Publications
211 results found
Abduljabbar R, Al-Kaabi MM, Negm OH, et al., 2015, Prognostic and biological significance of peroxisome proliferator-activated receptor-gamma in luminal breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 150, Pages: 511-522, ISSN: 0167-6806
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- Citations: 24
Abduljabbar R, Negm OH, Lai C-F, et al., 2015, Clinical and biological significance of glucocorticoid receptor (GR) expression in breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 150, Pages: 335-346, ISSN: 0167-6806
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- Citations: 66
Rudraraju B, Droog M, Abdel-Fatah TMA, et al., 2014, Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 147, Pages: 295-309, ISSN: 0167-6806
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- Citations: 13
Xu Y, Zhang H, Lit LC, et al., 2014, The Kinase LMTK3 Promotes Invasion in Breast Cancer Through GRB2-Mediated Induction of Integrin β<sub>1</sub>, SCIENCE SIGNALING, Vol: 7, ISSN: 1945-0877
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- Citations: 31
Brooke GN, Powell SM, Lavery DN, et al., 2014, Engineered repressors are potent inhibitors of androgen receptor activity, Oncotarget, Vol: 5, Pages: 959-969, ISSN: 1949-2553
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
Lai C-F, Flach KD, Alexi X, et al., 2013, Co-regulated gene expression by oestrogen receptor α and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells, NUCLEIC ACIDS RESEARCH, Vol: 41, Pages: 10228-10240, ISSN: 0305-1048
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- Citations: 36
Ottaviani S, Brooke GN, O'Hanlon-Brown C, et al., 2013, Characterisation of the androgen regulation of glycine <i>N</i>-methyltransferase in prostate cancer cells, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 51, Pages: 301-312, ISSN: 0952-5041
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- Citations: 13
Eccles SA, Aboagye EO, Ali S, et al., 2013, Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer, Breast Cancer Research, Vol: 15, Pages: R-R, ISSN: 1465-542X
IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease
Kaliszczak M, Patel H, Kroll SHB, et al., 2013, Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance, British Journal of Cancer, Vol: 109, Pages: 2356-2367, ISSN: 1532-1827
background: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.methods: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.results: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å2) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.conclusion: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.
Faronato M, Lombardo Y, Filipovic A, et al., 2013, Anti-Nicastrin antibodies for the treatment of endocrine resistant breast cancer., 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Long J, Delahanty RJ, Li G, et al., 2013, A Common Deletion in the <i>APOBEC3</i> Genes and Breast Cancer Risk, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol: 105, Pages: 573-579, ISSN: 0027-8874
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- Citations: 109
Rey J, Hu H, Kyle F, et al., 2012, Discovery of a New Class of Liver Receptor Homolog-1 (LRH-1) Antagonists: Virtual Screening, Synthesis and Biological Evaluation, CHEMMEDCHEM, Vol: 7, Pages: 1909-1914, ISSN: 1860-7179
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- Citations: 18
Lake MC, Quang-De N, Ali S, et al., 2012, Development of a novel molecular sensor for imaging estrogen receptor-coactivator protein-protein interactions, PLoS One, Vol: 7, Pages: 1-9, ISSN: 1932-6203
Anti-estrogens, in particular tissue selective anti-estrogens, have been the bedrock of adjuvant therapy for patients with estrogen receptor alpha (ERα) positive breast cancer. Though current therapies have greatly enhanced patient prognosis, there continues to be an impetus for the development of improved anti-estrogens. ERα is a nuclear receptor transcription factor which activates gene expression through the recruitment of transcriptional coactivator proteins. The SRC family of coactivators, which includes AIB1, has been shown to be of particular importance for ERα mediated transcription. ERα-AIB1 interactions are indicative of gene expression and are inhibited by anti-estrogen treatment. We have exploited the interaction between ERα and AIB1 as a novel method for imaging ERα activity using a split luciferase molecular sensor. By producing a range of ERα ligand binding domain (ER-LBD) and AIB1 nuclear receptor interacting domain (AIB-RID) N- and C-terminal firefly luciferase fragment fusion proteins, constructs which exhibited more than a 10-fold increase in luciferase activity with E2 stimulation were identified. The specificity of the E2-stimulated luciferase activity to ERα-AIB1 interaction was validated through Y537S and L539/540A ER-LBD fusion protein mutants. The primed nature of the split luciferase assay allowed changes in ERα activity, with respect to the protein-protein interactions preceding transcription, to be assessed soon after drug treatment. The novel assay split luciferase detailed in this report enabled modulation of ERα activity to be sensitively imaged in vitro and in living subjects and potentially holds much promise for imaging the efficacy of novel ERα specific therapies.
Ottaviani S, Brown CO, Waxman J, et al., 2012, Identification of glycine N-methyltransferase-regulated genes in prostate cancer cells, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Ross-Innes CS, Stark R, Teschendorff AE, et al., 2012, Differential oestrogen receptor binding is associated with clinical outcome in breast cancer, NATURE, Vol: 481, Pages: 389-U177, ISSN: 0028-0836
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- Citations: 1114
HART STEPHEN, ALI SIMAK, PUFONG BORIS TUMI, et al., 2012, Control of Gene Expression Using a Complex of an Oligonucleotide and a Regulatory Peptide
A method for suppressing the expression of a selected gene in a cell, the method comprising introducing into the cell a molecule comprising (1) a nucleic acid binding portion which binds to a site or associated with the selected gene which site is present in a genome and (2) an expression repressor portion, wherein the nucleic acid binding portion comprises an oligonucleotide or oligonucleotide mimic or analogue, and wherein the repressor portion comprises a polypeptide or peptidomimetic. Molecules for use in the methods of the invention are provided. The repressor may be a portion of a histone deacetylase or DNA methylase or polypeptide capable of recruiting a histone deacetylase or DNA methylase.
Ross-Innes CS, Stark AR, Teschendorff AE, et al., 2012, Differential oestrogen receptor binding is associated with clinical outcome in breast cancer, Nature, Vol: 481, Pages: 389-391
Oestrogen receptor-α (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems1, 2, 3. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes.
Patel BH, Mason AM, Patel H, et al., 2011, Conversion of α-Amino Acids into Bioactive <i>o</i>-Aminoalkyl Resorcylates and Related Dihydroxyisoindolinones, JOURNAL OF ORGANIC CHEMISTRY, Vol: 76, Pages: 6209-6217, ISSN: 0022-3263
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- Citations: 16
Tolhurst RS, Thomas RS, Kyle FJ, et al., 2011, Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth, BREAST CANCER RESEARCH AND TREATMENT, Vol: 128, Pages: 357-368, ISSN: 0167-6806
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- Citations: 21
Thiruchelvam PTR, Lai C-F, Hua H, et al., 2011, The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells, BREAST CANCER RESEARCH AND TREATMENT, Vol: 127, Pages: 385-396, ISSN: 0167-6806
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- Citations: 57
Giamas G, Filipovic A, Messier W, et al., 2011, Kinome Screening for Regulators of Estrogen Receptor Identifies a Novel Kinase as a New Therapeutic Target in Breast Cancer.
BULUWELA LAKI, WAXMAN JONATHAN, ALI SIMAK, et al., 2011, METHODS OF AIDING IN THE DIAGNOSIS OF PROSTATE CANCER
The current invention provides a method for aiding in the assessment of prostate cancer (including metastatic prostate cancer) and/or benign prostate hyperplasia in a patient, wherein the method comprises the step of determining the level of Glycine N-methyltransferase (GNMT) nucleic acid and/or protein in a sample from the patient. The invention also provides compounds that target Glycine N-methyltransferase (GNMT) protein and/or nucleic acid for use in treating prostate cancer. Also provided are screening methods for selecting a compound considered to be useful in treating prostate cancer, comprising the steps of determining the ability of a test compound to reduce GNMT activity and selecting a compound that reduces GNMT activity. The invention also provides methods for aiding in the diagnosis of prostate cancer in a patient comprising obtaining a sample from the patient and assessing said sample for a marker of GNMT activity.
Ali S, Buluwela L, Coombes RC, 2011, Antiestrogens and Their Therapeutic Applications in Breast Cancer and Other Diseases, ANNUAL REVIEW OF MEDICINE, VOL 62, 2011, Vol: 62, Pages: 217-232, ISSN: 0066-4219
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- Citations: 69
Buluwela L, Kamalati T, Photiou A, et al., 2010, A Simple Laboratory Practical to Illustrate RNA Mediated Gene Interference Using Drosophila Cell Culture, BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION, Vol: 38, Pages: 393-399, ISSN: 1470-8175
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- Citations: 1
Toumi M, Barbazanges M, Kroll SHB, et al., 2010, Concise, flexible syntheses of 4-(4-imidazolyl)pyrimidine cyclin-dependent kinase 2 (CDK2) inhibitors, TETRAHEDRON LETTERS, Vol: 51, Pages: 6126-6128, ISSN: 0040-4039
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- Citations: 1
Heathcote DA, Patel H, Kroll SH, et al., 2010, A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration, J Med Chem, Vol: 53, Pages: 8508-8522
Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.
Ali S, Buluwela L, Coombes RC, 2010, Antiestrogens and their therapeutic applications in breast cancer and other diseases, Annu Rev Med, Vol: 62, Pages: 217-232
The identification of the link between breast cancer and estrogens has led to the development of antiestrogens, in particular tamoxifen, to inhibit the activities of estrogen receptors (ERs) in breast cancer cells. The clinical use of tamoxifen has played a major part in decreasing breast cancer mortality over the past 30 years. Though antiestrogenic in the breast, some antiestrogens have estrogen-like actions in other tissues, acting to promote bone density and protect against cardiovascular disease, thus raising the possibility of their use in counteracting the effects of estrogen loss following menopause. Moreover, antiestrogens show efficacy as chemopreventive agents in women at high risk of developing breast cancer. Thus, antiestrogens define an important and well-understood class of cancer drug, which continue to be a mainstay in breast cancer treatment.
Thiruchelvam PTR, Hua H, Lai CF, et al., 2010, Characterization of estrogen responses in breast cancer cell lines highlights ERα as an LRH-1 regulated gene, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
JOGALEKAR ASHUTOSH S, SNYDER JAMES P, LIOTTA DENNIS C, et al., 2010, Selective Inhibitors for Cyclin-Dependent Kinases
This invention provides a class of compounds which are useful for specifically inhibiting cyclin-dependent kinases. This class of compounds finds use in treating diseases resulting from inappropriate activity of cyclin-dependent kinases, including cancer, viral infections (e.g., HIV) neurodegenerative disorders (e.g. Alzheimer's disease), and cardiovascular disorders (e.g. atherosclerosis). Moreover, certain members of this class are particularly useful for inhibiting cyclin-dependent kinase 7 and are especially useful for the treatment of breast cancer.
heathcote D, 2010, A Novel Pyrazolo[1,5-a]pyrimidine Is a Potent Inhibitor of Cyclin-Dependent Protein Kinases 1, 2, and 9, Which Demonstrates Antitumor Effects in Human Tumor Xenografts Following Oral Administration., J. Med. Chem.
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