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1. SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Author

Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N., Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., and Natrajan, Rachael

Published
2023
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4. Anti-EGFR antibody-drug conjugate carrying an inhibitor targeting CDK restricts triple-negative breast cancer growth

Author

Cheung, Anthony, primary, Chenoweth, Alicia M., additional, Johansson, Annelie, additional, Laddach, Roman, additional, Guppy, Naomi, additional, Trendell, Jennifer, additional, Esapa, Benjamina, additional, Mavousian, Antranik, additional, Navarro-Llinas, Blanca, additional, Haider, Syed, additional, Romero-Clavijo, Pablo, additional, Hoffmann, Ricarda M., additional, Andriollo, Paolo, additional, Rahman, Khondaker Miraz, additional, Jackson, Paul, additional, Tsoka, Sophia, additional, Irshad, Sheeba, additional, Roxanis, Ioannis, additional, Grigoriadis, Anita, additional, Thurston, David E., additional, Lord, Christopher J., additional, Tutt, Andrew N.J., additional, and Karagiannis, Sophia N., additional

Published
2024
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5. A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death

Author

Mannion, Jonathan, primary, Gifford, Valentina, additional, Bellenie, Benjamin, additional, Fernando, Winnie, additional, Ramos Garcia, Laura, additional, Wilson, Rebecca, additional, John, Sidonie Wicky, additional, Udainiya, Savita, additional, Patin, Emmanuel C., additional, Tiu, Crescens, additional, Smith, Angel, additional, Goicoechea, Maria, additional, Craxton, Andrew, additional, Moraes de Vasconcelos, Nathalia, additional, Guppy, Naomi, additional, Cheung, Kwai-Ming J., additional, Cundy, Nicholas J., additional, Pierrat, Olivier, additional, Brennan, Alfie, additional, Roumeliotis, Theodoros I., additional, Benstead-Hume, Graeme, additional, Alexander, John, additional, Muirhead, Gareth, additional, Layzell, Scott, additional, Lyu, Wenxin, additional, Roulstone, Victoria, additional, Allen, Mark, additional, Baldock, Holly, additional, Legrand, Arnaud, additional, Gabel, Florian, additional, Serrano-Aparicio, Natalia, additional, Starling, Chris, additional, Guo, Hongyan, additional, Upton, Jason, additional, Gyrd-Hansen, Mads, additional, MacFarlane, Marion, additional, Seddon, Benedict, additional, Raynaud, Florence, additional, Roxanis, Ioannis, additional, Harrington, Kevin, additional, Haider, Syed, additional, Choudhary, Jyoti S., additional, Hoelder, Swen, additional, Tenev, Tencho, additional, and Meier, Pascal, additional

Published
2024
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6. Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance

Author

Garcia, Laura Ramos, Tenev, Tencho, Newman, Richard, Haich, Rachel O., Liccardi, Gianmaria, John, Sidonie Wicky, Annibaldi, Alessandro, Yu, Lu, Pardo, Mercedes, Young, Samuel N., Fitzgibbon, Cheree, Fernando, Winnie, Guppy, Naomi, Kim, Hyojin, Liang, Lung-Yu, Lucet, Isabelle S., Kueh, Andrew, Roxanis, Ioannis, Gazinska, Patrycja, Sims, Martin, Smyth, Tomoko, Ward, George, Bertin, John, Beal, Allison M., Geddes, Brad, Choudhary, Jyoti S., Murphy, James M., Aurelia Ball, K., Upton, Jason W., and Meier, Pascal

Published
2021
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8. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response

Author

Nagarajan, Sankari, Rao, Shalini V., Sutton, Joseph, Cheeseman, Danya, Dunn, Shanade, Papachristou, Evangelia K., Prada, Jose-Enrique Gonzalez, Couturier, Dominique-Laurent, Kumar, Sanjeev, Kishore, Kamal, Chilamakuri, Chandra Sekhar Reddy, Glont, Silvia-Elena, Archer Goode, Emily, Brodie, Cara, Guppy, Naomi, Natrajan, Rachael, Bruna, Alejandra, Caldas, Carlos, Russell, Alasdair, Siersbæk, Rasmus, Yusa, Kosuke, Chernukhin, Igor, and Carroll, Jason S.

Published
2020
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9. Studies on the behaviour of human pancreatic carcinoma cell lines, with particular reference to stem cells

Author

Guppy, Naomi J.

Subjects
611, Medicine
Abstract

Stem cell therapy represents a potential -cell replacement strategy in diabetes and a pancreatic cancer (PC) stem cell is an attractive therapeutic target in this dire disease. However, a normal stem cell remains unidentified and proposed malignant stem cell markers await verification. Using human PC cell lines as an in vitro tumour model and human archival tissue, and proposed stem cell markers identified in other normal tissues and tumours, we attempted to identify a PC stem cell. These markers included high aldehyde dehydrogenase activity, the Side Population (SP) phenotype, and the cell surface markers CD44 and CD133. These markers were evaluated by flow cytometry, immunohistochemistry (IHC) and reverse-transcriptase PCR. Positive populations were isolated from cell lines using fluorescence activated cell sorting (FACS) and subjected to in vitro colony-forming assays to assess their relative proliferative capacities. The presence of a differentiation hierarchy was investigated in one line to test the assumptions of the tumour model. No single marker or combination thereof consistently identified a highly clonogenic fraction, though some differences in clonogenicity were seen. Furthermore, the dye Hoechst 33342 was found to inhibit proliferation, potentially inducing artefactual differences in clonogenicity between SP and non-SP cells. Recently, expression of trefoil factor family peptide (TFF) 3, a gastrointestinal motogen, was reported in human islets of Langerhans. Furthermore, this peptide was reported as a -cell mitogen in vitro, and a potential agent of functional -cell production. We employed isotopic in situ hybridization and IHC to evaluate TFF expression in normal human pancreas, chronic pancreatitis and PC. Expression of all three TFFs was increased in inflammation and cancer, and TFF3 mRNA was occasionally detected in islets. The motogenic activity of TFF peptides was investigated using in vitro wound healing and invasion assays on human PC lines and primary stellate cell cultures. TFF2 was seen to enhance migration in PC lines at high concentrations.

Published
2010

13. Data from BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Author

Busacca, Sara, primary, O'Regan, Laura, primary, Singh, Anita, primary, Sharkey, Annabel J., primary, Dawson, Alan G., primary, Dzialo, Joanna, primary, Parsons, Aimee, primary, Kumar, Neelam, primary, Schunselaar, Laurel M., primary, Guppy, Naomi, primary, Nakas, Apostolos, primary, Sheaff, Michael, primary, Mansfield, Aaron S., primary, Janes, Sam M., primary, Baas, Paul, primary, Fry, Andrew M., primary, and Fennell, Dean A., primary

Published
2023
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14. Table S3 from BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Author

Busacca, Sara, primary, O'Regan, Laura, primary, Singh, Anita, primary, Sharkey, Annabel J., primary, Dawson, Alan G., primary, Dzialo, Joanna, primary, Parsons, Aimee, primary, Kumar, Neelam, primary, Schunselaar, Laurel M., primary, Guppy, Naomi, primary, Nakas, Apostolos, primary, Sheaff, Michael, primary, Mansfield, Aaron S., primary, Janes, Sam M., primary, Baas, Paul, primary, Fry, Andrew M., primary, and Fennell, Dean A., primary

Published
2023
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15. Figure S5 from BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Author

Busacca, Sara, primary, O'Regan, Laura, primary, Singh, Anita, primary, Sharkey, Annabel J., primary, Dawson, Alan G., primary, Dzialo, Joanna, primary, Parsons, Aimee, primary, Kumar, Neelam, primary, Schunselaar, Laurel M., primary, Guppy, Naomi, primary, Nakas, Apostolos, primary, Sheaff, Michael, primary, Mansfield, Aaron S., primary, Janes, Sam M., primary, Baas, Paul, primary, Fry, Andrew M., primary, and Fennell, Dean A., primary

Published
2023
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16. Table S4 from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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17. Data from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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18. Supplementary Methods from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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19. Figure S1- S8 from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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20. Abstract P6-10-05: Mutations in the RNA Splicing Factor SF3B1 drive endocrine therapy resistance and confer a targetable replication stress response defect through PARP inhibition

Author

Bland, Phil, primary, Saville, Harry, additional, Read, Abigail, additional, Wai, Patty, additional, Muirhead, Gareth, additional, Curnow, Lucinda, additional, Nieminuszczy, Jadwiga, additional, Ravindran, Nivedita, additional, John, Marie, additional, Hedayat, Somaieh, additional, Barker, Holly, additional, Wright, James, additional, Yu, Lu, additional, Mavrommati, Ioanna, additional, Peck, Barrie, additional, Allen, Mark, additional, Gazinska, Patrycja, additional, Pemberton, Helen, additional, Gulati, Aditi, additional, Nash, Sarah, additional, Noor, Farzana, additional, Guppy, Naomi, additional, Roxanis, Ioannis, additional, Barlow, Samantha, additional, Kalirai, Helen, additional, Coupland, Sarah, additional, Broderick, Ronan, additional, Alsafadi, Samar, additional, Houy, Alexandre, additional, Stern, Marc-Henri, additional, Pettit, Stephen, additional, Choudhary, Jyoti, additional, Haider, Syed, additional, Niedzwiedz, Wojciech, additional, Lord, Christopher, additional, and Natrajan, Rachael, additional

Published
2023
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21. Author Correction: ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response

Author

Nagarajan, Sankari, Rao, Shalini V., Sutton, Joseph, Cheeseman, Danya, Dunn, Shanade, Papachristou, Evangelia K., Prada, Jose-Enrique Gonzalez, Couturier, Dominique-Laurent, Kumar, Sanjeev, Kishore, Kamal, Chilamakuri, Chandra Sekhar Reddy, Glont, Silvia-Elena, Goode, Emily Archer, Brodie, Cara, Guppy, Naomi, Natrajan, Rachael, Bruna, Alejandra, Caldas, Carlos, Russell, Alasdair, Siersbæk, Rasmus, Yusa, Kosuke, Chernukhin, Igor, and Carroll, Jason S.

Published
2020
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24. Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma

Author

Khalique, Saira, primary, Nash, Sarah, additional, Mansfield, David, additional, Wampfler, Julian, additional, Attygale, Ayoma, additional, Vroobel, Katherine, additional, Kemp, Harriet, additional, Buus, Richard, additional, Cottom, Hannah, additional, Roxanis, Ioannis, additional, Jones, Thomas, additional, von Loga, Katharina, additional, Begum, Dipa, additional, Guppy, Naomi, additional, Ramagiri, Pradeep, additional, Fenwick, Kerry, additional, Matthews, Nik, additional, Hubank, Michael, additional, Lord, Christopher, additional, Haider, Syed, additional, Melcher, Alan, additional, Banerjee, Susana, additional, and Natrajan, Rachael, additional

Published
2021
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26. SF3B1hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Author

Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N., Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., and Natrajan, Rachael

Abstract

SF3B1hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUTcells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUTcancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Published
2023
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27. 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, additional, Mavrommati, Ioanna, additional, Muirhead, Gareth, additional, Cottom, Hannah, additional, Wai, Patty T., additional, Maguire, Sarah L., additional, Barker, Holly E., additional, Morrison, Eamonn, additional, Kriplani, Divya, additional, Yu, Lu, additional, Gibson, Amy, additional, Falgari, Giulia, additional, Brennan, Keith, additional, Farnie, Gillian, additional, Buus, Richard, additional, Marlow, Rebecca, additional, Novo, Daniela, additional, Knight, Eleanor, additional, Guppy, Naomi, additional, Kolarevic, Daniela, additional, Susnjar, Snezana, additional, Milijic, Natasa Medic, additional, Naidoo, Kalnisha, additional, Gazinska, Patrycja, additional, Roxanis, Ioannis, additional, Pancholi, Sunil, additional, Martin, Lesley-Ann, additional, Holgersen, Erle M., additional, Cheang, Maggie C.U., additional, Noor, Farzana, additional, Postel-Vinay, Sophie, additional, Quinn, Gerard, additional, McDade, Simon, additional, Krasny, Lukas, additional, Huang, Paul, additional, Daley, Frances, additional, Wallberg, Fredrik, additional, Choudhary, Jyoti S., additional, Haider, Syed, additional, Tutt, Andrew N., additional, and Natrajan, Rachael, additional

Published
2021
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28. BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Author

Busacca, Sara, primary, O'Regan, Laura, additional, Singh, Anita, additional, Sharkey, Annabel J., additional, Dawson, Alan G., additional, Dzialo, Joanna, additional, Parsons, Aimee, additional, Kumar, Neelam, additional, Schunselaar, Laurel M., additional, Guppy, Naomi, additional, Nakas, Apostolos, additional, Sheaff, Michael, additional, Mansfield, Aaron S., additional, Janes, Sam M., additional, Baas, Paul, additional, Fry, Andrew M., additional, and Fennell, Dean A., additional

Published
2021
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33. Tumor Necrosis Factor (TNF) bioactivity at the site of an acute cell-mediated immune response Is preserved in rheumatoid arthritis patients responding to Anti-TNF therapy

Author

Byng-Maddick, Rachel, Turner, Carolin T., Pollara, Gabriele, Ellis, Matthew, Guppy, Naomi J., Bell, Lucy C. K., Ehrenstein, Michael R., and Noursadeghi, Mahdad

Subjects
rheumatoid arthritis, anti-tumor necrosis factor, tumor necrosis factor, Immunology, Immunology and Allergy, tuberculin skin test, transcriptional profiling
Abstract

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

Published
2017

35. Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells

Author

Kolluri, Krishna Kalyan, primary, Alifrangis, Constantine, additional, Kumar, Neelam, additional, Ishii, Yuki, additional, Price, Stacey, additional, Michaut, Magali, additional, Williams, Steven, additional, Barthorpe, Syd, additional, Lightfoot, Howard, additional, Busacca, Sara, additional, Sharkey, Annabel, additional, Yuan, Zhenqiang, additional, Sage, Elizabeth K, additional, Vallath, Sabarinath, additional, Le Quesne, John, additional, Tice, David A, additional, Alrifai, Doraid, additional, von Karstedt, Sylvia, additional, Montinaro, Antonella, additional, Guppy, Naomi, additional, Waller, David A, additional, Nakas, Apostolos, additional, Good, Robert, additional, Holmes, Alan, additional, Walczak, Henning, additional, Fennell, Dean A, additional, Garnett, Mathew, additional, Iorio, Francesco, additional, Wessels, Lodewyk, additional, McDermott, Ultan, additional, and Janes, Samuel M, additional

Published
2018
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36. EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen: Focused Compound Screen in Chordoma

Author

Barnard, Michelle, Guppy, Naomi, Drewry, David H., Scheipl, Susanne, Möller, Peter, Leithner, Andreas, Turlais, Fabrice, Leite, Ana P., Ye, Hongtao, Zuercher, William J., Jorgensen, Mette, Smith, James A., Amary, Fernanda, Cottone, Lucia, Strauss, Sandra J., Pillay, Nischalan, Flanagan, Adrienne M., Brüderlein, Silke, and Tirabosco, Roberto

Abstract

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Published
2016
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37. Author response: Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells

Author

Kolluri, Krishna Kalyan, primary, Alifrangis, Constantine, additional, Kumar, Neelam, additional, Ishii, Yuki, additional, Price, Stacey, additional, Michaut, Magali, additional, Williams, Steven, additional, Barthorpe, Syd, additional, Lightfoot, Howard, additional, Busacca, Sara, additional, Sharkey, Annabel, additional, Yuan, Zhenqiang, additional, Sage, Elizabeth K, additional, Vallath, Sabarinath, additional, Le Quesne, John, additional, Tice, David A, additional, Alrifai, Doraid, additional, von Karstedt, Sylvia, additional, Montinaro, Antonella, additional, Guppy, Naomi, additional, Waller, David A, additional, Nakas, Apostolos, additional, Good, Robert, additional, Holmes, Alan, additional, Walczak, Henning, additional, Fennell, Dean A, additional, Garnett, Mathew, additional, Iorio, Francesco, additional, Wessels, Lodewyk, additional, McDermott, Ultan, additional, and Janes, Samuel M, additional

Published
2017
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39. The Impact of Diet‐Induced Weight Loss on Biomarkers for Colorectal Cancer: An Exploratory Study (INTERCEPT)

Author

Beeken, Rebecca J., primary, Croker, Helen, additional, Heinrich, Malgorzata, additional, Obichere, Austin, additional, Finer, Nicholas, additional, Murphy, Neil, additional, Goldin, Robert, additional, Guppy, Naomi J., additional, Wilson, Rose, additional, Fisher, Abigail, additional, Steptoe, Andrew, additional, Gunter, Marc J., additional, and Wardle, Jane, additional

Published
2017
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43. EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen

Author

Scheipl, Susanne, primary, Barnard, Michelle, additional, Cottone, Lucia, additional, Jorgensen, Mette, additional, Drewry, David H, additional, Zuercher, William J, additional, Turlais, Fabrice, additional, Ye, Hongtao, additional, Leite, Ana P, additional, Smith, James A, additional, Leithner, Andreas, additional, Möller, Peter, additional, Brüderlein, Silke, additional, Guppy, Naomi, additional, Amary, Fernanda, additional, Tirabosco, Roberto, additional, Strauss, Sandra J, additional, Pillay, Nischalan, additional, and Flanagan, Adrienne M, additional

Published
2016
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44. Developing Raman spectroscopy as a diagnostic tool for label‐free antigen detection.

Author

Lewis, Aaran T., Gaifulina, Riana, Guppy, Naomi J., Isabelle, Martin, Dorney, Jennifer, Lloyd, Gavin R., Rodriguez‐Justo, Manuel, Kendall, Catherine, Stone, Nicholas, and Thomas, Geraint M.

Abstract

For several decades, a multitude of studies have documented the ability of Raman spectroscopy (RS) to differentiate between tissue types and identify pathological changes to tissues in a range of diseases. Furthermore, spectroscopists have illustrated that the technique is capable of detecting disease‐specific alterations to tissue before morphological changes become apparent to the pathologist. This study draws comparisons between the information that is obtainable using RS alongside immunohistochemistry (IHC), since histological examination is the current GOLD standard for diagnosing a wide range of diseases. Here, Raman spectral maps were generated using formalin‐fixed, paraffin‐embedded colonic tissue sections from healthy patients and spectral signatures from principal components analysis (PCA) were compared with several IHC markers to confirm the validity of their localizations. PCA loadings identified a number of signatures that could be assigned to muscle, DNA and mucin glycoproteins and their distributions were confirmed with antibodies raised against anti‐Desmin, anti‐Ki67 and anti‐MUC2, respectively. The comparison confirms that there is excellent correlation between RS and the IHC markers used, demonstrating that the technique is capable of detecting compositional changes in tissue in a label‐free manner, eliminating the need for antibodies. [ABSTRACT FROM AUTHOR]

Published
2018
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46. Trefoil Factor Family Peptides in Normal and Diseased Human Pancreas

Author

Guppy, Naomi J., primary, El-Bahrawy, Mona E., additional, Kocher, Hemant M., additional, Fritsch, Kornelia, additional, Qureshi, Yassar A., additional, Poulsom, Richard, additional, Jeffery, Rosemary E., additional, Wright, Nicholas A., additional, Otto, William R., additional, and Alison, Malcolm R., additional

Published
2012
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48. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response

Author

Nagarajan, Sankari, Rao, Shalini V, Sutton, Joseph, Cheeseman, Danya, Dunn, Shanade, Papachristou, Evangelia K, Prada, Jose-Enrique Gonzalez, Couturier, Dominique-Laurent, Kumar, Sanjeev, Kishore, Kamal, Chilamakuri, Chandra Sekhar Reddy, Glont, Silvia-Elena, Archer Goode, Emily, Brodie, Cara, Guppy, Naomi, Natrajan, Rachael, Bruna, Alejandra, Caldas, Carlos, Russell, Alasdair, Siersbæk, Rasmus, Yusa, Kosuke, Chernukhin, Igor, and Carroll, Jason S

Subjects
Hepatocyte Nuclear Factor 3-alpha, Estrogen Receptor alpha, Acetylation, Breast Neoplasms, Cell Cycle Proteins, Histone Deacetylase 1, Xenograft Model Antitumor Assays, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Mice, Inbred NOD, MCF-7 Cells, Animals, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, Female, Cell Proliferation, Transcription Factors
Abstract

Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the factors most critically required for response to two classes of estrogen receptor-alpha (ER) antagonists. In this context, SWI/SNF-specific gene deletion resulted in drug resistance. Unexpectedly, ARID1A was also the top candidate in regard to response to the bromodomain and extraterminal domain inhibitor JQ1, but in the opposite direction, with loss of ARID1A sensitizing breast cancer cells to bromodomain and extraterminal domain inhibition. We show that ARID1A is a repressor that binds chromatin at ER cis-regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but forkhead box A1-dependent and active, ER-independent manner. Deletion of ARID1A resulted in loss of histone deacetylase 1 binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease, and our findings provide mechanistic insight into this process while revealing rational treatment strategies for these patients.

49. Cellular pathways to beta-cell replacement.

Author

Fellous TG, Guppy NJ, Brittan M, and Alison MR

Subjects
Animals, Epithelial Cells physiology, Humans, Mesoderm physiology, Pancreas cytology, Stem Cell Transplantation, Diabetes Mellitus, Type 1 drug therapy, Insulin-Secreting Cells transplantation, Islets of Langerhans Transplantation methods
Abstract

In the twenty-first century, diabetic patients are likely to be one of the major beneficiaries from the advancement of regenerative medicine through cellular therapies. Though the existence of a specific self-renewing stem cell within the pancreas is still far from clear, a surprising variety of cells within the pancreas can differentiate towards a beta-cell phenotype: ductular cells, periductular mesenchymal cells and beta-cells themselves can all give rise to new beta-cells. Extra-pancreatic adult somatic stem cells, in particular, those originating from bone marrow may also be capable of differentiating to beta-cells, though equally well the beneficial effects of bone marrow cells may reside in their contribution to the damaged islet vasculature. Forced expression of the beta-cell-specific transcription factor Pdx1 in hepatocytes also holds promise as a therapeutic strategy to increase insulin levels in diabetic individuals. Embryonic stem (ES) cells are clearly another possible source for generating beta-cells, but ES cells are beyond the scope of this review, which focuses on adult stem and progenitor cells capable of producing beta-cells. Despite considerable endeavour, we still have much to learn in the field of pancreatic regeneration prior to any clinically applicable therapy based upon adult stem cells., (Copyright 2006 John Wiley & Sons, Ltd.)

Published
2007
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