Now showing items 1-20 of 55

    • Acute tumour response to a bispecific Ang-2-VEGF-A antibody: insights from multiparametric MRI and gene expression profiling. 

      Baker, LCJ; Boult, JKR; Thomas, M; Koehler, A; Nayak, T; Tessier, J; Ooi, C-H; Birzele, F; Belousov, A; Zajac, M; Horn, C; LeFave, C; Robinson, SP (2016-09)
      BACKGROUND:To assess antivascular effects, and evaluate clinically translatable magnetic resonance imaging (MRI) biomarkers of tumour response in vivo, following treatment with vanucizumab, a bispecific human antibody ...
    • The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN. 

      Guan, J; Tucker, ER; Wan, H; Chand, D; Danielson, LS; Ruuth, K; El Wakil, A; Witek, B; Jamin, Y; Umapathy, G; Robinson, SP; Johnson, TW; Smeal, T; Martinsson, T; Chesler, L; Palmer, RH; Hallberg, B (2016-09)
      The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in ...
    • ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma. 

      Carvalho, D; Taylor, KR; Olaciregui, NG; Molinari, V; Clarke, M; Mackay, A; Ruddle, R; Henley, A; Valenti, M; Hayes, A; Brandon, ADH; Eccles, SA; Raynaud, F; Boudhar, A; Monje, M; Popov, S; Moore, AS; Mora, J; Cruz, O; Vinci, M; Brennan, PE; Bullock, AN; Carcaboso, AM; Jones, C (2019-01)
      Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug ...
    • Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. 

      Sharp, A; Coleman, I; Yuan, W; Sprenger, C; Dolling, D; Rodrigues, DN; Russo, JW; Figueiredo, I; Bertan, C; Seed, G; Riisnaes, R; Uo, T; Neeb, A; Welti, J; Morrissey, C; Carreira, S; Luo, J; Nelson, PS; Balk, SP; True, LD; de Bono, JS; Plymate, SR (2019-01)
      BACKGROUND:Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant ...
    • Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation. 

      Yin, Y; Li, R; Xu, K; Ding, S; Li, J; Baek, G; Ramanand, SG; Ding, S; Liu, Z; Gao, Y; Kanchwala, MS; Li, X; Hutchinson, R; Liu, X; Woldu, SL; Xing, C; Desai, NB; Feng, FY; Burma, S; de Bono, JS; Dehm, SM; Mani, RS; Chen, BPC; Raj, GV (2017-09)
      In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. ...
    • ATR Is a Therapeutic Target in Synovial Sarcoma. 

      Jones, SE; Fleuren, EDG; Frankum, J; Konde, A; Williamson, CT; Krastev, DB; Pemberton, HN; Campbell, J; Gulati, A; Elliott, R; Menon, M; Selfe, JL; Brough, R; Pettitt, SJ; Niedzwiedz, W; van der Graaf, WTA; Shipley, J; Ashworth, A; Lord, CJ (2017-12)
      Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we ...
    • The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. 

      Wang, Y; Bernhardy, AJ; Cruz, C; Krais, JJ; Nacson, J; Nicolas, E; Peri, S; van der Gulden, H; van der Heijden, I; O'Brien, SW; Zhang, Y; Harrell, MI; Johnson, SF; Candido Dos Reis, FJ; Pharoah, PDP; Karlan, B; Gourley, C; Lambrechts, D; Chenevix-Trench, G; Olsson, H; Benitez, JJ; Greene, MH; Gore, M; Nussbaum, R; Sadetzki, S; Gayther, SA; Kjaer, SK; kConFab Investigators; D'Andrea, AD; Shapiro, GI; Wiest, DL; Connolly, DC; Daly, MB; Swisher, EM; Bouwman, P; Jonkers, J; Balmaña, J; Serra, V; Johnson, N (2016-05)
      Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this ...
    • BRD4 facilitates replication stress-induced DNA damage response. 

      Zhang, J; Dulak, AM; Hattersley, MM; Willis, BS; Nikkilä, J; Wang, A; Lau, A; Reimer, C; Zinda, M; Fawell, SE; Mills, GB; Chen, H (2018-07)
      Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. Here we describe a novel role for BRD4 in DNA damage response (DDR). BRD4 associates with and ...
    • Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects. 

      Brody, LP; Sahuri-Arisoylu, M; Parkinson, JR; Parkes, HG; So, PW; Hajji, N; Thomas, EL; Frost, GS; Miller, AD; Bell, JD (2017-01)
      Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a ...
    • CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours. 

      Costa-Cabral, S; Brough, R; Konde, A; Aarts, M; Campbell, J; Marinari, E; Riffell, J; Bardelli, A; Torrance, C; Lord, CJ; Ashworth, A (2016-01)
      Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent ...
    • Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival. 

      Oser, MG; Fonseca, R; Chakraborty, AA; Brough, R; Spektor, A; Jennings, RB; Flaifel, A; Novak, JS; Gulati, A; Buss, E; Younger, ST; McBrayer, SK; Cowley, GS; Bonal, DM; Nguyen, Q-D; Brulle-Soumare, L; Taylor, P; Cairo, S; Ryan, CJ; Pease, EJ; Maratea, K; Travers, J; Root, DE; Signoretti, S; Pellman, D; Ashton, S; Lord, CJ; Barry, ST; Kaelin, WG (2019-02)
      Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the ...
    • Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy. 

      Faisal, A; Mak, GWY; Gurden, MD; Xavier, CPR; Anderhub, SJ; Innocenti, P; Westwood, IM; Naud, S; Hayes, A; Box, G; Valenti, MR; De Haven Brandon, AK; O'Fee, L; Schmitt, J; Woodward, HL; Burke, R; vanMontfort, RLM; Blagg, J; Raynaud, FI; Eccles, SA; Hoelder, S; Linardopoulos, S (2017-04)
      BACKGROUND:The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents ...
    • CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy. 

      Barker, HE; Patel, R; McLaughlin, M; Schick, U; Zaidi, S; Nutting, CM; Newbold, KL; Bhide, S; Harrington, KJ (2016-09)
      Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a ...
    • 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)
      PURPOSE: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 targeted ...
    • 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 ...
    • 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 ERαWT and ERαMUT 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 ...