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Moore J.D.,Vernalis | Moore J.D.,Horizon Discovery
Nature Reviews Cancer | Year: 2013

Cyclin-dependent kinases (CDKs) are regulated by both cyclin abundance and cyclin localization. Increased cyclin expression in cancer was first observed two decades ago, and its role in pathogenesis has been investigated in great depth. This Opinion article focuses on the spatial deregulation of cyclin expression and its potential link to oncogenesis. It describes the contexts in which particular cyclins have been reported to be mislocalized in neoplasia, reviews the mechanisms underlying the dynamic subcellular localization of CDK-cyclin complexes in normal cells, and discusses how these controls can be disrupted in cancer. It also outlines the mechanisms by which cyclin mislocalization might disrupt cell cycle control and interfere with faithful chromosome segregation. Finally, it discusses the extent to which cyclin mislocalization might facilitate tumorigenesis in human cancer.© 2013 Macmillan Publishers Limited. All rights reserved.

Little A.S.,Babraham Institute | Little A.S.,Horizon Discovery | Smith P.D.,Astrazeneca | Cook S.J.,Babraham Institute
Oncogene | Year: 2013

The ERK1/2 (extracellular signal-regulated kinase 1 and 2) pathway, comprising the protein kinases RAF (v-raf-1 murine leukemia viral oncogene homolog 1), MEK1/2 (mitogen-activated protein kinase or ERK kinase 1 and 2) and ERK1/2 is frequently de-regulated in human cancers, due to mutations in RAS or BRAF (v-raf-1 murine leukemia viral oncogene homolog B1). New, highly selective inhibitors of BRAF and MEK1/2 have shown promise in clinical trials, including in previously intractable diseases such as melanoma. However, drug-resistant tumour cells invariably emerge leading to disease progression. It is important to understand the mechanisms underlying such acquired resistance since this may lead to the development of rational strategies either to delay its onset or to overcome it once established. It also offers unique insights into the plasticity of signalling pathways, which may in turn inform our understanding of the basic biology of these pathways and lead to the validation of new drug targets. Several recent reports have identified diverse mechanisms of acquired resistance to MEK1/2 or BRAF inhibitors. In this article, we review these studies, discuss the different mechanisms, identify common themes and consider their therapeutic implications. © 2013 Macmillan Publishers Limited.

Moore J.D.,Horizon Discovery
Drug Discovery Today | Year: 2015

The addition of an RNA-guided nuclease, Cas9, to the gene editing toolbox has increased the accessibility of gene editing technologies by greatly simplifying the design of editing reagents. Only a single 75-100 nucleotide RNA is required to guide Cas9 to the target gene of interest, which has meant that the established infrastructure of short-hairpin RNA interference screen could be readily adapted to genome-wide knock out screens. Cas9-based editing technology should streamline the generation of animal and cell-line models, make the generation of activity-dead mutations in target validation routine, and enable the discovery of a new generation of targets across therapeutic areas. © 2015 Published by Elsevier Ltd.

Moore J.D.,Horizon Discovery | Moore J.D.,Vernalis | Potter A.,Vernalis
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Compelling data supports the hypothesis that Pin1 inhibitors will be useful for the therapy of cancer: Pin1 deficient mice resist the induction of breast cancers normally evoked by expression of MMTV-driven Ras or Erb2 alleles. While Pin1 poses challenges for drug discovery, several groups have identified potent antagonists by structure based drug design, significant progress has been made designing peptidic inhibitors and a number of natural products have been found that blockade Pin1, notably epigallocatchechin gallate (EGCG), a major flavonoid in green tea. Here we critically discuss the modes of action and likely specificity of these compounds, concluding that a suitable chemical biology tool for probing the function of Pin1 has yet to be found. We conclude by outlining some open questions regarding the target validation of Pin1 and the prospects for identification of improved inhibitors in the future. © 2013 Elsevier Ltd. All rights reserved.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.1-8 | Award Amount: 8.20M | Year: 2011

Effective and long term treatment of cancer is now in sight, but will ultimately require an increasingly personalised approach where the right combination of drugs will be administered to the right patients, based on a detailed understanding of their genetic background and their co-associated sensitivity or resistance biomarkers. Efforts are specifically required to identify validated risk and patient-response stratification criteria, which can then be used to rationally develop companion diagnostic assays and more stream-lined clinical trials. COLTHERES will address these key issues by: 1) Molecularly profiling colon cancer patient samples using multiple omics based technologies for co-segregating lesions that could impart resistance to existing and emerging targeted therapies 2) The building and screening of predictive in vitro models based on this data, to enable the rapid and empirical determination of drug resistance biomarkers 3) The use of these models and of the clinical studies to prospectively screen for genes mediating resistance and sensitivity to targeted therapies in CRCs 4) The building of new algorithms to significantly accelerate the design of rational therapies, by integrating more predictive models, assays and biomarkers into all phases of drug discovery; including novel phase-0 (xenopatients) studies 5) The design of innovative and focused biomarker driven phase II trials based on knowledge gathered within the project COLTHERES has assembled a unique consortium, from both academia and industrial SMEs, of world- experts in the areas of; clinical design of innovative biomarker trials and improved therapeutic strategies omics technologies including genomic, transcriptomic, epigenomic and proteomic profiling Functional genomic and disease model-generation Bio-informatics and data analysis, to handle and interrogate the complexity of the data generated through the various approaches

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