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)

The last few years have seen a significant increase in our understanding of the molecular pathways governing cell function in cancer. This has led to an explosive interest in novel molecularly-targeted agents and, until recently, the focus of research effort has been to combine these agents with conventional cytotoxic chemotherapy. However, following a recent trial of an anti-EGFR targeted antibody in combination with radiation, a new paradigm is emerging in which these novel agents will be combined with external beam radiotherapy (RT). In this article we review classes of novel targeted radiosensitisers that are directed at specific aspects of cell function. Such agents are aimed at either single or multiple targets (the latter is a more attractive approach in view of cross-talk between different cell signaling pathways). We review available preclinical and clinical literature with a particular focus on novel agents targeting components of the ErbB and IGF-1R family cell signaling pathways. In this model, radiosensitisers can exert their effects at the cell membrane surface by preventing receptor activation or by interfering with the function of second messengers such as the Ras/PI3K/mTOR pathway. In addition, the effects of novel DNA repair inhibitors will be considered in the context of combination strategies with signal transduction pathway blockade. Other small molecule inhibitors, such as HSP90 inhibitors, that can disrupt signaling in a number of different pathways, will also be discussed. Ultimately, through the synergistic use of these innovative molecules and RT, the therapeutic index may be enhanced by modulating cellular metabolism, proliferation, repair, angiogenesis, and apoptosis. The rapid proliferation of available targeted agents and their entry into phase I clinical trials means that this is an extremely interesting area for research in radiation oncology.
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PMID:Novel targeted radiosensitisers in cancer treatment. 1951 37

Molecularly targeted therapies are transforming the care of patients with malignant gliomas, including glioblastoma, the most common malignant primary brain tumor of adults. With an arsenal of small molecule inhibitors and antibodies that target key components of the signal transduction machinery that are commonly activated in gliomas, neuro-oncologists and neurosurgeons are poised to transform the care of these patients. Nonetheless, successful application of targeted therapies remains a challenge. Strategies are lacking for directing kinase inhibitor or other pathway-specific therapies to individual patients most likely to benefit. In addition, response to targeted agents is determined not only by the presence of the key mutant kinases, but also by other critical changes in the molecular circuitry of cancer cells, such as loss of key tumor suppressor proteins, the selection for kinase-resistant mutants, and the deregulation of feedback loops. Understanding these signaling networks, and studying them in patients, will be critical for developing rational combination therapies to suppress resistance for malignant glioma patients. Here we review the current status of molecular targeted therapies for malignant gliomas. We focus initially on identifying some of the insights gained to date from targeting the EGFR/PI3K/Akt/mTOR signaling pathway in patients and on how this has led toward a reconceptualization of some of the challenges and directions for targeted treatment. We describe how advances from the world of genomics have the potential to transform our approaches toward targeted therapy, and describe how a deeper understanding of the complex nature of cancer, and its adeptness at rewiring molecular circuitry to evade targeted agents, has raised new challenges and identified new leads.
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PMID:Targeted therapy for malignant glioma patients: lessons learned and the road ahead. 1956 Jul 40

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 EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by (18)fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.
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PMID:The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. 1962 24

Multiple molecular, cellular, micro-environmental and systemic causes of anticancer drug resistance have been identified during the last 25 years. At the same time, genome-wide analysis of human tumor tissues has made it possible in principle to assess the expression of critical genes or mutations that determine the response of an individual patient's tumor to drug treatment. Why then do we, with a few exceptions, such as mutation analysis of the EGFR to guide the use of EGFR inhibitors, have no predictive tests to assess a patient's drug sensitivity profile. The problem urges the more with the expanding choice of drugs, which may be beneficial for a fraction of patients only. In this review we discuss recent studies and insights on mechanisms of anticancer drug resistance and try to answer the question: do we understand why a patient responds or fails to respond to therapy? We focus on doxorubicin as example of a classical cytotoxic, DNA damaging agent and on sunitinib, as example of the new generation of (receptor) tyrosine kinase-targeted agents. For both drugs, classical tumor cell autonomous resistance mechanisms, such as drug efflux transporters and mutations in the tumor cell's survival signaling pathways, as well as micro-environment-related resistance mechanisms, such as changes in tumor stromal cell composition, matrix proteins, vascularity, oxygenation and energy metabolism may play a role. Novel agents that target specific mutations in the tumor cell's damage repair (e.g. PARP inhibitors) or that target tumor survival pathways, such as Akt inhibitors, glycolysis inhibitors or mTOR inhibitors, are of high interest. In order to increase the therapeutic index of treatments, fine-tuned synergistic combinations of new and/or classical cytotoxic agents will be designed. More quantitative assessment of potential resistance mechanisms in real tumors and in real time, such as by kinase profiling methodology, will be developed to allow more precise prediction of the optimal drug combination to treat each patient.
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PMID:Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib. 1964 52

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

To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin-induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes. In these cells, Ang II specifically inhibited activation of insulin-induced Akt Thr(308) and its immediate downstream substrate GSK-3alpha/beta in a time-dependent fashion, with approximately 70% reduction at 15 min. These inhibitory actions were associated with increased IRS-1 phosphorylation of Ser(636)/Ser(639) that was prevented by selective blockade of EGFR tyrosine kinase activity with AG1478. Previous studies have shown that insulin-induced phosphorylation of IRS-1 on Ser(636)/Ser(639) is mediated mainly by the PI3K/mTOR/S6K-1 sequence. Studies with specific inhibitors of PI3K (wortmannin) and mTOR (rapamycin) revealed that Ang II stimulates IRS-1 phosphorylation of Ser(636)/Ser(639) via the PI3K/mTOR/S6K-1 pathway. Both inhibitors blocked the effect of Ang II on insulin-induced activation of Akt. Studies using the specific MEK inhibitor, PD98059, revealed that ERK1/2 activation also mediates Ang II-induced S6K-1 and IRS-1 phosphorylation, and the impairment of Akt Thr(308) and GSK-3alpha/beta phosphorylation. Further studies with selective inhibitors showed that PI3K activation was upstream of ERK, suggesting a new mechanism for Ang II-induced impairment of insulin signaling. These findings indicate that Ang II has a significant role in the development of insulin resistance by a mechanism that involves EGFR transactivation and the PI3K/ERK1/2/mTOR-S6K-1 pathway.
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PMID:Angiotensin-induced EGF receptor transactivation inhibits insulin signaling in C9 hepatic cells. 1987 50

YC-1 has recently been demonstrated to have potent anti-invasion and anti-metastatic activity in several cancer models, in addition to its anti-proliferation activity. However, the mechanism underlying its anti-invasion/anti-metastatic activity is largely unknown. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer in Southeast Asia. Here, we demonstrated that YC-1 inhibited invasiveness and proliferation of NPC cells, with the latter being accompanied by PARP cleavage, S-phase arrest and activation of Chk1/Chk2. We aimed at identifying novel anti-invasion mechanisms of YC-1 in NPC by a functional proteomic platform, the reverse phase protein array (RPPA). Our study revealed for the first time that multiple invasion-related signaling proteins (beta-catenin, caveolin, Src and EGFR), as well as several growth-related proteins (AMPKalpha, phospho-acetyl-CoA carboxylase (p-ACC), HER-2 and mTOR), which were previously un-described signaling proteins altered by YC-1, were found to be down-modulated by YC-1 in NPC cells. We hypothesized that YC-1-mediated downregulation of these invasion proteins contributed to its anti-invasion activity in NPC cells. Overexpression of EGFR, activated Src or caveolin, but not beta-catenin reversed the inhibitory effects of YC-1 on NPC cell invasion, with EGFR and activated Src having additional effects on rescuing NPC cells from YC-1-mediated growth inhibition. In summary, we have identified several novel anti-invasion mechanisms of YC-1 that could impact NPC, and possibly other cancers as well.
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PMID:Reverse phase protein array identifies novel anti-invasion mechanisms of YC-1. 1987 57

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

The development of EGFR inhibitors has influenced the field of targeted therapeutics significantly. Unfortunately, the benefits of EGFR inhibitors are limited by several mechanisms of drug resistance, which include KRAS mutations. Mutations in this gene result in constitutive activation of the Ras/Raf/MEK/ERK pathway, with loss of EGFR signaling control, rendering inhibitors of EGFR ineffective. Several strategies are being developed to overcome this mechanism of resistance, including MEK inhibitors, Braf inhibitors, Hsp90 inhibitors, K-Ras-directed immunotherapy, mTOR inhibitors and several combination approaches.
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PMID:The role of KRAS mutations in resistance to EGFR inhibition in the treatment of cancer. 1994 2


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