• Targeting molecular addictions in cancer. 

  Vivanco, I (2014-11)

  Cancer cells depend on a finite number of critical signals for their survival. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis ...
• A kinase-independent function of AKT promotes cancer cell survival. 

  Vivanco, I; Chen, ZC; Tanos, B; Oldrini, B; Hsieh, W-Y; Yannuzzi, N; Campos, C; Mellinghoff, IK (2014-12-31)

  The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function ...
• Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. 

  Litchfield, K; Summersgill, B; Yost, S; Sultana, R; Labreche, K; Dudakia, D; Renwick, A; Seal, S; Al-Saadi, R; Broderick, P; Turner, NC; Houlston, RS; Huddart, R; Shipley, J; Turnbull, C (2015-01-22)

  Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The mutation rate is uniformly ...
• Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. 

  Girotti, MR; Lopes, F; Preece, N; Niculescu-Duvaz, D; Zambon, A; Davies, L; Whittaker, S; Saturno, G; Viros, A; Pedersen, M; Suijkerbuijk, BMJM; Menard, D; McLeary, R; Johnson, L; Fish, L; Ejiama, S; Sanchez-Laorden, B; Hohloch, J; Carragher, N; Macleod, K; Ashton, G; Marusiak, AA; Fusi, A; Brognard, J; Frame, M; Lorigan, P; Marais, R; Springer, C (2015-01)

  BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway ...
• Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. 

  Hill, RM; Kuijper, S; Lindsey, JC; Petrie, K; Schwalbe, EC; Barker, K; Boult, JKR; Williamson, D; Ahmad, Z; Hallsworth, A; Ryan, SL; Poon, E; Robinson, SP; Ruddle, R; Raynaud, FI; Howell, L; Kwok, C; Joshi, A; Nicholson, SL; Crosier, S; Ellison, DW; Wharton, SB; Robson, K; Michalski, A; Hargrave, D; Jacques, TS; Pizer, B; Bailey, S; Swartling, FJ; Weiss, WA; Chesler, L; Clifford, SC (2015-01)

  We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, ...
• Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B. 

  Drouin, L; McGrath, S; Vidler, LR; Chaikuad, A; Monteiro, O; Tallant, C; Philpott, M; Rogers, C; Fedorov, O; Liu, M; Akhtar, W; Hayes, A; Raynaud, F; Müller, S; Knapp, S; Hoelder, S (2015-03)

  The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 ...
• 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 ...
• Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents. 

  Crespo, M; van Dalum, G; Ferraldeschi, R; Zafeiriou, Z; Sideris, S; Lorente, D; Bianchini, D; Rodrigues, DN; Riisnaes, R; Miranda, S; Figueiredo, I; Flohr, P; Nowakowska, K; de Bono, JS; Terstappen, LWMM; Attard, G (2015-03-31)

  BACKGROUND:Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based ...
• Higher Risk of Infections with PI3K-AKT-mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials. 

  Rafii, S; Roda, D; Geuna, E; Jimenez, B; Rihawi, K; Capelan, M; Yap, TA; Molife, LR; Kaye, SB; de Bono, JS; Banerji, U (2015-04)

  Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known ...
• Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. 

  Joshi, A; Newbatt, Y; McAndrew, PC; Stubbs, M; Burke, R; Richards, MW; Bhatia, C; Caldwell, JJ; McHardy, T; Collins, I; Bayliss, R (2015-05)

  IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although ...
• MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation. 

  Firth, NC; Atrash, B; Brown, N; Blagg, J (2015-06-09)

  We describe the development and application of an integrated, multiobjective optimization workflow (MOARF) for directed medicinal chemistry design. This workflow couples a rule-based molecular fragmentation scheme (SynDiR) ...
• First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014. 

  Basu, B; Dean, E; Puglisi, M; Greystoke, A; Ong, M; Burke, W; Cavallin, M; Bigley, G; Womack, C; Harrington, EA; Green, S; Oelmann, E; de Bono, JS; Ranson, M; Banerji, U (2015-08)

  PURPOSE:AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models. EXPERIMENTAL DESIGN:A rolling six-dose escalation was performed to ...
• Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity. 

  Mussai, F; Egan, S; Hunter, S; Webber, H; Fisher, J; Wheat, R; McConville, C; Sbirkov, Y; Wheeler, K; Bendle, G; Petrie, K; Anderson, J; Chesler, L; De Santo, C (2015-08)

  Neuroblastoma is the most common extracranial solid tumor of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not ...
• Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial. 

  Sclafani, F; Chau, I; Cunningham, D; Peckitt, C; Lampis, A; Hahne, JC; Braconi, C; Tabernero, J; Glimelius, B; Cervantes, A; Begum, R; Gonzalez De Castro, D; Hulkki Wilson, S; Eltahir, Z; Wotherspoon, A; Tait, D; Brown, G; Oates, J; Valeri, N (2015-09)

  BACKGROUND:Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary ...
• Investigating Apoptozole as a Chemical Probe for HSP70 Inhibition. 

  Evans, LE; Cheeseman, MD; Yahya, N; Jones, K (2015-01)

  The use of chemical tools to validate clinical targets has gained in popularity over recent years and the importance of understanding the activity, selectivity and mechanism of action of these compounds is well recognized. ...
• Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors. 

  Whittaker, SR; Cowley, GS; Wagner, S; Luo, F; Root, DE; Garraway, LA (2015-12)

  RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a ...
• Distinctive Behaviors of Druggable Proteins in Cellular Networks. 

  Mitsopoulos, C; Schierz, AC; Workman, P; Al-Lazikani, B (2015-12-23)

  The interaction environment of a protein in a cellular network is important in defining the role that the protein plays in the system as a whole, and thus its potential suitability as a drug target. Despite the importance ...
• Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models. 

  Zenke, FT; Zimmermann, A; Sirrenberg, C; Dahmen, H; Kirkin, V; Pehl, U; Grombacher, T; Wilm, C; Fuchss, T; Amendt, C; Vassilev, LT; Blaukat, A (2020-05)

  Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer ...
• Inhibitors in AKTion: ATP-competitive vs allosteric. 

  Lazaro, G; Kostaras, E; Vivanco, I (2020-06)

  Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and thus has been intensely pursued as a therapeutic target. Multiple AKT ...
• First-in-human study of AT13148, a dual ROCK-AKT inhibitor in patients with solid tumors. 

  McLeod, R; Kumar, R; Papadatos-Pastos, D; Mateo, J; Brown, J; Ingles Garces, AH; Ruddle, R; Decordova, SA; Jueliger, S; Ferraldeschi, R; Maiques, O; Sanz-Moreno, V; Jones, P; Traub, S; Halbert, G; Mellor, S; Swales, KE; Raynaud, FI; Garrett, MD; Banerji, U (2020-07-02)

  PURPOSE:AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have anti-metastatic and anti-proliferative activity. EXPERIMENTAL DESIGN:The ...

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