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1. Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma

Author

Priya Sriskandarajah, Alexis De Haven Brandon, Kenneth MacLeod, Neil O. Carragher, Vladimir Kirkin, Martin Kaiser, and Steven R. Whittaker

Subjects
Multiple myeloma, Trametinib, Dexamethasone, Apoptosis, RAS, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RAS-mutant MM. Methods The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time. Results The Tra/Dex combination demonstrated synergistic cytotoxicity in KRAS G12A mutant lines MM.1S and RPMI-8226. The induction of apoptosis was associated with decreased MCL-1 expression and increased BIM expression. Reverse phase proteomic arrays revealed suppression of FAK, PYK2, FLT3, NDRG1 and 4EBP1 phosphorylation with the Tra/Dex combination. Notably, NDRG1 expression was associated with the synergistic response to Tra/Dex. MM cells were sensitive to PDK1 inhibition and IGF1-induced signalling partially protected from Tra/Dex treatment, highlighting the importance of this pathway. In the MM.1S tumor xenograft model, only the combination of Tra/Dex resulted in a significant inhibition of tumor growth. Conclusions Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM.

Published
2020
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2. Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones

Author

Alice C. Harnden, Owen A. Davis, Gary M. Box, Angela Hayes, Louise D. Johnson, Alan T. Henley, Alexis K. de Haven Brandon, Melanie Valenti, Kwai-Ming J. Cheung, Alfie Brennan, Rosemary Huckvale, Olivier A. Pierrat, Rachel Talbot, Michael D. Bright, Hafize Aysin Akpinar, Daniel S. J. Miller, Dalia Tarantino, Sharon Gowan, Selby de Klerk, Peter Craig McAndrew, Yann-Vaï Le Bihan, Mirco Meniconi, Rosemary Burke, Vladimir Kirkin, Rob L. M. van Montfort, Florence I. Raynaud, Olivia W. Rossanese, Benjamin R. Bellenie, and Swen Hoelder

Subjects
Drug Discovery, Molecular Medicine
Published
2023
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4. Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Author

Wagner, Steve, Vlachogiannis, Georgios, De Haven Brandon, Alexis, Valenti, Melanie, Box, Gary, Jenkins, Liam, Mancusi, Caterina, Self, Annette, Manodoro, Floriana, Assiotis, Ioannis, Robinson, Penny, Chauhan, Ritika, Rust, Alistair G., Matthews, Nik, Eason, Kate, Khan, Khurum, Starling, Naureen, Cunningham, David, Sadanandam, Anguraj, Isacke, Clare M., Kirkin, Vladimir, Valeri, Nicola, and Whittaker, Steven R.

Published
2019
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7. Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones

Author

Harnden, Alice C., primary, Davis, Owen A., additional, Box, Gary M., additional, Hayes, Angela, additional, Johnson, Louise D., additional, Henley, Alan T., additional, de Haven Brandon, Alexis K., additional, Valenti, Melanie, additional, Cheung, Kwai-Ming J., additional, Brennan, Alfie, additional, Huckvale, Rosemary, additional, Pierrat, Olivier A., additional, Talbot, Rachel, additional, Bright, Michael D., additional, Akpinar, Hafize Aysin, additional, Miller, Daniel S. J., additional, Tarantino, Dalia, additional, Gowan, Sharon, additional, de Klerk, Selby, additional, McAndrew, Peter Craig, additional, Le Bihan, Yann-Vaï, additional, Meniconi, Mirco, additional, Burke, Rosemary, additional, Kirkin, Vladimir, additional, van Montfort, Rob L. M., additional, Raynaud, Florence I., additional, Rossanese, Olivia W., additional, Bellenie, Benjamin R., additional, and Hoelder, Swen, additional

Published
2023
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8. Supplementary Figure 1 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, primary, Ang, Joo Chew, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de Haven Brandon, Alexis, primary, Baird, Richard D., primary, Friedman, Lori, primary, Derynck, Mika, primary, Vanhaesebroeck, Bart, primary, Eccles, Suzanne A., primary, Kaye, Stan B., primary, Workman, Paul, primary, de Bono, Johann S., primary, and Raynaud, Florence I., primary

Published
2023
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9. Supplementary Figure 1 from Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma

Author

Ang, Joo Ern, primary, Pal, Akos, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de haven Brandon, Alexis, primary, Revell, Victoria L., primary, Skene, Debra J., primary, Venturi, Miro, primary, Rueger, Ruediger, primary, Meresse, Valerie, primary, Eccles, Suzanne A., primary, de Bono, Johann S., primary, Kaye, Stanley B., primary, Workman, Paul, primary, Banerji, Udai, primary, and Raynaud, Florence I., primary

Published
2023
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10. Supplementary Table 3 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, primary, Ang, Joo Chew, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de Haven Brandon, Alexis, primary, Baird, Richard D., primary, Friedman, Lori, primary, Derynck, Mika, primary, Vanhaesebroeck, Bart, primary, Eccles, Suzanne A., primary, Kaye, Stan B., primary, Workman, Paul, primary, de Bono, Johann S., primary, and Raynaud, Florence I., primary

Published
2023
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11. Supplementary Table 1 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, primary, Ang, Joo Chew, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de Haven Brandon, Alexis, primary, Baird, Richard D., primary, Friedman, Lori, primary, Derynck, Mika, primary, Vanhaesebroeck, Bart, primary, Eccles, Suzanne A., primary, Kaye, Stan B., primary, Workman, Paul, primary, de Bono, Johann S., primary, and Raynaud, Florence I., primary

Published
2023
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12. Supplementary Table 5 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, primary, Ang, Joo Chew, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de Haven Brandon, Alexis, primary, Baird, Richard D., primary, Friedman, Lori, primary, Derynck, Mika, primary, Vanhaesebroeck, Bart, primary, Eccles, Suzanne A., primary, Kaye, Stan B., primary, Workman, Paul, primary, de Bono, Johann S., primary, and Raynaud, Florence I., primary

Published
2023
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13. Data from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Bielen, Aleksandra, primary, Perryman, Lara, primary, Box, Gary M., primary, Valenti, Melanie, primary, de Haven Brandon, Alexis, primary, Martins, Vanessa, primary, Jury, Alexa, primary, Popov, Sergey, primary, Gowan, Sharon, primary, Jeay, Sebastien, primary, Raynaud, Florence I., primary, Hofmann, Francesco, primary, Hargrave, Darren, primary, Eccles, Suzanne A., primary, and Jones, Chris, primary

Published
2023
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14. Supplementary Table 1 from Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma

Author

Ang, Joo Ern, primary, Pal, Akos, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de haven Brandon, Alexis, primary, Revell, Victoria L., primary, Skene, Debra J., primary, Venturi, Miro, primary, Rueger, Ruediger, primary, Meresse, Valerie, primary, Eccles, Suzanne A., primary, de Bono, Johann S., primary, Kaye, Stanley B., primary, Workman, Paul, primary, Banerji, Udai, primary, and Raynaud, Florence I., primary

Published
2023
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15. Supplementary Figures 1-4 from Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

Author

Yap, Timothy A., primary, Walton, Mike I., primary, Hunter, Lisa-Jane K., primary, Valenti, Melanie, primary, de Haven Brandon, Alexis, primary, Eve, Paul D., primary, Ruddle, Ruth, primary, Heaton, Simon P., primary, Henley, Alan, primary, Pickard, Lisa, primary, Vijayaraghavan, Gowri, primary, Caldwell, John J., primary, Thompson, Neil T., primary, Aherne, Wynne, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Workman, Paul, primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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16. Data from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, primary, Ang, Joo Chew, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de Haven Brandon, Alexis, primary, Baird, Richard D., primary, Friedman, Lori, primary, Derynck, Mika, primary, Vanhaesebroeck, Bart, primary, Eccles, Suzanne A., primary, Kaye, Stan B., primary, Workman, Paul, primary, de Bono, Johann S., primary, and Raynaud, Florence I., primary

Published
2023
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17. Data from Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma

Author

Ang, Joo Ern, primary, Pal, Akos, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de haven Brandon, Alexis, primary, Revell, Victoria L., primary, Skene, Debra J., primary, Venturi, Miro, primary, Rueger, Ruediger, primary, Meresse, Valerie, primary, Eccles, Suzanne A., primary, de Bono, Johann S., primary, Kaye, Stanley B., primary, Workman, Paul, primary, Banerji, Udai, primary, and Raynaud, Florence I., primary

Published
2023
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18. Supplementary Table 4 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, primary, Ang, Joo Chew, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de Haven Brandon, Alexis, primary, Baird, Richard D., primary, Friedman, Lori, primary, Derynck, Mika, primary, Vanhaesebroeck, Bart, primary, Eccles, Suzanne A., primary, Kaye, Stan B., primary, Workman, Paul, primary, de Bono, Johann S., primary, and Raynaud, Florence I., primary

Published
2023
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19. Supplementary Figure 1 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Bielen, Aleksandra, primary, Perryman, Lara, primary, Box, Gary M., primary, Valenti, Melanie, primary, de Haven Brandon, Alexis, primary, Martins, Vanessa, primary, Jury, Alexa, primary, Popov, Sergey, primary, Gowan, Sharon, primary, Jeay, Sebastien, primary, Raynaud, Florence I., primary, Hofmann, Francesco, primary, Hargrave, Darren, primary, Eccles, Suzanne A., primary, and Jones, Chris, primary

Published
2023
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20. Supplementary Figure 3 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Bielen, Aleksandra, primary, Perryman, Lara, primary, Box, Gary M., primary, Valenti, Melanie, primary, de Haven Brandon, Alexis, primary, Martins, Vanessa, primary, Jury, Alexa, primary, Popov, Sergey, primary, Gowan, Sharon, primary, Jeay, Sebastien, primary, Raynaud, Florence I., primary, Hofmann, Francesco, primary, Hargrave, Darren, primary, Eccles, Suzanne A., primary, and Jones, Chris, primary

Published
2023
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21. Supplementary Figure 4 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Bielen, Aleksandra, primary, Perryman, Lara, primary, Box, Gary M., primary, Valenti, Melanie, primary, de Haven Brandon, Alexis, primary, Martins, Vanessa, primary, Jury, Alexa, primary, Popov, Sergey, primary, Gowan, Sharon, primary, Jeay, Sebastien, primary, Raynaud, Florence I., primary, Hofmann, Francesco, primary, Hargrave, Darren, primary, Eccles, Suzanne A., primary, and Jones, Chris, primary

Published
2023
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22. Supplementary Figure 2 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Bielen, Aleksandra, primary, Perryman, Lara, primary, Box, Gary M., primary, Valenti, Melanie, primary, de Haven Brandon, Alexis, primary, Martins, Vanessa, primary, Jury, Alexa, primary, Popov, Sergey, primary, Gowan, Sharon, primary, Jeay, Sebastien, primary, Raynaud, Florence I., primary, Hofmann, Francesco, primary, Hargrave, Darren, primary, Eccles, Suzanne A., primary, and Jones, Chris, primary

Published
2023
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23. Supplementary Table 2 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, primary, Ang, Joo Chew, primary, Asad, Yasmin J., primary, Henley, Alan T., primary, Valenti, Melanie, primary, Box, Gary, primary, de Haven Brandon, Alexis, primary, Baird, Richard D., primary, Friedman, Lori, primary, Derynck, Mika, primary, Vanhaesebroeck, Bart, primary, Eccles, Suzanne A., primary, Kaye, Stan B., primary, Workman, Paul, primary, de Bono, Johann S., primary, and Raynaud, Florence I., primary

Published
2023
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24. Supplementary Figure Legends 1-4 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Bielen, Aleksandra, primary, Perryman, Lara, primary, Box, Gary M., primary, Valenti, Melanie, primary, de Haven Brandon, Alexis, primary, Martins, Vanessa, primary, Jury, Alexa, primary, Popov, Sergey, primary, Gowan, Sharon, primary, Jeay, Sebastien, primary, Raynaud, Florence I., primary, Hofmann, Francesco, primary, Hargrave, Darren, primary, Eccles, Suzanne A., primary, and Jones, Chris, primary

Published
2023
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25. Supplementary Table 1 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Florence I. Raynaud, Johann S. de Bono, Paul Workman, Stan B. Kaye, Suzanne A. Eccles, Bart Vanhaesebroeck, Mika Derynck, Lori Friedman, Richard D. Baird, Alexis de Haven Brandon, Gary Box, Melanie Valenti, Alan T. Henley, Yasmin J. Asad, Joo Chew Ang, Rupinder Pandher, and Joo Ern Ang

Abstract

Metabolite changes that constitute the Venn diagram in Figure 2. Significant changes listed are reductions (labelled "-1") or increases (labelled "1") in concentrations relative to the relevant controls.

Published
2023
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26. Data from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Chris Jones, Suzanne A. Eccles, Darren Hargrave, Francesco Hofmann, Florence I. Raynaud, Sebastien Jeay, Sharon Gowan, Sergey Popov, Alexa Jury, Vanessa Martins, Alexis de Haven Brandon, Melanie Valenti, Gary M. Box, Lara Perryman, and Aleksandra Bielen

Abstract

Pediatric glioblastoma (pGBM), although rare, is one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. We have identified IGF1R to be a potential therapeutic target in pGBM due to gene amplification and high levels of IGF2 expression in some tumor samples, as well as constitutive receptor activation in pGBM cell lines. To evaluate the therapeutic potential of strategies targeting the receptor, we have carried out in vitro and in vivo preclinical studies using the specific IGF1R inhibitor NVP-AEW541. A modest inhibitory effect was seen in vitro, with GI50 values of 5 to 6 μmol/L, and concurrent inhibition of receptor phosphorylation. Specific targeting of IGF1R with short interfering RNA decreased cell viability, diminished downstream signaling through phosphoinositide 3-kinase (PI3K), and induced G1 arrest, effects mimicked by NVP-AEW541, both in the absence and presence of IGF2. Hallmarks of PI3K inhibition were observed after treatment with NVP-AEW541 by expression profiling and Western blot analysis. Phospho–receptor tyrosine kinase (RTK) arrays showed phosphorylation of platelet-derived growth factor receptor (PDGFR) α/β in pGBM cells, suggesting coactivation of an alternative RTK pathway. Treatment of KNS42 with the PDGFR inhibitor imatinib showed additional effects targeting the mitogen-activated protein kinase pathway, and cotreatment of the PDGFR inhibitor imatinib with NVP-AEW541 resulted in a highly synergistic interaction in vitro and increased efficacy after 14 days therapy in vivo compared with either agent alone. These data provide evidence that inhibition of IGF1R, in combination with other targeted agents, may be a useful and novel therapeutic strategy in pGBM. Mol Cancer Ther; 10(8); 1407–18. ©2011 AACR.

Published
2023
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27. Supplementary Figure 3 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Chris Jones, Suzanne A. Eccles, Darren Hargrave, Francesco Hofmann, Florence I. Raynaud, Sebastien Jeay, Sharon Gowan, Sergey Popov, Alexa Jury, Vanessa Martins, Alexis de Haven Brandon, Melanie Valenti, Gary M. Box, Lara Perryman, and Aleksandra Bielen

Abstract

Supplementary Figure 3 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Published
2023
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28. Supplementary Figure 1 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Chris Jones, Suzanne A. Eccles, Darren Hargrave, Francesco Hofmann, Florence I. Raynaud, Sebastien Jeay, Sharon Gowan, Sergey Popov, Alexa Jury, Vanessa Martins, Alexis de Haven Brandon, Melanie Valenti, Gary M. Box, Lara Perryman, and Aleksandra Bielen

Abstract

Supplementary Figure 1 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Published
2023
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29. Supplementary Table 2 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Florence I. Raynaud, Johann S. de Bono, Paul Workman, Stan B. Kaye, Suzanne A. Eccles, Bart Vanhaesebroeck, Mika Derynck, Lori Friedman, Richard D. Baird, Alexis de Haven Brandon, Gary Box, Melanie Valenti, Alan T. Henley, Yasmin J. Asad, Joo Chew Ang, Rupinder Pandher, and Joo Ern Ang

Abstract

Summary of baseline reproducibility of candidate plasma metabolite biomarkers (n=17 patients).

Published
2023
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30. Supplementary Table 3 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Florence I. Raynaud, Johann S. de Bono, Paul Workman, Stan B. Kaye, Suzanne A. Eccles, Bart Vanhaesebroeck, Mika Derynck, Lori Friedman, Richard D. Baird, Alexis de Haven Brandon, Gary Box, Melanie Valenti, Alan T. Henley, Yasmin J. Asad, Joo Chew Ang, Rupinder Pandher, and Joo Ern Ang

Abstract

Characteristics of dose-dependent changes in candidate plasma metabolite pharmacodynamic biomarker concentrations in 41 patients, as determined on day 1 of pictilisib clinical trial. Cells with p-values

Published
2023
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31. Supplementary Figures 1-4 from Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

Author

Michelle D. Garrett, Ian Collins, Paul Workman, Suzanne A. Eccles, Florence I. Raynaud, Wynne Aherne, Neil T. Thompson, John J. Caldwell, Gowri Vijayaraghavan, Lisa Pickard, Alan Henley, Simon P. Heaton, Ruth Ruddle, Paul D. Eve, Alexis de Haven Brandon, Melanie Valenti, Lisa-Jane K. Hunter, Mike I. Walton, and Timothy A. Yap

Abstract

Supplementary Figures 1-4 from Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

Published
2023
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32. Supplementary Figure Legends and Supplementary Table 1 from Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

Author

Michelle D. Garrett, Ian Collins, Paul Workman, Suzanne A. Eccles, Florence I. Raynaud, Wynne Aherne, Neil T. Thompson, John J. Caldwell, Gowri Vijayaraghavan, Lisa Pickard, Alan Henley, Simon P. Heaton, Ruth Ruddle, Paul D. Eve, Alexis de Haven Brandon, Melanie Valenti, Lisa-Jane K. Hunter, Mike I. Walton, and Timothy A. Yap

Abstract

Supplementary Figure Legends and Supplementary Table 1 from Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

Published
2023
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33. Supplementary Table 4 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Florence I. Raynaud, Johann S. de Bono, Paul Workman, Stan B. Kaye, Suzanne A. Eccles, Bart Vanhaesebroeck, Mika Derynck, Lori Friedman, Richard D. Baird, Alexis de Haven Brandon, Gary Box, Melanie Valenti, Alan T. Henley, Yasmin J. Asad, Joo Chew Ang, Rupinder Pandher, and Joo Ern Ang

Abstract

Changes in candidate plasma metabolite pharmacodynamic biomarker concentrations over first 2 weeks in 17 patients treated with {greater than or equal to}330 mg once-daily of pictilisib. Cells with p-values

Published
2023
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34. Supplementary Figure 1 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Florence I. Raynaud, Johann S. de Bono, Paul Workman, Stan B. Kaye, Suzanne A. Eccles, Bart Vanhaesebroeck, Mika Derynck, Lori Friedman, Richard D. Baird, Alexis de Haven Brandon, Gary Box, Melanie Valenti, Alan T. Henley, Yasmin J. Asad, Joo Chew Ang, Rupinder Pandher, and Joo Ern Ang

Abstract

Heat map of changes (relative to vehicle control) in candidate plasma and tumor metabolite biomarkers at 8 hours post-dosing of mice bearing U87MG xenografts with pictilisib 75mg/kg or buparlisib 60mg/kg (a, acyl; aa, acyl-acyl; ae, acyl-alkyl; Cx:y, where x is the number of carbons in the fatty acid side chain; y is the number of double bonds in the fatty acid side chain; AC, acylcarnitine; DC, decarboxyl; M, methyl; OH, hydroxyl; PC, phosphatidylcholine)

Published
2023
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35. Supplementary Table 5 from Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Florence I. Raynaud, Johann S. de Bono, Paul Workman, Stan B. Kaye, Suzanne A. Eccles, Bart Vanhaesebroeck, Mika Derynck, Lori Friedman, Richard D. Baird, Alexis de Haven Brandon, Gary Box, Melanie Valenti, Alan T. Henley, Yasmin J. Asad, Joo Chew Ang, Rupinder Pandher, and Joo Ern Ang

Abstract

Changes in plasma metabolites across timepoints by patient/sample.

Published
2023
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36. Data from Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

Author

Michelle D. Garrett, Ian Collins, Paul Workman, Suzanne A. Eccles, Florence I. Raynaud, Wynne Aherne, Neil T. Thompson, John J. Caldwell, Gowri Vijayaraghavan, Lisa Pickard, Alan Henley, Simon P. Heaton, Ruth Ruddle, Paul D. Eve, Alexis de Haven Brandon, Melanie Valenti, Lisa-Jane K. Hunter, Mike I. Walton, and Timothy A. Yap

Abstract

AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G1 arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials. Mol Cancer Ther; 10(2); 360–71. ©2010 AACR.

Published
2023
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37. Supplementary Figure 2 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Chris Jones, Suzanne A. Eccles, Darren Hargrave, Francesco Hofmann, Florence I. Raynaud, Sebastien Jeay, Sharon Gowan, Sergey Popov, Alexa Jury, Vanessa Martins, Alexis de Haven Brandon, Melanie Valenti, Gary M. Box, Lara Perryman, and Aleksandra Bielen

Abstract

Supplementary Figure 2 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Published
2023
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38. Supplementary Figure 4 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Chris Jones, Suzanne A. Eccles, Darren Hargrave, Francesco Hofmann, Florence I. Raynaud, Sebastien Jeay, Sharon Gowan, Sergey Popov, Alexa Jury, Vanessa Martins, Alexis de Haven Brandon, Melanie Valenti, Gary M. Box, Lara Perryman, and Aleksandra Bielen

Abstract

Supplementary Figure 4 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Published
2023
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39. Supplementary Table 1 from Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma

Author

Florence I. Raynaud, Udai Banerji, Paul Workman, Stanley B. Kaye, Johann S. de Bono, Suzanne A. Eccles, Valerie Meresse, Ruediger Rueger, Miro Venturi, Debra J. Skene, Victoria L. Revell, Alexis de haven Brandon, Gary Box, Melanie Valenti, Alan T. Henley, Yasmin J. Asad, Akos Pal, and Joo Ern Ang

Abstract

Time of day variation in metabolites in healthy volunteers and in patients treated with the MEK inhibitor.

Published
2023
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40. Supplementary Figure Legends 1-4 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Chris Jones, Suzanne A. Eccles, Darren Hargrave, Francesco Hofmann, Florence I. Raynaud, Sebastien Jeay, Sharon Gowan, Sergey Popov, Alexa Jury, Vanessa Martins, Alexis de Haven Brandon, Melanie Valenti, Gary M. Box, Lara Perryman, and Aleksandra Bielen

Abstract

Supplementary Figure Legends 1-4 from Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Published
2023
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42. Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo

Author

Rosemary Huckvale, Alice C. Harnden, Kwai-Ming J. Cheung, Olivier A. Pierrat, Rachel Talbot, Gary M. Box, Alan T. Henley, Alexis K. de Haven Brandon, Albert E. Hallsworth, Michael D. Bright, Hafize Aysin Akpinar, Daniel S. J. Miller, Dalia Tarantino, Sharon Gowan, Angela Hayes, Emma A. Gunnell, Alfie Brennan, Owen A. Davis, Louise D. Johnson, Selby de Klerk, Craig McAndrew, Yann-Vaï Le Bihan, Mirco Meniconi, Rosemary Burke, Vladimir Kirkin, Rob L. M. van Montfort, Florence I. Raynaud, Olivia W. Rossanese, Benjamin R. Bellenie, and Swen Hoelder

Subjects
Gene Expression Regulation, Neoplastic, Mice, Carcinogenesis, Drug Discovery, Proto-Oncogene Proteins c-bcl-6, Animals, Humans, Molecular Medicine
Abstract

The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader

Published
2022
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43. Supplementary Table 5A from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Author

Yap, Timothy A., primary, Walton, Mike I., primary, Grimshaw, Kyla M., primary, te Poele, Robert H., primary, Eve, Paul D., primary, Valenti, Melanie R., primary, de Haven Brandon, Alexis K., primary, Martins, Vanessa, primary, Zetterlund, Anna, primary, Heaton, Simon P., primary, Heinzmann, Kathrin, primary, Jones, Paul S., primary, Feltell, Ruth E., primary, Reule, Matthias, primary, Woodhead, Steven J., primary, Davies, Thomas G., primary, Lyons, John F., primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Workman, Paul, primary, Thompson, Neil T., primary, and Garrett, Michelle D., primary

Published
2023
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44. Supplementary Table and Figures from Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo

Author

Renshaw, Jane, primary, Taylor, Kathryn R., primary, Bishop, Ryan, primary, Valenti, Melanie, primary, De Haven Brandon, Alexis, primary, Gowan, Sharon, primary, Eccles, Suzanne A., primary, Ruddle, Ruth R., primary, Johnson, Louise D., primary, Raynaud, Florence I., primary, Selfe, Joanna L., primary, Thway, Khin, primary, Pietsch, Torsten, primary, Pearson, Andrew D., primary, and Shipley, Janet, primary

Published
2023
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45. CCR Translation for This Article from Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo

Author

Renshaw, Jane, primary, Taylor, Kathryn R., primary, Bishop, Ryan, primary, Valenti, Melanie, primary, De Haven Brandon, Alexis, primary, Gowan, Sharon, primary, Eccles, Suzanne A., primary, Ruddle, Ruth R., primary, Johnson, Louise D., primary, Raynaud, Florence I., primary, Selfe, Joanna L., primary, Thway, Khin, primary, Pietsch, Torsten, primary, Pearson, Andrew D., primary, and Shipley, Janet, primary

Published
2023
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46. Supplementary Figure 5 from CCT244747 Is a Novel Potent and Selective CHK1 Inhibitor with Oral Efficacy Alone and in Combination with Genotoxic Anticancer Drugs

Author

Walton, Mike I., primary, Eve, Paul D., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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47. Supplementary Figure 2 from Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941

Author

Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Patel, Sonal, primary, Alix, Sonia, primary, Box, Gary, primary, Chuckowree, Irina, primary, Folkes, Adrian, primary, Gowan, Sharon, primary, De Haven Brandon, Alexis, primary, Di Stefano, Francesca, primary, Hayes, Angela, primary, Henley, Alan T., primary, Lensun, Letitia, primary, Pergl-Wilson, Giles, primary, Robson, Anthony, primary, Saghir, Nahid, primary, Zhyvoloup, Alexander, primary, McDonald, Edward, primary, Sheldrake, Peter, primary, Shuttleworth, Stephen, primary, Valenti, Melanie, primary, Wan, Nan Chi, primary, Clarke, Paul A., primary, and Workman, Paul, primary

Published
2023
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48. Supplementary Table 6A from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Author

Yap, Timothy A., primary, Walton, Mike I., primary, Grimshaw, Kyla M., primary, te Poele, Robert H., primary, Eve, Paul D., primary, Valenti, Melanie R., primary, de Haven Brandon, Alexis K., primary, Martins, Vanessa, primary, Zetterlund, Anna, primary, Heaton, Simon P., primary, Heinzmann, Kathrin, primary, Jones, Paul S., primary, Feltell, Ruth E., primary, Reule, Matthias, primary, Woodhead, Steven J., primary, Davies, Thomas G., primary, Lyons, John F., primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Workman, Paul, primary, Thompson, Neil T., primary, and Garrett, Michelle D., primary

Published
2023
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49. Supplementary Figure 3 from CCT244747 Is a Novel Potent and Selective CHK1 Inhibitor with Oral Efficacy Alone and in Combination with Genotoxic Anticancer Drugs

Author

Walton, Mike I., primary, Eve, Paul D., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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50. Supplementary Figure 4 from CCT244747 Is a Novel Potent and Selective CHK1 Inhibitor with Oral Efficacy Alone and in Combination with Genotoxic Anticancer Drugs

Author

Walton, Mike I., primary, Eve, Paul D., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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