Recent submissions

  • Molecular profiling and combinatorial activity of CCT068127: A potent CDK2 and CDK9 inhibitor. 

    Whittaker, SR; Barlow, C; Martin, MP; Mancusi, C; Wagner, S; Self, A; Barrie, E; Te Poele, R; Sharp, S; Brown, N; Wilson, S; Jackson, W; Fischer, PM; Clarke, PA; Walton, MI; McDonald, E; Blagg, J; Noble, M; Garrett, MD; Workman, P (2017-10-24)
    Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. ...
  • Inhibitors of cyclin-dependent kinases as cancer therapeutics. 

    Whittaker, SR; Mallinger, A; Workman, P; Clarke, PA (2017-05)
    Over the past two decades there has been a great deal of interest in the development of inhibitors of the cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that different CDK isoforms have ...
  • A Phase 1 open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers. 

    Banerji, U; Dean, E; Pérez-Fidalgo, JA; Batist, G; Bedard, PL; You, B; Westin, SN; Kabos, P; Garrett, MD; Tall, M; Ambrose, HJ; Barrett, JC; Carr, TH; Cheung, SA; Corcoran, C; Cullberg, M; Davies, BR; de Bruin, EC; Elvin, P; Foxley, A; Lawrence, P; Lindemann, JPO; Maudsley, R; Pass, M; Rowlands, V; Rugman, P; Schiavon, G; Yates, JW; Schellens, JHM (2017-10-24)
    PURPOSE: This Phase 1, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives ...
  • A study of PD-L1 expression in KRAS mutant non-small cell lung cancer cell lines exposed to relevant targeted treatments. 

    Minchom, A; Thavasu, P; Ahmad, Z; Stewart, A; Georgiou, A; O'Brien, MER; Popat, S; Bhosle, J; Yap, TA; de Bono, J; Banerji, U (2017)
    We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected ...
  • Characterisation of the immune-related transcriptome in resected biliary tract cancers. 

    Ghidini, M; Cascione, L; Carotenuto, P; Lampis, A; Trevisani, F; Previdi, MC; Hahne, JC; Said-Huntingford, I; Raj, M; Zerbi, A; Mescoli, C; Cillo, U; Rugge, M; Roncalli, M; Torzilli, G; Rimassa, L; Santoro, A; Valeri, N; Fassan, M; Braconi, C (2017-10-05)
    Although biliary tract cancers (BTCs) are known to have an inflammatory component, a detailed characterisation of immune-related transcripts has never been performed. In these studies, nCounter PanCancer Immune Profiling ...
  • The PI3K pathway at the crossroads of cancer and the immune system: strategies for next generation immunotherapy combinations. 

    Collins, D; Chenard-Poirier, M; Lopez, J (2017-09-26)
    Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for a subset of patients with advanced cancers. Increasingly, research has identified links between ...
  • 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 (2017-10-16)
    Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterised by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we ...
  • Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution. 

    Hayes, A; Mok, NY; Liu, M; Thai, C; Henley, AT; Atrash, B; Lanigan, RM; Sejberg, J; Le Bihan, YV; Bavetsias, V; Blagg, J; Raynaud, FI (2016-09-12)
    1.We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2.Although exemplar compound 1 ...
  • Erratum to: investigation of metabolites for estimating blood deposition time. 

    Lech, K; Liu, F; Davies, SK; Ackermann, K; Ang, JE; Middleton, B; Revell, VL; Raynaud, FI; Hoveijn, I; Hut, RA; Skene, DJ; Kayser, M (2017-08-24)
  • Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent. 

    van Erp, AEM; Versleijen-Jonkers, YMH; Hillebrandt-Roeffen, MHS; van Houdt, L; Gorris, MAJ; van Dam, LS; Mentzel, T; Weidema, ME; Savci-Heijink, CD; Desar, IME; Merks, HHM; van Noesel, MM; Shipley, J; van der Graaf, WTA; Flucke, UE; Meyer-Wentrup, FAG (2017-07-07)
    In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 ...
  • AKT Inhibition in Solid Tumors With AKT1 Mutations. 

    Hyman, DM; Smyth, LM; Donoghue, MTA; Westin, SN; Bedard, PL; Dean, EJ; Bando, H; El-Khoueiry, AB; Pérez-Fidalgo, JA; Mita, A; Schellens, JHM; Chang, MT; Reichel, JB; Bouvier, N; Selcuklu, SD; Soumerai, TE; Torrisi, J; Erinjeri, JP; Ambrose, H; Barrett, JC; Dougherty, B; Foxley, A; Lindemann, JPO; McEwen, R; Pass, M; Schiavon, G; Berger, MF; Chandarlapaty, S; Solit, DB; Banerji, U; Baselga, J; Taylor, BS (2017-07-10)
    Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary ...
  • Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma. 

    Qin, EY; Cooper, DD; Abbott, KL; Lennon, J; Nagaraja, S; Mackay, A; Jones, C; Vogel, H; Jackson, PK; Monje, M (2017-08-24)
    The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that ...
  • Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. 

    Mackay, A; Burford, A; Carvalho, D; Izquierdo, E; Fazal-Salom, J; Taylor, KR; Bjerke, L; Clarke, M; Vinci, M; Nandhabalan, M; Temelso, S; Popov, S; Molinari, V; Raman, P; Waanders, AJ; Han, HJ; Gupta, S; Marshall, L; Zacharoulis, S; Vaidya, S; Mandeville, HC; Bridges, LR; Martin, AJ; Al-Sarraj, S; Chandler, C; Ng, H-K; Li, X; Mu, K; Trabelsi, S; Brahim, DH-B; Kisljakov, AN; Konovalov, DM; Moore, AS; Carcaboso, AM; Sunol, M; de Torres, C; Cruz, O; Mora, J; Shats, LI; Stavale, JN; Bidinotto, LT; Reis, RM; Entz-Werle, N; Farrell, M; Cryan, J; Crimmins, D; Caird, J; Pears, J; Monje, M; Debily, M-A; Castel, D; Grill, J; Hawkins, C; Nikbakht, H; Jabado, N; Baker, SJ; Pfister, SM; Jones, DTW; Fouladi, M; von Bueren, AO; Baudis, M; Resnick, A; Jones, C (2017-10-09)
    We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating ...
  • Lysine-Targeting Covalent Inhibitors. 

    Pettinger, J; Jones, K; Cheeseman, MD (2017-08-29)
    Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small-molecule/protein crystal structures to design ...
  • Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors. 

    Wagner, AJ; Banerji, U; Mahipal, A; Somaiah, N; Hirsch, H; Fancourt, C; Johnson-Levonas, AO; Lam, R; Meister, AK; Russo, G; Knox, CD; Rose, S; Hong, DS (2017-04-20)
    Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was ...
  • Targeting TAO Kinases Using a New Inhibitor Compound Delays Mitosis and Induces Mitotic Cell Death in Centrosome Amplified Breast Cancer Cells. 

    Koo, C-Y; Giacomini, C; Reyes-Corral, M; Olmos, Y; Tavares, IA; Marson, CM; Linardopoulos, S; Tutt, AN; Morris, JDH (2017-11)
    Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and ...
  • Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach. 

    Pollock, K; Ranes, M; Collins, I; Guettler, S (2017)
    The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins ...
  • Dynamic Equilibrium of the Aurora A Kinase Activation Loop Revealed by Single-Molecule Spectroscopy. 

    Gilburt, JAH; Sarkar, H; Sheldrake, P; Blagg, J; Ying, L; Dodson, CA (2017-09-11)
    The conformation of the activation loop (T-loop) of protein kinases underlies enzymatic activity and influences the binding of small-molecule inhibitors. By using single-molecule fluorescence spectroscopy, we have determined ...
  • Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform. 

    Almeida, GS; Panek, R; Hallsworth, A; Webber, H; Papaevangelou, E; Boult, JK; Jamin, Y; Chesler, L; Robinson, SP (2017-09-05)
    BACKGROUND: The use of clinical MRI scanners to conduct pre-clinical research facilitates comparisons with clinical studies. Here the utility and sensitivity of anatomical and functional MRI data/biomarkers acquired from ...

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