Current development of mTOR inhibitors as anticancer agents

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Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation.

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The NF1 tumor suppressor critically regulates TSC2 and mTOR

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An expanding role for mTOR in cancer

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Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma

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1997 • 511 citations

Synergistic Augmentation of Rapamycin-Induced Autophagy in Malignant Glioma Cells by Phosphatidylinositol 3-Kinase/Protein Kinase B Inhibitors

2005 • 511 citations

Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer

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Inhibition of Intimal Thickening After Balloon Angioplasty in Porcine Coronary Arteries by Targeting Regulators of the Cell Cycle

1999 • 502 citations

Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases.

1996 • 499 citations

The expanding TOR signaling network

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The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 Translation

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Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

2005 • 467 citations

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1997 • 458 citations

AMPK, the metabolic syndrome and cancer

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Frequent Mutation of the PIK3CA Gene in Ovarian and Breast Cancers

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Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme

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The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling

2001 • 390 citations

Inhibition of mTOR Activity Restores Tamoxifen Response in Breast Cancer Cells with Aberrant Akt Activity

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Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) ‐dependent signaling

2002 • 378 citations

Distinctive activation mechanisms and functions for protein kinase Cδ

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Rapamycin Inhibition of the G1 to S Transition Is Mediated by Effects on Cyclin D1 mRNA and Protein Stability

1998 • 338 citations

The prevalence of PIK3CA mutations in gastric and colon cancer

2005 • 333 citations

Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells

2004 • 323 citations

Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells.

1999 • 313 citations

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1995 • 268 citations

AKT activation predicts outcome in breast cancer patients treated with tamoxifen

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The Principal Rapamycin-Sensitive p70^s6k Phosphorylation Sites, T-229 and T-389, Are Differentially Regulated by Rapamycin-Insensitive Kinase Kinases

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1995 • 239 citations

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Inhibition of the Phosphatidylinositol 3-Kinase/p70S6-Kinase Pathway Induces B16 Melanoma Cell Differentiation

1996 • 232 citations

Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro.

1995 • 230 citations

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1995 • 225 citations

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1996 • 217 citations

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Rapamycin Resistance Tied to Defective Regulation of p27^Kip1

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B cell receptor-associated protein α4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A

1997 • 212 citations

Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells.

1999 • 211 citations

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1997 • 193 citations

The Extracellular Signal-regulated Kinase Pathway Regulates the Phosphorylation of 4E-BP1 at Multiple Sites

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Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells.

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The Mammalian Target of Rapamycin Phosphorylates Sites Having a (Ser/Thr)-Pro Motif and Is Activated by Antibodies to a Region near Its COOH Terminus

1997 • 165 citations

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1998 • 164 citations

Frequent activation of AKT2 kinase in human pancreatic carcinomas

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2000 • 156 citations

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2001 • 148 citations

Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope

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Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes.

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Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen

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The Upregulation of p27Kip1 by Rapamycin Results in G1 Arrest in Exponentially Growing T-Cell Lines

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Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma

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A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)

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Silencing of the PTEN tumor‐suppressor gene in anaplastic thyroid cancer

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1997 • 103 citations

Reduced Expression of PTEN Protein and Its Prognostic Implications in Invasive Ductal Carcinoma of the Breast

2005 • 100 citations

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

2003 • 100 citations

4E-binding Proteins, the Suppressors of Eukaryotic Initiation Factor 4E, Are Down-regulated in Cells with Acquired or Intrinsic Resistance to Rapamycin

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Role of Glycogen Synthase Kinase 3β in Rapamycin-Mediated Cell Cycle Regulation and Chemosensitivity

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Insulin-like growth factors and breast cancer

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Long‐term androgen‐ablation causes increased resistance to PI3K/Akt pathway inhibition in prostate cancer cells

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Epigenetic and genetic alternation of PTEN in cervical neoplasm

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Modulation of transcription of rRNA genes by rapamycin

1994 • 91 citations

Oncogenic K-ras Drives Cell Cycle Progression and Phenotypic Conversion of Primary Pancreatic Duct Epithelial Cells

2004 • 88 citations

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

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Regulation of Ribosomal S6 Kinase 2 by Mammalian Target of Rapamycin

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cAMP Counter-regulates Insulin-mediated Protein Phosphatase-2A Inactivation in Rat Skeletal Muscle Cells

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Translation initiation factors induce DNA synthesis and transform NIH 3T3 cells.

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Allelic imbalance and mutations of thePTEN gene in ovarian cancer

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Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma

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IRS-1: Auditing the effectiveness of mTOR inhibitors

2006 • 72 citations

EGR1 Predicts PTEN and Survival in Patients With Non–Small-Cell Lung Cancer

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A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid tumors

2005 • 63 citations

PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma

2005 • 62 citations

The assessment of PTEN tumor suppressor gene in combination with Gleason scoring and serum PSA to evaluate progression of prostate carcinoma

2004 • 62 citations

Mutation of the PTEN gene in advanced cervical cancer correlated with tumor progression and poor outcome after radiotherapy

2001 • 60 citations

Evidence That Phosphatidylinositol 3-Kinase- and Mitogen-activated Protein Kinase Kinase-4/c-Jun NH2-terminal Kinase-dependent Pathways Cooperate to Maintain Lung Cancer Cell Survival

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Rapamycin reduces hybridoma cell death and enhances monoclonal antibody production

2001 • 56 citations

Allelic imbalance and mutations of thePTEN gene in ovarian cancer

2000 • 56 citations

Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase

2001 • 54 citations

The Role of the Insulin‐like Growth Factor I Receptor in Transformation and Apoptosis

1998 • 53 citations

A phase I/II trial of the oral mTOR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: Study update

2005 • 46 citations

Study of the PTEN gene expression and FAK phosphorylation in human hepatocarcinoma tissues and cell lines

2004 • 45 citations

Phase II study of RAD001 (everolimus) and depot octreotide (Sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma (LGNET)

2006 • 43 citations

Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies

2004 • 41 citations

Phosphatidylinositol 3' kinase signaling in mammary tumorigenesis.

2001 • 35 citations

Okadaic acid induces cellular hypertrophy in AKR-2B fibroblasts: involvement of the p70S6 kinase in the onset of protein and rRNA synthesis.

1996 • 34 citations

Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma

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Characterization of Cell Death Pathways in Human Immunodeficiency Virus-Associated Encephalitis

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Therapeutic Monitoring of Rapamycin

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Mutation Analysis of the Putative Tumor Suppressor Gene PTEN/MMAC1 in Cervical Cancer

2000 • 28 citations

Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-κB

2005 • 28 citations

Control of Phosphatase and Tensin Homolog (PTEN) Gene Expression in Normal and Neoplastic Thyroid Cells

2004 • 27 citations

TOR signaling and control of cell growth

2007 • 27 citations

Down-regulation ofPTENexpression due to loss of promoter activity in human hepatocellular carcinoma cell lines

2005 • 27 citations

Phase I/II trial of gefitinib and RAD001 (everolimus) in patients (pts) with advanced non-small cell lung cancer (NSCLC)

2005 • 25 citations

EFFECT OF A SHORT COURSE OF RAPAMYCIN, CYCLOSPORIN A, AND DONOR-SPECIFIC TRANSFUSION ON RAT CARDIAC ALLOGRAFT SURVIVAL

1993 • 24 citations

Use of rapamycin-impregnated stents in coronary arteries

2003 • 23 citations

Lack of somatic mutation in the PTEN gene in squamous cell carcinomas of human skin

1999 • 23 citations

Early response evaluation of therapy with AP23573 (an mTOR inhibitor) in sarcoma using [¹⁸F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan

2005 • 20 citations

Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: A phase II trial in the North Central Cancer Treatment Group

2006 • 19 citations

Pharmacodynamic study of skin biopsy specimens in patients (pts) with refractory or advanced malignancies following administration of AP23573, an mTOR inhibitor

2005 • 18 citations

Optimization of cyclosporine therapy.

1993 • 13 citations

A phase II trial of temsirolimus in metastatic neuroendocrine carcinomas (NECs)

2005 • 8 citations

mTOR inhibition as a potential treatment for progesterone refractory endometrial hyperplasia

2005 • 5 citations

411 Pharmacodynamic evaluation of the mTOR inhibitor AP23573 in phase 1 clinical trials

2004 • 4 citations