Cancer Research United Kingdom

Cambridge, United Kingdom

Cancer Research United Kingdom

Cambridge, United Kingdom
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Quintin J.,French Electricity Transmission Network | Peron C.L.,French Electricity Transmission Network | Palierne G.,French Electricity Transmission Network | Bizot M.,French Electricity Transmission Network | And 16 more authors.
Molecular and Cellular Biology | Year: 2014

Estradiol signaling is ideally suited for analyzing the molecular and functional linkages between the different layers of information directing transcriptional regulations: the DNA sequence, chromatin modifications, and the spatial organization of the genome. Hence, the estrogen receptor (ER) can bind at a distance from its target genes and engages timely and spatially coordinated processes to regulate their expression. In the context of the coordinated regulation of colinear genes, identifying which ER binding sites (ERBSs) regulate a given gene still remains a challenge. Here, we investigated the coordination of such regulatory events at a 2-Mb genomic locus containing the estrogen-sensitive trefoil factor (TFF) cluster of genes in breast cancer cells. We demonstrate that this locus exhibits a hormone- and cohesin-dependent reduction in the plasticity of its three-dimensional organization that allows multiple ERBSs to be dynamically brought to the vicinity of estrogen-sensitive genes. Additionally, by using triplex-forming oligonucleotides, we could precisely document the functional links between ER engagement at given ERBSs and the regulation of particular genes. Hence, our data provide evidence of a formerly suggested cooperation of enhancers toward gene regulation and also show that redundancy between ERBSs can occur. © 2014, American Society for Microbiology.


PubMed | The Royal Marsden NHS Foundation Trust, United Kingdom The Institute Of Cancer Research, Northern Institute for Cancer Research, Cancer Research United Kingdom and 6 more.
Type: Clinical Trial, Phase I | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2015

A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity.AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5, and 23 mg/m(2)/d). Pharmacokinetic and PD assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies.Thirty-three patients were evaluable for toxicity. There were six dose-limiting toxicities and the MTD was 18.5 mg/m(2)/d. Most common drug-related toxicities were hematologic (neutropenia, anemia, and thrombocytopenia in 36.4%, 18.2%, and 21.2% of patients), which were grade 3 in 30.3%, 6.1%, and 3% of patients. Nonhematologic toxicities included fatigue, infections, febrile neutropenia and ALT elevation. One patient with central nervous system-primitive neuroectodermal tumor (CNS-PNET) achieved a partial response after 16 cycles and 3 cases were stable for four or more cycles. Plasma concentrations were comparable with those in adults at the same dose level, clearance was similar although half-life was shorter (4.9 1.5 hours, compared with 8.4 3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17 of 18 patients treated at 11.5 mg/m(2)/d.AT9283 was well tolerated in children and adolescents with solid tumors with manageable hematologic toxicity. Target inhibition was demonstrated. Disease stabilization was documented in intracranial and extracranial pediatric solid tumors and a phase II dose determined.


Chaplin N.,King's College London | Tendeng C.,King's College London | Tendeng C.,Cancer Research United Kingdom | Wingate R.J.T.,King's College London
Journal of Neuroscience | Year: 2010

The granule cell layer of the cerebellum comprises the largest population of neurons in the vertebrate CNS. In amniotes, its precursors undergo a unique phase of transit amplification, regulated by Sonic hedgehog. They do so within a prominent but transient secondary proliferative epithelium, the external germinal layer, which is formed by tangential migration of precursor cells from the rhombic lip. This behavior is a hallmark of bird and mammal cerebellum development. Despite its significance for both development and disease, it is unclear whether an external germinal layer is a requirement for granule cell production or an expedient of transit amplification. Evidence for its existence in more basal vertebrates is contradictory. We therefore examined cerebellum development in the zebrafish, specifically in relation to the expression of the basic helix-loop- helix gene Atonal 1, which definitively characterizes granule cell precursors. The expression of Atoh1a-Atoh1c, in combination with patterns of proliferation and fate maps, define precursor pools at the rhombic lip and cerebellar midline but demonstrate that an external germinal layer is absent. Sonic hedgehog signaling is correspondingly absent in the zebrafish cerebellum. Sustained roof-plate-derived signals suggest that, in the absence of transit amplification, primary granule cell precursor pools are maintained throughout development. To determine whether this pattern is specific to zebrafish or reflects a more general anamniote organization, we examined the expression of similar genes in the dogfish, Scylliorhinus canicula.We show that these anamniotes share a common ground plan of granule cell production that does not include an external germinal layer. Copyright © 2010 the authors.


Jones D.T.,Queen Mary, University of London | Lechertier T.,Queen Mary, University of London | Mitter R.,Cancer Research United Kingdom | Herbert J.M.J.,University of Birmingham | And 6 more authors.
PLoS ONE | Year: 2012

Angiogenesis is essential for solid tumour growth, whilst the molecular profiles of tumour blood vessels have been reported to be different between cancer types. Although presently available anti-angiogenic strategies are providing some promise for the treatment of some cancers it is perhaps not surprisingly that, none of the anti-angiogenic agents available work on all tumours. Thus, the discovery of novel anti-angiogenic targets, relevant to individual cancer types, is required. Using Affymetrix microarray analysis of laser-captured, CD31-positive blood vessels we have identified 63 genes that are upregulated significantly (5-72 fold) in angiogenic blood vessels associated with human invasive ductal carcinoma (IDC) of the breast as compared with blood vessels in normal human breast. We tested the angiogenic capacity of a subset of these genes. Genes were selected based on either their known cellular functions, their enriched expression in endothelial cells and/or their sensitivity to anti-VEGF treatment; all features implicating their involvement in angiogenesis. For example, RRM2, a ribonucleotide reductase involved in DNA synthesis, was upregulated 32-fold in IDC-associated blood vessels; ATF1, a nuclear activating transcription factor involved in cellular growth and survival was upregulated 23-fold in IDC-associated blood vessels and HEX-B, a hexosaminidase involved in the breakdown of GM2 gangliosides, was upregulated 8-fold in IDC-associated blood vessels. Furthermore, in silico analysis confirmed that AFT1 and HEX-B also were enriched in endothelial cells when compared with non-endothelial cells. None of these genes have been reported previously to be involved in neovascularisation. However, our data establish that siRNA depletion of Rrm2, Atf1 or Hex-B had significant anti-angiogenic effects in VEGF-stimulated ex vivo mouse aortic ring assays. Overall, our results provide proof-of-principle that our approach can identify a cohort of potentially novel anti-angiogenic targets that are likley to be, but not exclusivley, relevant to breast cancer. © 2012 Jones et al.


Dodd R.H.,Cancer Research United Kingdom | Marlow L.A.V.,Cancer Research United Kingdom | Waller J.,Cancer Research United Kingdom
Head and Neck | Year: 2016

Background The role of human papillomavirus (HPV) in oropharyngeal squamous cell cancer (SCC) has now been well established. Clinicians' experiences and challenges of talking to patients about HPV have yet to be explored. Methods Fifteen health professionals caring for patients with oropharyngeal SCC were interviewed. Interviews were analyzed thematically. Results Participants expressed mixed views about explaining the causal role of HPV to their patients. Normalizing HPV and emphasizing the positive prognosis associated with it were regarded as key messages to be communicated. Challenging experiences included managing couples in a consultation and patients' concerns about transmitting HPV to their partners. Some participants described limitations to their HPV knowledge and identified the need for further information and training. Conclusion This study identified challenges experienced by health professionals working with patients with oropharyngeal SCC and highlights some key messages to convey to patients. Clinical guidance for health professionals and further information for patients about HPV-positive oropharyngeal SCC are needed. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc.


Moreno L.,Royal Marsden NHS Foundation Trust | Marshall L.V.,Royal Marsden NHS Foundation Trust | Marshall L.V.,Institute of Cancer Research | Pearson A.D.J.,Royal Marsden NHS Foundation Trust | And 16 more authors.
Clinical Cancer Research | Year: 2015

Purpose: A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity. Experimental Design: AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5, and 23 mg/m2/d). Pharmacokinetic and PD assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies. Results: Thirty-three patients were evaluable for toxicity. There were six dose-limiting toxicities and the MTD was 18.5 mg/m2/d. Most common drug-related toxicities were hematologic (neutropenia, anemia, and thrombocytopenia in 36.4%, 18.2%, and 21.2% of patients), which were grade ≥3 in 30.3%, 6.1%, and 3%of patients. Nonhematologic toxicities included fatigue, infections, febrile neutropenia and ALT elevation. One patient with central nervous system-primitive neuroectodermal tumor (CNS-PNET) achieved a partial response after 16 cycles and 3 cases were stable for four or more cycles. Plasma concentrations were comparable with those in adults at the same dose level, clearance was similar although half-life was shorter (4.9 ± 1.5 hours, compared with 8.4 ± 3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17 of 18 patients treated at ≥11.5 mg/m2/d. Conclusion: AT9283 was well tolerated in children and adolescents with solid tumors with manageable hematologic toxicity. Target inhibition was demonstrated. Disease stabilization was documented in intracranial and extracranial pediatric solid tumors and a phase II dose determined. © 2014 American Association for Cancer Research.


Jones D.T.,Queen Mary, University of London | Jones D.T.,University of Oxford | Lechertier T.,Queen Mary, University of London | Reynolds L.E.,Queen Mary, University of London | And 4 more authors.
DMM Disease Models and Mechanisms | Year: 2013

Cellular ribosomal protein L29 (RPL29) is known to be important in protein synthesis, but its function during angiogenesis has never been described before. We have shown previously that mice lacking b3-integrins support enhanced tumour angiogenesis and, therefore, deletion of endothelial αvα3 can provide a method for discovery of novel regulators of tumour angiogenesis. Here, we describe significant upregulation of RPL29 in α3-null endothelial cells at both the mRNA and protein level. Ex vivo, we show that VEGF-stimulated microvessel sprouting was reduced significantly in Rpl29-heterozygous and Rpl29-null aortic ring assays compared with wild-type controls. Moreover, we provide in vivo evidence that RPL29 can regulate tumour angiogenesis. Tumour blood vessel density in subcutaneously grown Lewis lung carcinomas was reduced significantly in Rpl29-mutant mice. Additionally, depletion of Rpl29 using RNA interference inhibited VEGF-induced aortic ring sprouting, suggesting that anti-RPL29 strategies might have anti-angiogenic potential. Overall, our results identify that loss or depletion of RPL29 can reduce angiogenesis in vivo and ex vivo.


Clear A.J.,Institute of Cancer | Lee A.M.,Institute of Cancer | Calaminici M.,Institute of Cancer | Ramsay A.G.,Institute of Cancer | And 6 more authors.
Blood | Year: 2010

Follicular lymphoma has considerable clinical heterogeneity, and there is a need for easily quantifiable prognostic biomarkers. Microvessel density has been shown to be a useful prognostic factor based on numerical assessment of vessel numbers within histologic sections in some studies, but assessment of tumor neovascularization through angiogenic sprouting may be more relevant. We therefore examined the smallest vessels, single-staining structures measuring less than 30 μm2 in area, seen within histologic sections, and confirmed that they were neovascular angiogenic sprouts using extended focal imaging. Tissue microarrays composing diagnostic biopsies from patients at the extremes of survival of follicular lymphoma were analyzed with respect to numbers of these sprouts. This analysis revealed higher angiogenic activity in the poor prognostic group and demonstrated an association between increased sprouting and elevated numbers of infiltrating CD163+ macrophages within the immediate microenvironment surrounding the neovascular sprout. © 2010 by The American Society of Hematology.


There are several factors that can enhance chances of developing bile duct cancer (cholangiocarcinoma). According to American Society of Clinical Oncology (ASCO), fewer than 3,000 people are affected with the disease annually in the U.S. and around 1,600 people are affected by the disease in the U.K., according to Cancer Research United Kingdom. Major indications of cholangiocarcinoma include abnormal liver function, abdominal pain, weight loss, generalized itching, discoloration of stool and urine etc. Causes of cholangiocarcinoma are not known but factors such as exposure to thorium dioxide, liver fluke infections and cholangitis have been known to increase the chances. Bile duct cancer treatment market is driven by the technological advancement in healthcare sector and increase in prevalence of cancer patients across the globe. Also, enhanced emphasis of pharmaceutical companies on R&D to come up with potential treatment for bile duct cancer (cholangiocarcinoma). However, high cost associated with latest clinical trials and approvals act as a major barrier for global bile duct cancer (cholangiocarcinoma) treatment market. Global bile duct cancer (cholangiocarcinoma) treatment market is classified on the basis of disease indication, by treatment type and geography. Based on the disease indication, the global bile duct cancer (cholangiocarcinoma) treatment market is segmented into the following: Based on the treatment type, the global bile duct cancer (cholangiocarcinoma) treatment market is segmented into the following: Based on the region, the global bile duct cancer (cholangiocarcinoma) treatment market is segmented into the following: Due of the availability of variety of chemotherapeutic agents for the bile duct cancer (cholangiocarcinoma) treatment, market for chemotherapeutic agents is expected to hold a greater share in global bile duct cancer (cholangiocarcinoma) treatment market. Innovative bile duct cancer (cholangiocarcinoma) treatment procedures are expected to launch into the market in the forecast period. Depending on geographic region bile duct cancer (cholangiocarcinoma) treatment market is segmented into five key regions: North America, Latin America, Europe, Asia Pacific, and Middle East & Africa. North America accounts maximum in global bile duct cancer (cholangiocarcinoma) market share. Market for bile duct cancer (cholangiocarcinoma) treatment is maximum in North America due to advanced healthcare facilities, adequate reimbursement policies and greater awareness towards health care. Europe and Asia-Pacific market is expected to register a healthy CAGR over the forecast period. Some of the key players in bile duct cancer (cholangiocarcinoma) are Johnson & Johnson Services, Inc., ConMed Corporation, W. L. Gore & Associates, Inc., Dispomedica GmbH, InSitu Technologies Inc., Boston Scientific Corporation, Medtronic Plc, Pauldrach medical Handels- und Vertriebs GmbH, OptiMed Medizinische Instrumente GmbH among several others.

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