Armelle Logié

AstraZeneca (United Kingdom)

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Barry R. Davies

AstraZeneca (United Kingdom)

Robert W. Wilkinson

University of Bath

Paul D. Smith

Swedish University of Agricultural Sciences

Paul D. Smith

AstraZeneca (United Kingdom)

Sylvie M. Guichard

Novo Nordisk (United States)

Sarah V. Holt

AstraZeneca (United Kingdom)

Vivien N. Jacobs

Intermountain Medical Center

Stephen R. Wedge

Newcastle University

Christine Gicquel

Baker Heart and Diabetes Institute

Yves Le Bouc

Inserm

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AstraZeneca (United Kingdom)

118

AstraZeneca (Brazil)

University of Manchester

Inserm

Cancer Research UK

Cancer Research UK Manchester Institute

Array BioPharma (United States)

AstraZeneca (United States)

AstraZeneca (France)

Sorbonne Université

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Abstract 4434: Combined targeting of Aurora B (AZD1152) and MEK1/2 (AZD6244) kinases leads to enhancement of anti-tumour effects in vivo.

Cancer Research (2010)

Rajesh Odedra Simon P. Heaton Armelle Logié Kirsten Mundt Elizabeth A. Anderson

Abstract Future cancer treatment regimes may involve novel drug combinations aimed at targeting different pathways involved in tumour proliferation and survival. Understanding the mechanisms involved in such combinations and identifying the optimum schedule/sequence will be key to guiding clinical development. The Aurora kinases play a critical role in mitosis and have been suggested as promising targets for therapy due to their frequent over expression in a variety of tumours. AZD1152 is a selective Aurora B kinase inhibitor, with a novel anti-tumour mechanism of action, inducing endoreduplication, apoptosis and inhibition of cytokinesis. The MAPK signaling pathway is implicated in uncontrolled cell proliferation and cell survival in many cancers. AZD6244 (ARRY-142886), a selective, ATP non-competitive inhibitor of MEK1/2, has demonstrated G1 arrest and anti-tumour activity in a range of preclinical models. In the present study, we dosed AZD1152 and AZD6244 in combination to nude mice bearing human NSCLC tumour (Calu-6) xenografts. Pharmacodynamic analysis of Calu-6 xenografts treated with either AZD1152 or AZD6244 as monotherapies (MonTx) indicated downstream biomarker effects in accordance with their targets (for e.g. suppression of phosphorylation of histone H3 and ERK, respectively). When the same doses of AZD1152 (150mg/Kg/day s.c. for 2 days via osmotic minipumps) or AZD6244 (25mg/kg/BID p.o.) were dosed in a chronic disease setting, both drugs significantly suppressed Calu-6 tumour growth (versus respective vehicle groups, p<0.005). In combination, the two drugs were dosed in sequence, either AZD1152 → AZD6244 or AZD6244 → AZD1152. Whilst both sequences proved superior to the vehicle arms, only AZD1152 → AZD6244 proved superior to both MonTx arms in terms of apoptosis induction and tumour growth inhibition. These data indicate a promising therapeutic strategy for combining AZD1152 and AZD6244, and suggest that the sequence of drug administration may be critical when combining these inhibitors. Both AZD1152 and AZD6244 are currently in clinical trials. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4434.

Aurora B kinase

Aurora inhibitor

Endoreduplication

10.1158/1538-7445.am10-4434

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Data from Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)

Sarah V. Holt Armelle Logié Barry R. Davies Denis Alférez Sarah Runswick

<div>AbstractThe mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal–regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non–small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy. Cancer Res; 72(7); 1804–13. ©2012 AACR.</div>

Selumetinib

10.1158/0008-5472.c.6503583

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AZD6244 (ARRY-142886), a potent and highly selective MEK1/2 inhibitor, demonstrates anti-HIF properties, and increases the therapeutic response in a lung tumor xenograft model when combined with radiotherapy

Aoife M. Shannon Brian A. Telfer Muhammed Babur Paul D. Smith Armelle Logié

A244 Introduction: AZD6244 is a potent and selective, uncompetitive MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models and is currently being evaluated as monotherapy in Phase II clinical trials. The primary objective of this study was to determine whether AZD6244 and radiotherapy can be used in combination to greater therapeutic effect than either modality alone, and to examine the impact of MEK1/2 inhibition on the molecular responses to hypoxia in a human lung tumor xenograft model (Calu-6; mutant KRAS).  Methods: The impact of scheduling AZD6244 treatment (before, after or concomitantly) in combination with radiotherapy was investigated in vitro using clonogenic assays. Western immunoblotting was performed to assess the effect of AZD6244 and radiation on the biomarker (phospho-ERK), and on HIF-1α and its downstream targets under hypoxic (1% O2) conditions. HIF-1α is only detectable under hypoxic conditions and is a useful marker of hypoxia. The effect of drug on HIF-specific transactivation was assessed by a hypoxia-response element (HRE)-luciferase reporter assay, using a Calu-6 (dual clone: DC) cell line stably expressing a firefly luciferase gene under the control of a hypoxia-driven promoter.  In vivo, short-term pharmacodynamic studies were performed in Calu-6 DC xenografts with oral dosing of AZD6244 (25 mg/kg BID); tumors were harvested 4 h after a single dose of AZD6244 or following five days of dosing. Subsequently, a course of 10-day treatment with AZD6244 (25 mg/kg BID) was combined with fractionated radiotherapy (5 x 2 Gy) during the first or last five days of drug therapy. Tumors were allowed to reach three times their original pre-treatment tumor volume.  Results: Clonogenic assays demonstrated that the neo-adjuvant schedule (48h AZD6244 treatment before irradiation) was more effective than sequential (drug after irradiation) or concomitant treatment in vitro. AZD6244 (≥ 2 nM) reduced phospho-ERK expression in the Calu-6 human lung cancer cell line in vitro and within 4 h of one dose of AZD6244 (25 mg/kg) in vivo. Radiation alone had no effect on ERK activation in vitro. AZD6244 ablated HIF-1 transactivation in vitro and in vivo (5 days). Furthermore, in vitro there was a reduction in HIF-1α protein expression following 6-24 h treatment with 200 nM AZD6244 under hypoxic conditions, as well as a reduction in GLUT-1 expression (after 24 h).  AZD6244 resulted in tumor growth stasis from the first day of treatment in the Calu-6 tumor xenograft model. Combination treatment with 10-day AZD6244 and fractionated radiotherapy resulted in a significantly enhanced tumor growth delay compared to either modality alone. This enhancement was independent of whether radiotherapy was administered during the first or last five days of AZD6244 treatment.  Conclusions: In summary, a regime combining AZD6244 and radiotherapy in the Calu-6 xenograft model demonstrates significant therapeutic benefit compared to single therapy treatment. Collectively, these data support the clinical development of AZD6244 in combination with radiotherapy and indicate a novel role for AZD6244 in inhibiting the tumor hypoxia response.

Clonogenic assay

Hypoxia

Tumor Hypoxia

Combination therapy

Selumetinib

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Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers

Oncotarget (2016)

James Bradford Mark Wappett Garry Beran Armelle Logié Oona Delpuech

// James R. Bradford 1 , Mark Wappett 2 , Garry Beran 2 , Armelle Logie 2 , Oona Delpuech 2 , Henry Brown 2 , Joanna Boros 2 , Nicola J. Camp 3 , Robert McEwen 2 , Anne Marie Mazzola 4 , Celina D'Cruz 4 , Simon T. Barry 2 1 Department of Oncology and Metabolism, University of Sheffield, Sheffield, South Yorkshire, UK 2 Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK 3 Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA 4 Oncology iMED, AstraZeneca Pharmaceuticals, Gatehouse Park, Massachusetts, USA Correspondence to: James R. Bradford, e-mail: J.R.Bradford@sheffield.ac.uk Keywords: patient-derived xenograft, RNA-Seq, tumor stroma, biomarker discovery, pre-clinical research Received: November 09, 2015 Accepted: February 18, 2016 Published: March 09, 2016 ABSTRACT The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX). Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6 . Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment. In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery.

10.18632/oncotarget.8014

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Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055

Biochemical Society Transactions (2011)

Gayle Marshall Zoë Howard Jonathan R. Dry Sarah E. Fenton Dan Heathcote

AZD8055 is a small-molecule inhibitor of mTOR (mammalian target of rapamycin) kinase activity. The present review highlights molecular and phenotypic differences between AZD8055 and allosteric inhibitors of mTOR such as rapamycin. Biomarkers, some of which are applicable to clinical studies, as well as biological effects such as autophagy, growth inhibition and cell death are compared between AZD8055 and rapamycin. Potential ways to develop rational combinations with mTOR kinase inhibitors are also discussed. Overall, AZD8055 may provide a better therapeutic strategy than rapamycin and analogues.

10.1042/bst0390456

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Citations (35)

Supplementary Figures 1-2 from AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models

Barry R. Davies Armelle Logié Jennifer S. McKay Paul Martin Samantha Steele

PDF file - 18K

ASK1

10.1158/1535-7163.22485294

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The nature of iron released by resident and stimulated mouse peritoneal macrophages

Biochimica et Biophysica Acta (BBA) - General Subjects (1984)

J. F. Brock Inmaculada Esparza Armelle Logié

Transferrin receptor

Incubation period

10.1016/0304-4165(84)90388-x

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157 The mTOR kinase inhibitor AZD8055 induces cell death in Her2+ tumours partially or intrinsically resistant to ErbB2 inhibitors

European Journal of Cancer Supplements (2010)

Sarah V. Holt Gayle Marshall Armelle Logié Zoë Howard Sarah E. Fenton

10.1016/s1359-6349(10)71862-0

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Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors

Molecular Cancer Therapeutics (2015)

Barry R. Davies Nin Guan Armelle Logié Claire Crafter Lyndsey Hanson

Abstract AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1E17K mutation is not known. Expression of exogenous copies of AKT1E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1E17K mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1E17K mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1E17K and FGFR3Y373C mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1E17K mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor. Mol Cancer Ther; 14(11); 2441–51. ©2015 AACR.

10.1158/1535-7163.mct-15-0230

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Data from AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models

Barry R. Davies Armelle Logié Jennifer S. McKay Paul Martin Samantha Steele

<div>AbstractConstitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel. [Mol Cancer Ther 2007;6(8):2209–19]</div>

10.1158/1535-7163.c.6531879

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