Research & development Programmes

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Theranostic strategies are often directed against complex and redundant growth signalling networks from surface ligands and receptors through transducers to downstream effector molecules.

However the redundancy of these networks can result in low efficacy of molecularly targeted drugs and constraints on the performance of cancer biomarkers directed at these pathways.

An alternative approach is to target the cell cycle machinery, which acts as a convergence point for information transduced through upstream signalling networks and therefore represents an exceptionally attractive diagnostic and therapeutic target.

cell-cycle

Selected publications

  • Immunophenotypic analysis of cell cycle status in acute myeloid leukaemia: relationship to cytogenetics, genotype and clinical outcome
    Sellar RS, Gale RE, Khwaja A, Garbowski M, Loddo M, Stoeber K, Williams GH, Linch DC (2018)
    Br J Haematol. 2018 May;181(4):486-494. doi: 10.1111/bjh.15211. Epub 2018 Apr 20.
  • DNA replication licensing factor MCM2, geminin, and Ki67 define proliferative state and are linked with survival in oral squamous cell carcinoma.
    Al-Hazmi N, Alhazzazi T, Williams G, Stoeber K, Al-Dabbagh R (2018)
    Eur J Oral Sci. 2018 Jun;126(3):186-196. doi: 10.1111/eos.12420.
  • A novel p53-Cdc7 link induced by genotoxic stress
    Hisao Masai (2017)
    Cell Cycle, DOI: 10.1080/15384101.2017.1304746
  • Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL
    Zandra C Deans, Jose Luis Costa, Ian Cree, Els Dequeker, Anders Edsjö, Shirley Henderson, Michael Hummel, Marjolijn JL Ligtenberg, Marco Loddo, Jose Carlos Machado, Antonio Marchetti, Katherine Marquis, Joanne Mason, Nicola Normanno, Etienne Rouleau, Ed Schuuring, Keeda-Marie Snelson, Erik Thunnissen, Bastiaan Tops, Gareth Williams, Han van Krieken, Jacqueline A Hall, On behalf of IQN Path ASBL (2016)
    Virchows Arch (2016). doi:10.1007/s00428-016-2025-7
  • p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress.
    Tudzarova S, Mulholland P, Dey A, Stoeber K, Okorokov AL, Williams GH (2016)
    Cell Cycle. 2016 Sep 9:0
  • Cell cycle status in AML blast cells from peripheral blood, bone marrow aspirates and trephines and implications for biological studies and treatment
    Sellar RS, Fraser L, Khwaja A, Gale RE, Marafioti T, Akarca A, Hubank M, Brooks T, Stoeber K,Williams G, Linch DC. (2016)
    Br J Haematol. 2016 Apr 8. doi: 10.1111/bjh.14055.
  • Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint
    Huggett MT, Tudzarova S, Proctor I, Loddo M, Keane MG, Stoeber K, Williams GH, Pereira SP. (2016)
    Oncotarget. 2016 Feb 23. doi: 10.18632/oncotarget.7611.
  • Pregnancy-associated plasma protein A regulates mitosis and is epigenetically silenced in breast cancer
    Loddo M, Andryszkiewicz J, Rodriguez-Acebes S, Stoeber K, Jones A, Dafou D, Apostolidou S, Wollenschlaeger A, Widschwendter M, Sainsbury R, Tudzarova S, Williams GH. (2014)
    J Pathol. 2014 Aug;233(4):344-56.
  • Subcellular proteomics reveals a role for nucleo-cytoplasmic trafficking at the DNA replication origin activation checkpoint.
    Mulvey CM, Tudzarova S, Crawford M, Williams GH, Stoeber K, Godovac-Zimmermann J. (2013)
    J Proteome Res. 2013 Mar 1;12(3):1436-53.
  • Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22.
    3: Kelly JD, Dudderidge TJ, Wollenschlaeger A, Okoturo O, Burling K, Tulloch F, Halsall I, Prevost T, Prevost AT, Vasconcelos JC, Robson W, Leung HY, Vasdev N, Pickard RS, Williams GH, Stoeber K. (2012)
    PLoS One. 2012;7(7):e40305
  • The cell cycle and cancer.
    Williams GH, Stoeber K. (2012)
    J Pathol. 2012 Jan;226(2):352-64.
  • Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA.
    Gooding M, Tudzarova S, Worthington RJ, Kingsbury SR, Rebstock AS, Dube H, Simone MI, Visintin C, Lagos D, Quesada JM, Laman H, Boshoff C, Williams GH, Stoeber K, Selwood DL. (2012)
    Chem Biol Drug Des. 2012 Jan;79(1):9-21.
  • Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-beta-TrCP, sequentially regulate glycolysis during the cell cycle.
    Tudzarova S, Colombo SL, Stoeber K, Carcamo S, Williams GH, Moncada S. (2011)
    Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5278-83.
  • Molecular architecture of the DNA replication origin activation checkpoint.
    Tudzarova S, Trotter MW, Wollenschlaeger A, Mulvey C, Godovac-Zimmermann J, Williams GH, Stoeber K. (2010)
    EMBO J. 2010 Oct 6;29(19):3381-94.
  • Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53-mutant breast cancers.
    Rodriguez-Acebes S, Proctor I, Loddo M, Wollenschlaeger A, Rashid M, Falzon M, Prevost AT, Sainsbury R, Stoeber K, Williams GH. (2010)
    Am J Pathol. 2010 Oct;177(4):2034-45.
  • Diagnosis of prostate cancer by detection of minichromosome maintenance 5 protein in urine sediments.
    Dudderidge TJ, Kelly JD, Wollenschlaeger A, Okoturo O, Prevost T, Robson W, Leung HY, Williams GH, Stoeber K. (2010)
    Br J Cancer. 2010 Aug 24;103(5):701-7.
  • DNA replication licensing factors and aneuploidy are linked to tumor cell cycle state and clinical outcome in penile carcinoma.
    Kayes OJ, Loddo M, Patel N, Patel P, Minhas S, Ambler G, Freeman A, Wollenschlaeger A, Ralph DJ, Stoeber K, Williams GH. (2009)
    Clin Cancer Res. 2009 Dec 1;15(23):7335-44.
  • Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma.
    Kulkarni AA, Kingsbury SR, Tudzarova S, Hong HK, Loddo M, Rashid M, Rodriguez-Acebes S, Prevost AT, Ledermann JA, Stoeber K, Williams GH. (2009)
    Clin Cancer Res. 2009 Apr 1;15(7):2417-25.
  • Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer.
    Loddo M, Kingsbury SR, Rashid M, Proctor I, Holt C, Young J, El-Sheikh S, Falzon M, Eward KL, Prevost T, Sainsbury R, Stoeber K, Williams GH. (2009)
    Br J Cancer. 2009 Mar 24;100(6):959-70.
  • Modular assembly using sequential palladium coupling gives easy access to the SMoC class of cellular transporters.
    Rebstock AS, Visintin C, Leo E, Garcia Posada C, Kingsbury SR, Williams GH, Stoeber K, Selwood DL. (2008)
    Chembiochem. 2008 Jul 21;9(11):1787-96.
  • Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates.
    Ayaru L, Stoeber K, Webster GJ, Hatfield AR, Wollenschlaeger A, Okoturo O, Rashid M, Williams G, Pereira SP. (2008)
    Br J Cancer. 2008 May 6;98(9):1548-54.
  • Cell cycle markers in clinical oncology.
    Williams GH, Stoeber K. (2007)
    Curr Opin Cell Biol. 2007 Dec;19(6):672-9.
  • DNA replication licensing factors and aurora kinases are linked to aneuploidy and clinical outcome in epithelial ovarian carcinoma.
    Kulkarni AA, Loddo M, Leo E, Rashid M, Eward KL, Fanshawe TR, Butcher J, Frost A, Ledermann JA, Williams GH, Stoeber K. (2007)
    Clin Cancer Res. 2007 Oct 15;13(20):6153-61.
  • Hexameric ring structure of human MCM10 DNA replication factor.
    Okorokov AL, Waugh A, Hodgkinson J, Murthy A, Hong HK, Leo E, Sherman MB, Stoeber K, Orlova EV, Williams GH. (2007)
    EMBO Rep. 2007 Oct;8(10):925-30.
  • DNA replication licensing, and survival are linked in prostate cancer.
    Dudderidge TJ, McCracken SR, Loddo M, Fanshawe TR, Kelly JD, Neal DE, Leung HY, Williams GH, Stoeber K. (2007)
    Br J Cancer. 2007 May 7;96(9):1384-93.
  • Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells.
    Okuyama M, Laman H, Kingsbury SR, Visintin C, Leo E, Eward KL, Stoeber K, Boshoff C, Williams GH, Selwood DL. (2007)
    Nat Methods. 2007 Feb;4(2):153-9.
  • DNA replication licensing and cell cycle kinetics of normal and neoplastic breast.
    Shetty A, Loddo M, Fanshawe T, Prevost AT, Sainsbury R, Williams GH, Stoeber K. (2005)
    Br J Cancer. 2005 Nov 28;93(11):1295-300.
  • Mcm2, Geminin, and KI67 define proliferative state and are prognostic markers in renal cell carcinoma.
    Dudderidge TJ, Stoeber K, Loddo M, Atkinson G, Fanshawe T, Griffiths DF, Williams GH. (2005)
    Clin Cancer Res. 2005 Apr 1;11(7):2510-7.
  • DNA replication licensing in peripheral B-cell lymphoma.
    Obermann EC, Eward KL, Dogan A, Paul EA, Loddo M, Munson P, Williams GH, Stoeber K. (2005)
    J Pathol. 2005 Feb;205(3):318-28.
  • DNA replication licensing in somatic and germ cells.
    Eward KL, Obermann EC, Shreeram S, Loddo M, Fanshawe T, Williams C, Jung HI, Prevost AT, Blow JJ, Stoeber K, Williams GH. (2004)
    J Cell Sci. 2004 Nov 15;117(Pt 24):5875-86.
  • Molecular structure of human geminin.
    Okorokov AL, Orlova EV, Kingsbury SR, Bagneris C, Gohlke U, Williams GH, Stoeber K. (2004)
    Nat Struct Mol Biol. 2004 Oct;11(10):1021-2.
  • Diagnosis of oesophageal cancer by detection of minichromosome maintenance 5 protein in gastric aspirates.
    Williams GH, Swinn R, Prevost AT, De Clive-Lowe P, Halsall I, Going JJ, Hales CN, Stoeber K, Middleton SJ. (2004)
    Br J Cancer. 2004 Aug 16;91(4):714-9.
  • Diagnosis of genito-urinary tract cancer by detection of minichromosome maintenance 5 protein in urine sediments.
    Stoeber K, Swinn R, Prevost AT, de Clive-Lowe P, Halsall I, Dilworth SM, Marr J, Turner WH, Bullock N, Doble A, Hales CN, Williams GH. (2002)
    J Natl Cancer Inst. 2002 Jul 17;94(14):1071-9.
  • Aberrant expression of minichromosome maintenance proteins 2 and 5, and Ki-67 in dysplastic squamous oesophageal epithelium and Barrett's mucosa.
    Going JJ, Keith WN, Neilson L, Stoeber K, Stuart RC, Williams GH. (2002)
    Gut. 2002 Mar;50(3):373-7.
  • Minichromosome maintenance protein 2 expression in prostate: characterization and association with outcome after therapy for cancer.
    Meng MV, Grossfeld GD, Williams GH, Dilworth S, Stoeber K, Mulley TW, Weinberg V, Carroll PR, Tlsty TD. (2001)
    Clin Cancer Res. 2001 Sep;7(9):2712-8.
  • DNA replication licensing and human cell proliferation.
    Stoeber K, Tlsty TD, Happerfield L, Thomas GA, Romanov S, Bobrow L, Williams ED, Williams GH. (2001)
    J Cell Sci. 2001 Jun;114(Pt 11):2027-41.
  • Immunoassay for urothelial cancers that detects DNA replication protein Mcm5 in urine.
    Stoeber K, Halsall I, Freeman A, Swinn R, Doble A, Morris L, Coleman N, Bullock N, Laskey RA, Hales CN, Williams GH. (1999)
    Lancet. 1999 Oct 30;354(9189):1524-5.
  • Minichromosome maintenance proteins as biological markers of dysplasia and malignancy.
    Freeman A, Morris LS, Mills AD, Stoeber K, Laskey RA, Williams GH, Coleman N. (1999)
    Clin Cancer Res. 1999 Aug;5(8):2121-32.
  • Clinical applications of a novel mammalian cell-free DNA replication system.
    Williams G, Stoeber K. (1999)
    Br J Cancer. 1999 Jul;80 Suppl 1:20-4.
  • Cdc6 protein causes premature entry into S phase in a mammalian cell-free system.
    Stoeber K, Mills AD, Kubota Y, Krude T, Romanowski P, Marheineke K, Laskey RA, Williams GH. (1998)
    EMBO J. 1998 Dec 15;17(24):7219-29.
  • Improved cervical smear assessment using antibodies against proteins that regulate DNA replication.
    Williams GH, Romanowski P, Morris L, Madine M, Mills AD, Stoeber K, Marr J, Laskey RA, Coleman N. (1998)
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14932-7.