Now showing items 21-40 of 79

    • Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. 

      Tacconi, EM; Badie, S; De Gregoriis, G; Reisländer, T; Lai, X; Porru, M; Folio, C; Moore, J; Kopp, A; Baguña Torres, J; Sneddon, D; Green, M; Dedic, S; Lee, JW; Batra, AS; Rueda, OM; Bruna, A; Leonetti, C; Caldas, C; Cornelissen, B; Brino, L; Ryan, A; Biroccio, A; Tarsounas, M (2019-07)
      Due to compromised homologous recombination (HR) repair, BRCA1- and BRCA2-mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically ...
    • The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma. 

      Walton, MI; Eve, PD; Hayes, A; Henley, AT; Valenti, MR; De Haven Brandon, AK; Box, G; Boxall, KJ; Tall, M; Swales, K; Matthews, TP; McHardy, T; Lainchbury, M; Osborne, J; Hunter, JE; Perkins, ND; Aherne, GW; Reader, JC; Raynaud, FI; Eccles, SA; Collins, I; Garrett, MD (2016-01)
      CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently ...
    • Correlation of Ultrasound Shear Wave Elastography with Pathological Analysis in a Xenografic Tumour Model. 

      Elyas, E; Papaevangelou, E; Alles, EJ; Erler, JT; Cox, TR; Robinson, SP; Bamber, JC (2017-03-13)
      The objective of this study was to evaluate the potential value of ultrasound (US) shear wave elastography (SWE) in assessing the relative change in elastic modulus in colorectal adenocarcinoma xenograft models in vivo and ...
    • CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. 

      Zimmermann, M; Murina, O; Reijns, MAM; Agathanggelou, A; Challis, R; Tarnauskaitė, Ž; Muir, M; Fluteau, A; Aregger, M; McEwan, A; Yuan, W; Clarke, M; Lambros, MB; Paneesha, S; Moss, P; Chandrashekhar, M; Angers, S; Moffat, J; Brunton, VG; Hart, T; de Bono, J; Stankovic, T; Jackson, AP; Durocher, D (2018-07-04)
      The observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in ...
    • Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. 

      Dolman, MEM; Poon, E; Ebus, ME; den Hartog, IJM; van Noesel, CJM; Jamin, Y; Hallsworth, A; Robinson, SP; Petrie, K; Sparidans, RW; Kok, RJ; Versteeg, R; Caron, HN; Chesler, L; Molenaar, JJ (2015-11)
      <h4>Purpose</h4>MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that ...
    • Detection of circulating tumour cell clusters in human glioblastoma. 

      Krol, I; Castro-Giner, F; Maurer, M; Gkountela, S; Szczerba, BM; Scherrer, R; Coleman, N; Carreira, S; Bachmann, F; Anderson, S; Engelhardt, M; Lane, H; Evans, TRJ; Plummer, R; Kristeleit, R; Lopez, J; Aceto, N (2018-08)
      Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular ...
    • Diffusion-weighted MRI for imaging cell death after cytotoxic or apoptosis-inducing therapy. 

      Papaevangelou, E; Almeida, GS; Jamin, Y; Robinson, SP; deSouza, NM (2015-04-16)
      <h4>Background</h4>Non-invasive serial imaging is desirable to detect processes such as necrotic and apoptotic cell death in cancer patients undergoing treatment. This study investigated the use of diffusion-weighted (DW-) ...
    • Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. 

      Mallinger, A; Crumpler, S; Pichowicz, M; Waalboer, D; Stubbs, M; Adeniji-Popoola, O; Wood, B; Smith, E; Thai, C; Henley, AT; Georgi, K; Court, W; Hobbs, S; Box, G; Ortiz-Ruiz, M-J; Valenti, M; De Haven Brandon, A; TePoele, R; Leuthner, B; Workman, P; Aherne, W; Poeschke, O; Dale, T; Wienke, D; Esdar, C; Rohdich, F; Raynaud, F; Clarke, PA; Eccles, SA; Stieber, F; Schiemann, K; Blagg, J (2015-02-13)
      WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted ...
    • Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19. 

      Mallinger, A; Schiemann, K; Rink, C; Stieber, F; Calderini, M; Crumpler, S; Stubbs, M; Adeniji-Popoola, O; Poeschke, O; Busch, M; Czodrowski, P; Musil, D; Schwarz, D; Ortiz-Ruiz, M-J; Schneider, R; Thai, C; Valenti, M; de Haven Brandon, A; Burke, R; Workman, P; Dale, T; Wienke, D; Clarke, PA; Esdar, C; Raynaud, FI; Eccles, SA; Rohdich, F; Blagg, J (2016-02)
      The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 ...
    • Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα<sup>WT</sup> and ERα<sup>MUT</sup> Breast Cancer. 

      Puyang, X; Furman, C; Zheng, GZ; Wu, ZJ; Banka, D; Aithal, K; Agoulnik, S; Bolduc, DM; Buonamici, S; Caleb, B; Das, S; Eckley, S; Fekkes, P; Hao, M-H; Hart, A; Houtman, R; Irwin, S; Joshi, JJ; Karr, C; Kim, A; Kumar, N; Kumar, P; Kuznetsov, G; Lai, WG; Larsen, N; Mackenzie, C; Martin, L-A; Melchers, D; Moriarty, A; Nguyen, T-V; Norris, J; O'Shea, M; Pancholi, S; Prajapati, S; Rajagopalan, S; Reynolds, DJ; Rimkunas, V; Rioux, N; Ribas, R; Siu, A; Sivakumar, S; Subramanian, V; Thomas, M; Vaillancourt, FH; Wang, J; Wardell, S; Wick, MJ; Yao, S; Yu, L; Warmuth, M; Smith, PG; Zhu, P; Korpal, M (2018-09)
      Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant ...
    • EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer. 

      Oldrini, B; Hsieh, W-Y; Erdjument-Bromage, H; Codega, P; Carro, MS; Curiel-García, A; Campos, C; Pourmaleki, M; Grommes, C; Vivanco, I; Rohle, D; Bielski, CM; Taylor, BS; Hollmann, TJ; Rosenblum, M; Tempst, P; Blenis, J; Squatrito, M; Mellinghoff, IK (2017-12-11)
      Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains ...
    • Evaluation of the Response of Intracranial Xenografts to VEGF Signaling Inhibition Using Multiparametric MRI. 

      Boult, JKR; Box, G; Vinci, M; Perryman, L; Eccles, SA; Jones, C; Robinson, SP (2017-09)
      Vascular endothelial growth factor A (VEGF-A) is considered one of the most important factors in tumor angiogenesis, and consequently, a number of therapeutics have been developed to inhibit VEGF signaling. Therapeutic ...
    • Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. 

      Arce Vargas, F; Furness, AJS; Litchfield, K; Joshi, K; Rosenthal, R; Ghorani, E; Solomon, I; Lesko, MH; Ruef, N; Roddie, C; Henry, JY; Spain, L; Ben Aissa, A; Georgiou, A; Wong, YNS; Smith, M; Strauss, D; Hayes, A; Nicol, D; O'Brien, T; Mårtensson, L; Ljungars, A; Teige, I; Frendéus, B; TRACERx Melanoma; TRACERx Renal; TRACERx Lung consortia; Pule, M; Marafioti, T; Gore, M; Larkin, J; Turajlic, S; Swanton, C; Peggs, KS; Quezada, SA (2018-04)
      With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion ...
    • Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. 

      Aarts, M; Sharpe, R; Garcia-Murillas, I; Gevensleben, H; Hurd, MS; Shumway, SD; Toniatti, C; Ashworth, A; Turner, NC (2012-06)
      Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. ...
    • Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. 

      Pettitt, SJ; Krastev, DB; Brandsma, I; Dréan, A; Song, F; Aleksandrov, R; Harrell, MI; Menon, M; Brough, R; Campbell, J; Frankum, J; Ranes, M; Pemberton, HN; Rafiq, R; Fenwick, K; Swain, A; Guettler, S; Lee, J-M; Swisher, EM; Stoynov, S; Yusa, K; Ashworth, A; Lord, CJ (2018-05-10)
      Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 ...
    • High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial. 

      Pearson, A; Smyth, E; Babina, IS; Herrera-Abreu, MT; Tarazona, N; Peckitt, C; Kilgour, E; Smith, NR; Geh, C; Rooney, C; Cutts, R; Campbell, J; Ning, J; Fenwick, K; Swain, A; Brown, G; Chua, S; Thomas, A; Johnston, SRD; Ajaz, M; Sumpter, K; Gillbanks, A; Watkins, D; Chau, I; Popat, S; Cunningham, D; Turner, NC (2016-08)
      <h4>Unlabelled</h4>FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with ...
    • Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation. 

      Dalton, WB; Helmenstine, E; Walsh, N; Gondek, LP; Kelkar, DS; Read, A; Natrajan, R; Christenson, ES; Roman, B; Das, S; Zhao, L; Leone, RD; Shinn, D; Groginski, T; Madugundu, AK; Patil, A; Zabransky, DJ; Medford, A; Lee, J; Cole, AJ; Rosen, M; Thakar, M; Ambinder, A; Donaldson, J; DeZern, AE; Cravero, K; Chu, D; Madero-Marroquin, R; Pandey, A; Hurley, PJ; Lauring, J; Park, BH (2019-08-08)
      Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are ...
    • HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target. 

      Fok, JHL; Hedayat, S; Zhang, L; Aronson, LI; Mirabella, F; Pawlyn, C; Bright, MD; Wardell, CP; Keats, JJ; De Billy, E; Rye, CS; Chessum, NEA; Jones, K; Morgan, GJ; Eccles, SA; Workman, P; Davies, FE (2018-05)
      Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) ...
    • Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells. 

      Klampatsa, A; Achkova, DY; Davies, DM; Parente-Pereira, AC; Woodman, N; Rosekilly, J; Osborne, G; Thayaparan, T; Bille, A; Sheaf, M; Spicer, JF; King, J; Maher, J (2017-05)
      Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. ...
    • Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response. 

      Georgopoulou, D; Callari, M; Rueda, OM; Shea, A; Martin, A; Giovannetti, A; Qosaj, F; Dariush, A; Chin, S-F; Carnevalli, LS; Provenzano, E; Greenwood, W; Lerda, G; Esmaeilishirazifard, E; O'Reilly, M; Serra, V; Bressan, D; IMAXT Consortium; Mills, GB; Ali, HR; Cosulich, SS; Hannon, GJ; Bruna, A; Caldas, C (2021-03-31)
      The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized ...