Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We herein report the design and synthesis of furoquinoline based novel molecules (16-36) and their in vitro multiple targeted inhibitory potency against PI3K/Akt phosphorylation and mTOR using cell based and cell-free kinase assay. In particular, compound 23 in addition to PI3K-mTOR inhibitory potency, it has shown potent inhibition of hypoxia-induced accumulation of HIF-1alpha protein in U251-HRE cell line. The inhibitory activities of compound 23 were confirmed by Western blot analysis, using human non-small cell lung carcinoma H-460 cell line and glioblastoma U251 cell lines.
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PMID:Design and synthesis of novel furoquinoline based inhibitors of multiple targets in the PI3K/Akt-mTOR pathway. 1850 1

An early event of cell migration is characterized as the rapid reorganization of the actin cytoskeleton. Recently, we have demonstrated that rapamycin inhibits tumor cell motility. To understand the underlying mechanism, this study was set to determine whether rapamycin inhibition of cell motility is related to its prevention of F-actin reorganization. We found that rapamycin prevented type I insulin-like growth factor (IGF-I)-stimulated F-actin reorganization in human rhabdomyosarcoma (Rh30), Ewing sarcoma (Rh1), glioblastoma (U-373) and prostate carcinoma (PC-3) cells, and concurrently inhibited phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK), paxillin and p130(Cas) in the cells. The effect of rapamycin was blocked by expression of a rapamycin-resistant mutant of mTOR (mTORrr), but not a kinase-dead mTORrr. Downregulation of raptor mimicked the effect of rapamycin. Cells infected with a recombinant adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6 kinase 1 (S6K1) conferred to resistance to rapamycin. Further, IGF-I failed to stimulate F-actin reorganization and phosphorylation of the focal adhesion proteins in the S6K1-downregulated cells. Expression of constitutively hypophosphorylated eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1-5A) inhibited IGF-I-stimulated F-actin reorganization, but did not alter the cellular protein or phosphorylation levels of the focal adhesion proteins. The results suggest that rapamycin inhibits IGF-I-induced F-actin reorganization and phosphorylation of the focal adhesion proteins by disruption of mTOR-raptor complex. Both S6K1 and 4E-BP1 pathways, mediated by the mTOR-raptor complex, are involved in the regulation of IGF-I-stimulated F-actin reorganization, but only the former controls IGF-I-stimulated phosphorylation of the focal adhesion proteins.
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PMID:Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. 1850 40

The aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway has been reported to correlate with adverse clinical outcome in human glioblastoma in vivo. However, the question of how this survival network can be successfully targeted to restore the sensitivity of glioblastoma to apoptosis induction has not yet been answered. Here, we report that inhibition of PI3K by LY294002 broadly sensitizes wild-type and mutant PTEN glioblastoma cells to both death receptor- and chemotherapy-induced apoptosis, whereas mammalian target of rapamycin (mTOR) inhibition is not sufficient to restore apoptosis sensitivity. LY294002 significantly enhances apoptosis triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), agonistic anti-CD95 antibodies, or several anticancer drugs (i.e., doxorubicin, etoposide, and vincristine) in a highly synergistic manner. In addition, LY294002 cooperates with TRAIL or doxorubicin to suppress colony formation, thus also showing a strong effect on long-term survival. Similarly, genetic knockdown of PI3K subunits p110alpha and/or p110beta by RNA interference (RNAi) primes glioblastoma cells for TRAIL- or doxorubicin-mediated apoptosis. In contrast to PI3K inhibition, pharmacologic or genetic blockade of mTOR by RAD001 (everolimus), rapamycin, or RNAi fails to enhance TRAIL- or doxorubicin-induced apoptosis. Analysis of apoptosis pathways reveals that PI3K inhibition acts in concert with TRAIL or doxorubicin to trigger mitochondrial membrane permeabilization, caspase activation, and caspase-dependent apoptosis, which are abolished by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Most importantly, PI3K inhibition by LY294002 sensitizes primary cultured glioblastoma cells obtained from surgical specimens to TRAIL- or chemotherapy-induced cell death. By showing that PI3K inhibition broadly primes glioblastoma cells for apoptosis, our findings provide the rationale for using PI3K inhibitors in combination regimens to enhance TRAIL- or chemotherapy-induced apoptosis in glioblastoma.
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PMID:Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. 1867 51

The identification of brain tumor stem-like cells (BTSCs) has implicated a role of biological self-renewal mechanisms in clinical brain tumor initiation and propagation. The molecular mechanisms underlying the tumor-forming capacity of BTSCs, however, remain unknown. Here, we have generated molecular signatures of glioblastoma multiforme (GBM) using gene expression profiles of BTSCs and have identified both Sonic Hedgehog (SHH) signaling-dependent and -independent BTSCs and their respective glioblastoma surgical specimens. BTSC proliferation could be abrogated in a pathway-dependent fashion in vitro and in an intracranial tumor model in athymic mice. Both SHH-dependent and -independent brain tumor growth required phosphoinositide 3-kinase-mammalian target of rapamycin signaling. In human GBMs, the levels of SHH and PTCH1 expression were significantly higher in PTEN-expressing tumors than in PTEN-deficient tumors. In addition, we show that hyperactive SHH-GLI signaling in PTEN-coexpressing human GBM is associated with reduced survival time. Thus, distinct proliferation signaling dependence may underpin glioblastoma propagation by BTSCs. Modeling these BTSC proliferation mechanisms may provide a rationale for individualized glioblastoma treatment.
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PMID:Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. 1878 6

Twenty-two patients with recurrent glioblastoma (GBM) were prospectively treated with everolimus and gefitinib, designed to test the combined inhibition of mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR) as part of a larger clinical trial. The primary endpoint was radiographic response rate. Secondary endpoints included progression-free survival and correlation of molecular profiles with treatment response. 36% of patients had stable disease and 14% a partial response; however, responses were not durable and only one patient was progression-free at six months. Radiographic changes were not well characterized by conventional response criteria, and implied differential effects of therapy within the tumor and/or antiangiogenic effects. EGFR and PTEN status did not clearly predict response to treatment.
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PMID:A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). 1901 75

Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commonly in glioblastoma, leading to activation of downstream kinases including phosphatidylinositol 3'-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Here, we show that phosphorylation of mTOR and its downstream substrate rpS6 (ribosomal protein S6) are robust biomarkers for the antiproliferative effect of EGFR inhibitors. Inhibition of EGFR signaling correlated with decreased abundance of phosphorylated mTOR (p-mTOR) and rpS6 (p-rpS6) in cells wild type for the gene encoding PTEN (phosphatase and tensin homolog on chromosome 10), a negative regulator of PI3K. In contrast, inhibition of EGFR signaling failed to affect p-mTOR or p-rpS6 in cells mutant for PTEN, which are resistant to EGFR inhibitors. Although the abundance of phosphorylated Akt (p-Akt) decreased in response to inhibition of EGFR signaling, Akt was dispensable for signaling between EGFR and mTOR. We identified an Akt-independent pathway linking EGFR to mTOR that was critically dependent on protein kinase C (PKC). Consistent with these observations, the abundance of EGFR generally correlated with phosphorylation of rpS6 and PKC in primary human glioblastoma tumors, and correlated poorly with phosphorylation of Akt. Inhibition of PKC led to decreased viability of glioma cells regardless of PTEN or EGFR status, suggesting that PKC inhibitors should be tested in glioma. These findings underline the importance of signaling between EGFR and mTOR in glioma, identify PKCalpha as essential to this network, and question the necessity of Akt as a critical intermediate coupling EGFR and mTOR in glioma.
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PMID:EGFR signals to mTOR through PKC and independently of Akt in glioma. 1917 18

The tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is often mutated in glioblastoma. Because PTEN can interact with c-Met-dependent signaling, we studied the effects of PTEN on c-Met-induced malignancy and associated molecular events and assessed the potential therapeutic value of combining PTEN restoration approaches with HGF/c-Met inhibition. We studied the effects of c-Met activation on cell proliferation, cell cycle progression, cell migration, cell invasion, and associated molecular events in the settings of restored or inhibited PTEN expression in glioblastoma cells. We also assessed the experimental therapeutic effects of combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition. PTEN significantly inhibited HGF-induced proliferation, cell cycle progression, migration, and invasion of glioblastoma cells. PTEN attenuated HGF-induced changes of signal transduction proteins Akt, GSK-3, JNK, and mTOR as well as cell cycle regulatory proteins p27, cyclin E, and E2F-1. Combining PTEN restoration to PTEN-null glioblastoma cells with c-Met and HGF inhibition additively inhibited tumor cell proliferation and cell cycle progression. Similarly, combining a monoclonal anti-HGF antibody (L2G7) with the mTOR inhibitor rapamycin had additive inhibitory effects on glioblastoma cell proliferation. Systemic in vivo delivery of L2G7 and PTEN restoration as well as systemic in vivo deliveries of L2G7 and rapamycin additively inhibited intracranial glioma xenograft growth. These preclinical studies show for the first time that PTEN loss amplifies c-Met-induced glioblastoma malignancy and suggest that combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition is worth testing in a clinical setting.
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PMID:Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy. 1919 Jan 20

Despite major advances in the management of malignant gliomas of which glioblastomas represent the ultimate grade of malignancy, they remain characterized by dismal prognoses. Glioblastoma patients have a median survival expectancy of only 14 months on the current standard treatment of surgical resection to the extent feasible, followed by adjuvant radiotherapy plus temozolomide, given concomitantly with and after radiotherapy. Malignant gliomas are associated with such dismal prognoses because glioma cells can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Clinical and experimental data have demonstrated that invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) as compared to the highly cellular centre of the tumor, and this may contribute to their resistance to conventional pro-apoptotic chemotherapy and radiotherapy. Resistance to apoptosis results from changes at the genomic, transcriptional and post-transcriptional level of proteins, protein kinases and their transcriptional factor effectors. The PTEN/ PI3K/Akt/mTOR/NF-kappaB and the Ras/Raf/MEK/ERK signaling cascades play critical roles in the regulation of gene expression and prevention of apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer, notably glioblastomas. Monoclonal antibodies and low molecular-weight kinase inhibitors of these pathways are the most common classes of agents in targeted cancer treatment. However, most clinical trials of these agents as monotherapies have failed to demonstrate survival benefit. Despite resistance to apoptosis being closely linked to tumorigenesis, tumor cells can still be induced to die by non-apoptotic mechanisms such as necrosis, senescence, autophagy (type II programmed cell death) and mitotic catastrophe. Temozolomide brings significant therapeutic benefits in glioblastoma treatment. Part of temozolomide cytotoxic activity is exerted through pro-autophagic processes and also through the induction of late apoptosis. Autophagy, type II programmed cell death, represents an alternative mechanism to overcome, at least partly, the dramatic resistance of many cancers to pro-apoptotic-related therapies. Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which then should restore a level of sensitivity to pro-apoptotic drugs. Recent series of studies have supported the concept that malignant gliomas might be seen as an orchestration of cross-talks between cancer cells, microenvironment, vasculature and cancer stem cells. The present chapter focuses on (i) the major signaling pathways making glioblastomas resistant to apoptosis, (ii) the signaling pathways distinctly activated by pro-autophagic drugs as compared to pro-apoptotic ones, (iii) autophagic cell death as an alternative to combat malignant gliomas, (iv) the major scientific data already obtained by researchers to prove that temozolomide is actually a pro-autophagic and pro-apoptotic drug, (v) the molecular and cellular therapies and local drug delivery which could be used to complement conventional treatments, and a review of some of the currently ongoing clinical trials, (vi) the fact that reducing the levels of malignant glioma cell motility can restore pro-apoptotic drug sensitivity, (vii) the observation that inhibiting the sodium pump activity reduces both glioma cell proliferation and migration, (viii) the brain tumor stem cells as a target to complement conventional treatment.
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PMID:Present and potential future adjuvant issues in high-grade astrocytic glioma treatment. 1936 79

The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signaling pathways are aberrantly activated in many tumors, including highly proliferative glioblastomas, but how they are wired with the cell cycle remains imperfectly understood. Inhibitors of MEK/ERK and mTOR pathways are tested as anticancer agents. They are generally considered to induce a G(1) cell cycle arrest through down-regulation of D-type cyclins and up-regulation of p27(kip1). Here, we examined the effect of targeting mTOR by rapamycin and/or MEK by PD184352 in human glioblastoma cell lines. In combination, these drugs cooperatively and potently inhibited the G(1)-S transition and retinoblastoma protein phosphorylation. Their cooperation could not be explained by their partial and differential inhibitory effects on cyclin D1 or D3 but instead by their synergistic inhibition of the activating T172 phosphorylation of cyclin-dependent kinase (CDK) 4. This appeared independent of p27 and unrelated to weak modulations of the CDK-activating kinase activity. The T172 phosphorylation of CDK4 thus appears as a crucial node integrating the activity of both MEK/ERK and mTOR pathways. Combined inhibition of both pathways should be considered as a promising strategy for treatment of tumors harboring a deregulated CDK4 activity.
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PMID:Combined inhibition of MEK and mammalian target of rapamycin abolishes phosphorylation of cyclin-dependent kinase 4 in glioblastoma cell lines and prevents their proliferation. 1945 76

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


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