9 results on '"Robert H. te Poele"'
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2. Supplementary Table 5B from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
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Michelle D. Garrett, Neil T. Thompson, Paul Workman, Suzanne A. Eccles, Florence I. Raynaud, John F. Lyons, Thomas G. Davies, Steven J. Woodhead, Matthias Reule, Ruth E. Feltell, Paul S. Jones, Kathrin Heinzmann, Simon P. Heaton, Anna Zetterlund, Vanessa Martins, Alexis K. de Haven Brandon, Melanie R. Valenti, Paul D. Eve, Robert H. te Poele, Kyla M. Grimshaw, Mike I. Walton, and Timothy A. Yap more...
- Abstract
XLS file - 703K, Gene expression data for CCT128930: Genes that showed at least a 1.5 Fold Change in at least one treated sample compared to vehicle control and were differentially expressed between the treatment groups (Welch ANOVA FDR5%) more...
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- 2023
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Catalog
3. Data from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
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Michelle D. Garrett, Neil T. Thompson, Paul Workman, Suzanne A. Eccles, Florence I. Raynaud, John F. Lyons, Thomas G. Davies, Steven J. Woodhead, Matthias Reule, Ruth E. Feltell, Paul S. Jones, Kathrin Heinzmann, Simon P. Heaton, Anna Zetterlund, Vanessa Martins, Alexis K. de Haven Brandon, Melanie R. Valenti, Paul D. Eve, Robert H. te Poele, Kyla M. Grimshaw, Mike I. Walton, and Timothy A. Yap more...
- Abstract
Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component.Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148.Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed.Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial. Clin Cancer Res; 18(14); 3912–23. ©2012 AACR. more...
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- 2023
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4. Supplementary Table 6C from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
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Michelle D. Garrett, Neil T. Thompson, Paul Workman, Suzanne A. Eccles, Florence I. Raynaud, John F. Lyons, Thomas G. Davies, Steven J. Woodhead, Matthias Reule, Ruth E. Feltell, Paul S. Jones, Kathrin Heinzmann, Simon P. Heaton, Anna Zetterlund, Vanessa Martins, Alexis K. de Haven Brandon, Melanie R. Valenti, Paul D. Eve, Robert H. te Poele, Kyla M. Grimshaw, Mike I. Walton, and Timothy A. Yap more...
- Abstract
XLS file - 66K, Genes that showed at least a 1.5 Fold Change in at least one treated sample compared to vehicle control and were differentially expressed between the treatment groups (Welch ANOVA FDR5%) for both CCT128930 and AT13148 more...
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- 2023
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5. Supplementary Figures 1-7, Tables 1-4 from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
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Michelle D. Garrett, Neil T. Thompson, Paul Workman, Suzanne A. Eccles, Florence I. Raynaud, John F. Lyons, Thomas G. Davies, Steven J. Woodhead, Matthias Reule, Ruth E. Feltell, Paul S. Jones, Kathrin Heinzmann, Simon P. Heaton, Anna Zetterlund, Vanessa Martins, Alexis K. de Haven Brandon, Melanie R. Valenti, Paul D. Eve, Robert H. te Poele, Kyla M. Grimshaw, Mike I. Walton, and Timothy A. Yap more...
- Abstract
PDF file - 553K, Supplementary Figure 1. Phosphorylation of AKT substrates remains suppressed, despite pSer473 AKT induction. Supplementary Figure 2. The pharmacokinetic-pharmacodynamic profile and antitumor activity of AT13148 in PTEN-deficient PC3 human prostate cancer xenografts. Supplementary Figure 3. Pharmacodynamic biomarker study of AT13148(40mg/kg) in MES-SA human tumor xenografts. Supplementary Figure 4. The antitumour activity of AT13148 in mutant KRAS A549 human lung cancer xenografts. Supplementary Figure 5. Mouse body weight data for the MES-SA (Figure 4B) and BT474 (Figure 4C) efficacy studies. Supplementary Figure 6. The effect of AT13148 versus CCT128930 on apoptosis and cell cycle distribution in U87MG human glioblastoma cells. Supplementary Figure 7. Differential effects of 24h treatment of 10M each of the AGC kinase inhibitor AT13148 and the selective AKT inhibitor CCT128930 on cell cycle effects in PTEN-deficient U87MG human glioblastoma cells. Supplementary Table 1. Summary of the inhibitory activity of 10��M AT13148 against in vitro. Supplementary Table 2. Summary of the inhibitory activity of AT13148 against a panel of protein kinases Supplementary Table 3. Summary of the in vitro cytotoxicity of AT13148 against a panel of human tumor cell lines harboring different defects in the PI3K-AKT signaling pathway. Supplementary Table 4. Summary of the pharmacokinetics of AT13148 in mouse plasma and tissues following iv or oral administration more...
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- 2023
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6. Supplementary Table 1, Figure 1 from Histone Deacetylase Inhibition Increases Levels of Choline Kinase α and Phosphocholine Facilitating Noninvasive Imaging in Human Cancers
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Yuen-Li Chung, Martin O. Leach, Paul Workman, Ian R. Judson, John R. Griffiths, Geoffrey S. Payne, L. Elizabeth Jackson, Anne-Christine Wong Te Fong, Robert H. te Poele, Helen Troy, Vaitha Arunan, and Mounia Beloueche-Babari more...
- Abstract
PDF file - 94K
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- 2023
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7. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling.
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Simon R Stockwell, Georgina Platt, S Elaine Barrie, Georgia Zoumpoulidou, Robert H Te Poele, G Wynne Aherne, Stuart C Wilson, Peter Sheldrake, Edward McDonald, Mathilde Venet, Christelle Soudy, Frédéric Elustondo, Laurent Rigoreau, Julian Blagg, Paul Workman, Michelle D Garrett, and Sibylle Mittnacht more...
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Medicine ,Science - Abstract
Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes. more...
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- 2012
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8. Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways
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Helen J, Knowles, Robert H, te Poele, Robert, Te Poole, Paul, Workman, and Adrian L, Harris
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Transcriptional Activation ,Blotting, Western ,Prostaglandin ,Enzyme-Linked Immunosorbent Assay ,Receptors, Nicotinic ,Biology ,Pharmacology ,Medical sciences ,Pertussis toxin ,Niacin ,Biochemistry ,Receptors, G-Protein-Coupled ,chemistry.chemical_compound ,Cell Line, Tumor ,Cyclic AMP ,Humans ,Receptor ,U937 cell ,Macrophages ,digestive, oral, and skin physiology ,food and beverages ,Cell Hypoxia ,PPAR gamma ,B vitamins ,Oncology ,chemistry ,Prostaglandins ,Signal transduction ,Intracellular ,Signal Transduction - Abstract
HM74 and HM74a have been identified as receptors for niacin. HM74a mediates the pharmacological anti-lipolytic effects of niacin in adipocytes by reducing intracellular cyclic AMP (cAMP) and inhibiting release of free fatty acids into the circulation. In macrophages, niacin induces peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent and cAMP-dependent expression of genes mediating reverse cholesterol transport, although via an unidentified receptor. We describe constitutive expression of HM74a mRNA and hypoxia- and IFNgamma-inducible expression of HM74 and HM74a in human monocytic cell lines and primary cells in culture. In U937 cells niacin-induced expression of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent endogenous ligand of PPARgamma. Both niacin and the structurally distinct HM74/HM74a ligand acifran-induced nuclear expression of PPARgamma protein and enhanced PPARgamma transcriptional activity. Niacin-induced PPARgamma transcriptional activity was pertussis toxin sensitive and required activity of phospholipase A(2) (EC 3.1.1.4), cyclo-oxygenase (EC 1.14.99.1) and prostaglandin D(2) synthase (EC 5.3.99.2). Niacin also induced PPARgamma transcriptional activity in HM74 and HM74a CHO cell transfectants, although not in vector-only control cells. This was sensitive to pertussis toxin and to inhibition of phoshoplipase A(2) and cyclo-oxygenase activity. Additionally, niacin increased intracellular cAMP in U937 via a pertussis toxin and cyclo-oxygenase-sensitive mechanism. These results indicate that HM74 and HM74a can mediate macrophage responses to niacin via activation of the prostaglandin synthesis pathway and induction and activation of PPARgamma. This suggests a novel mechanism(s) mediating the clinical effects of pharmacological doses of niacin. more...
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- 2006
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9. DNA damage is able to induce senescence in tumor cells in vitro and in vivo
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Robert H, te Poele, Andrei L, Okorokov, Lesley, Jardine, Jeffrey, Cummings, and Simon P, Joel
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Cyclin-Dependent Kinase Inhibitor p21 ,Cell Cycle ,Apoptosis ,Breast Neoplasms ,Irinotecan ,beta-Galactosidase ,Antineoplastic Agents, Phytogenic ,Neoadjuvant Therapy ,Cyclins ,Humans ,Camptothecin ,Tumor Suppressor Protein p53 ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,DNA Damage ,Etoposide - Abstract
Often the use of cytotoxic drugs in cancer therapy results in stable disease rather than regression of the tumor, and this is typically seen as a failure of treatment. We now show that DNA damage is able to induce senescence in tumor cells expressing wild-type p53. We also show that cytotoxics are capable of inducing senescence in tumor tissue in vivo. Our results suggest that p53 and p21 play a central role in the onset of senescence, whereas p16(INK4a) function may be involved in maintaining senescence. Thus, like apoptosis, senescence appears to be a p53-induced cellular response to DNA damage and an important factor in determining treatment outcome. more...
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- 2002
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