A5082438939- Microtubule and mitosis dynamics
- PI3K/AKT/mTOR signaling in cancer
- Cancer Treatment and Pharmacology
- Glioma Diagnosis and Treatment
- Estrogen and related hormone effects
- Cancer-related Molecular Pathways
- Melanoma and MAPK Pathways
- Cancer Research and Treatments
- HER2/EGFR in Cancer Research
- Advanced Breast Cancer Therapies
- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
- Cancer therapeutics and mechanisms
- 14-3-3 protein interactions
- Fibroblast Growth Factor Research
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Cancer Mechanisms and Therapy
- Protein Kinase Regulation and GTPase Signaling
- Renal cell carcinoma treatment
- Protein Degradation and Inhibitors
- Neurofibromatosis and Schwannoma Cases
- Angiogenesis and VEGF in Cancer
- Monoclonal and Polyclonal Antibodies Research
- Multiple Myeloma Research and Treatments
Basilea Pharmaceutica (Switzerland)
2015-2024
Murdoch Children's Research Institute
2024
Novartis (Switzerland)
2001-2023
Novartis Institutes for BioMedical Research
2004-2012
Novartis (France)
2010
Brigham and Women's Hospital
2009
Hospital Clínico Universitario Lozano Blesa
2009
Imperial College London
2009
Friedrich Miescher Institute
1989-2008
Institut Gustave Roussy
2008
Abstract Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in substrate-1 expression leading to feedback down-regulation signaling through pathway. In model systems, tumors exhibiting mutational activation phosphoinositide-3-kinase/Akt kinase, a common event cancers, are hypersensitive mTOR inhibitors, rapamycin. Despite activity patients,...
Mammalian polo-like kinase 1 (Plk1) is structurally related to the polo gene product of Drosophila melanogaster, Cdc5p Saccharomyces cerevisiae, and plo1+ Schizosaccharomyces pombe, a newly emerging family serine-threonine kinases implicated in cell cycle regulation. Based on data obtained for its putative homologues invertebrates yeasts, human Plk1 suspected regulate some fundamental aspect(s) mitosis, but no direct experimental evidence support this hypothesis has previously been reported....
Cross-talk between the estrogen receptor (ER) and phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism resistance to endocrine therapy, blockade both enhances antitumor activity in preclinical models. This study explored whether sensitivity letrozole was enhanced with oral mTOR inhibitor, everolimus (RAD001).Two hundred seventy postmenopausal women operable ER-positive breast cancer were randomly assigned receive 4 months neoadjuvant treatment...
Everolimus is a selective mammalian target of rapamycin (mTOR) inhibitor with promising anticancer activity. In order to identify rationally based dose and schedule for cancer treatment, we have conducted tumor pharmacodynamic phase I study in patients advanced solid tumors.Fifty-five were treated everolimus cohorts 20, 50, 70 mg weekly or 5 10 daily. Dose escalation depended on limiting toxicity (DLT) rate during the first 4-week period. Pre- on-treatment steady-state skin biopsies...
Tuberous sclerosis (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently (Meikle et al., 2007) mouse neuronal model of TSC Tsc1 ablated most neurons during cortical development. tested rapamycin RAD001 [40- O -(2-hydroxyethyl)-rapamycin], both mammalian target mTORC1 inhibitors, as potential therapeutic agents this model. Median survival improved from 33 d more than 100...
To identify the optimal regimen and dosage of oral mammalian target rapamycin inhibitor everolimus (RAD001).We performed a dose-escalation study in advanced cancer patients administering 5 to 30 mg/wk, with pharmacokinetic (PK) pharmacodynamic (PD) studies. PD data prompted investigation 50 70 mg weekly daily dosing at 10 mg.Ninety-two were treated. Dose-limiting toxicity was seen one patient each mg/wk (stomatitis fatigue) mg/d (hyperglycemia); hence, maximum-tolerated dose not reached. S6...
RAD001 (everolimus), a mammalian target of rapamycin (mTOR) pathway inhibitor in phase II clinical trials oncology, exerts potent antiproliferative/antitumor activities. Many breast cancers are dependent for proliferation on estrogens synthesized from androgens (i.e., androstenedione) by aromatase. Letrozole (Femara) is an aromatase used treatment postmenopausal women with hormone-dependent cancers. The role the mTOR estrogen-driven and effects combining letrozole were examined vitro two...
Highly glycolytic cancer cells prevent intracellular acidification by excreting the end-products lactate and H+ via monocarboxylate transporters 1 (MCT1) 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 MCT4 inhibitor (with 60-fold higher potency on MCT4) prevents efflux. Syrosingopine elicits synthetic lethality with metformin, of mitochondrial NADH dehydrogenase. NAD+, required for ATP-generating steps glycolysis, regenerated from dehydrogenase or treatment...
NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In setting, selectively induced death presenting either HER2 amplification and/or PIK3CA mutation, but not with PTEN loss function or KRAS mutations, for which resistance could be attributed, part ERK pathway activity. An depth analysis markers revealed observed upon...
Abstract The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of pathway and possesses potent immunosuppressive anticancer activities. Here, antitumor activity was evaluated in CA20948 syngeneic rat pancreatic tumor model. demonstrated dose-dependent with daily weekly administration schedules; statistically significant effects were observed 2.5 0.5 mg/kg administered [treated versus control size (T/C), 23% 23–30%, respectively], 3–5 once (T/C,...
Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, squamous carcinoma of head neck). In addition, a constitutively active EGFR type III deletion mutant has been identified non-small cell lung cancer, glioblastomas, breast tumors. Hence, members the family viewed as promising therapeutic targets fight against cancer. similar vein, vascular...
Overexpression of the ErbB2 receptor, a major component ErbB receptor signaling network, contributes to development number human cancers. presents itself, therefore, as target for antibody-mediated therapies. In this respect, anti-ErbB2 monoclonal antibody 4D5 specifically inhibits growth tumor cells overexpressing ErbB2. We have analyzed effect 4D5-mediated inhibition on cell cycle breast line BT474. treatment BT474 resulted in G1 arrest, preceded by rapid dephosphorylation ErbB2,...
Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies inhibit a single molecular target may slow tumor progression, but likely not dependent on signal transduction pathway. Rather, malignant exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases mammalian rapamycin (mTOR). AEE788 is novel orally active kinase inhibitor decreases activity associated with epidermal factor and, at higher...
Comparison of the antiangiogenic/vascular properties oral mammalian target rapamycin (mTOR) inhibitor RAD001 (everolimus) and vascular endothelial growth factor receptor (VEGFR) vatalanib (PTK/ZK).Antiproliferative activity against various tumor histotypes downstream effects on mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, levels measured. Activity several different angiogenic/vascular assays vitro vivo was assessed compared with PTK/ZK.RAD001 inhibited...
Abstract Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are sensitive, some not. Selective inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on cell proliferation viability. Rictor...
To use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal regimens of everolimus, a novel oral mammalian target rapamycin (mTOR) inhibitor, carry forward expanded phase I with tumor biopsy studies in cancer patients.Inhibition S6 kinase 1 (S6K1), molecular marker mTOR signaling, was selected for PD analysis peripheral blood mononuclear cells (PBMCs) trial. PK were measured up 11 days after the fourth weekly dose. A PK/PD model used describe...
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status gastrointestinal tumors not characterized thoroughly. We have found the mTORC1 pathway activated with increased expression protein intestinal polyps Apc(Delta716) heterozygous mutant mouse, model for familial adenomatous polyposis. An 8-week treatment RAD001 (everolimus) suppressed...