currently being evaluated include an increase in EGFR gene copy number and additional data suggest that other EGFR downstream pathways such as the PI3K/PTEN/AKT/mTOR and JAK/STAT pathways are also important when considering mechanisms of EGFR antibody resistance. New data seem to support the role of BRAF mutational status. In addition, high mRNA levels of the EGFR-ligands Epiregulin and Amphiregulin have been associated with increased responsiveness to cetuximab. In this article we will review the available clinical and experimental data potentially useful for a better patients' selection.
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PMID:Anti-EGFR therapy in colorectal cancer: how to choose the right patient. 1966 67

Aberrant genetic alternations in human gliomas, such as amplification of epidermal growth factor receptor, mutation and/or deletion of tumor suppressor gene PTEN, and mutations of PIK3CA, contribute to constitutive activation of the phosphatidylinositol 3-kinase (PI3K) pathway. We investigated the potential antitumor activity of NVP-BEZ235, which is a novel dual PI3K/mammalian target of rapamycin (mTOR) inhibitor in gliomas. The compound suppressed glioma cell proliferation with IC(50) values in the low nanomolar range by specifically inhibiting the activity of target proteins including Akt, S6K1, S6, and 4EBP1 in the PI3K/Akt/mTOR signaling pathway. NVP-BEZ235 treatment of glioma cell lines led to G(1) cell cycle arrest and induced autophagy. Furthermore, expression of the vascular endothelial growth factor (VEGF), which is an important angiogenic modulator in glioma cells, was significantly decreased, suggesting that NVP-BEZ235 may also exert an antiangiogenic effect. Preclinical testing of the therapeutic efficacy of NVP-BEZ235 showed that it significantly prolonged the survival of tumor-bearing animals without causing any obvious toxicity. Tumor extracts harvested from animals after treatment showed that the compound inhibited the activity of target proteins in the PI3K/Akt/mTOR cascade. Immunohistochemical analyses also showed a significant reduction in staining for VEGF von Willebrand factor (factor VIII) in NVP-BEZ235-treated tumor sections compared with controls, further confirming that NVP-BEZ235 has an antiangiogenic effect in vivo. We conclude from these findings that NVP-BEZ235 antagonizes PI3K and mTOR signaling and induces cell cycle arrest, down-regulation of VEGF, and autophagy. These results warrant further development of NVP-BEZ235 for clinical trials for human gliomas or other advanced cancers with altered PI3K/Akt/mTOR signaling.
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PMID:NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. 1967 62

Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor kappaB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.
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PMID:Novel targeted therapeutics for metastatic castration-resistant prostate cancer. 1971 25

Abnormal expression of Aurora-A and epidermal growth factor receptor (EGFR) is observed in different kinds of cancer and associated with poor prognosis in cancer patients. However, the relationship between Aurora-A and EGFR in tumour development was not clear. In previous reports, we found that EGFR translocates to nucleus to activate Aurora-A expression after EGF treatment in EGFR-overexpressed cells. However, we also observed that not all the EGFR-overexpressed cells have the nuclear EGFR pathway to mediate the Aurora-A expression. In this study, we demonstrated that EGF signalling increased the Aurora-A protein expression in EGFR-overexpressed colorectal cancer cell lines via increasing the translational efficiency. In addition, the overexpression of EGFR was also associated with higher expression of Aurora-A in clinical colorectal samples. Activation of the PI3K/Akt/mTOR and MEK/ERK pathways mediated the effect of EGF-induced translational up-regulation. Besides, only the splicing variants containing exon 2 of Aurora-A mRNA showed increased interaction with the translational complex to synthesize Aurora-A protein under EGF stimulus. Besides, the exon 2 containing splicing variants were the major Aurora-A splicing forms expressed in human colorectal cancers. Taken together, our results propose a novel regulatory mechanism for the abnormal expression of Aurora-A in EGFR-overexpressed cancers, and highlight the importance of alternative 5'-UTR splicing variants in regulating Aurora-A expression. Furthermore, the specific expression of exon 2 containing splicing variants in cancer tissues may serve as a potential target for cancer therapy in the future.
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PMID:Translational up-regulation of Aurora-A in EGFR-overexpressed cancer. 1979 48


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