Publications
177 results found
Weinberg PD, Hernandez ADR, Brown R, 2017, Engineering solutions for cancer, CONVERGENT SCIENCE PHYSICAL ONCOLOGY, Vol: 3, ISSN: 2057-1739
Flower KJ, Ghaem-Maghami S, Brown R, 2017, Is there a role for epigenetic enhancement of immunomodulatory approaches to cancer treatment?, Current Cancer Drug Targets, Vol: 17, ISSN: 1873-5576
The efficacy of cancer immunotherapy relies on the ability of the host immune system to recognise the cancer as non-self and eliminate it from the body. Whilst this is an extremely fertile area of medical research, with positive clinical trials showing durable responses, attention must be paid to the subset of patients that do not respond to these treatments. Immune surveillance and immunoediting by the host could itself select for immune-evasive tumour cells during tumour development leading to immunotherapy resistance. One such mechanism of non-efficacy or resistance is the epigenetic silencing of a specific gene required in the immunotherapy response pathway. Epigenetics is the study of the control of expression patterns in a cell via mechanisms not involving a change in DNA sequence. All tumour types show aberrant epigenetic regulation of genes involved in all the hallmarks of cancer, including immunomodulation. Inhibition of key enzymes involved in maintenance of epigenetic states is another important area of research for new treatment strategies for cancer. Could epigenetic therapies be used to successfully enhance the action of immunomodulatory agents in cancer, and are they acting in the way we imagine? An understanding of the effects of epigenetic therapies on immunological pathways in both the tumour and host cells, especially the tumour microenvironment, will be essential to further develop such combination approaches.
Tutt A, Cheang MCU, Kilburn L, et al., 2017, BRCA1 methylation status, silencing and treatment effect in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012), San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Flanagan JM, Curry E, Stirling L, et al., 2017, Epigenome-wide association study for breast cancer risk using whole genome and target captured bisulphite sequencing: A pooled case-control study nested in the breakthrough generations study, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Wilhelm-Benartzi CS, Mt-Isa S, Fiorentino F, et al., 2016, Challenges and methodology in the incorporation of biomarkers in cancer clinical trials., Critical Reviews in Oncology/Hematology, Vol: 110, Pages: 49-61, ISSN: 1040-8428
Biomarkers can be used to establish more homogeneous groups using the genetic makeup of the tumour to inform the selection of treatment for each individual patient. However, proper preclinical work and stringent validation are needed before taking forward biomarkers into confirmatory studies. Despite the challenges, incorporation of biomarkers into clinical trials could better target appropriate patients, and potentially be lifesaving. The authors conducted a systematic review to describe marker-based and adaptive design methodology for their integration in clinical trials, and to further describe the associated practical challenges. Studies published between 1990 to November 2015 were searched on PubMed. Titles, abstracts and full text articles were reviewed to identify relevant studies. Of the 4438 studies examined, 57 studies were included. The authors conclude that the proposed approaches may readily help researchers to design biomarker trials, but novel approaches are still needed.
Doria ML, McKenzie JS, Mroz A, et al., 2016, Epithelial ovarian carcinoma diagnosis by desorption electrospray ionization mass spectrometry imaging, Scientific Reports, Vol: 6, ISSN: 2045-2322
Ovarian cancer is highly prevalent among European women, and is the leading cause of gynaecological cancer death. Current histopathological diagnoses of tumour severity are based on interpretation of, for example, immunohistochemical staining. Desorption electrospray mass spectrometry imaging (DESI-MSI) generates spatially resolved metabolic profiles of tissues and supports an objective investigation of tumour biology. In this study, various ovarian tissue types were analysed by DESI-MSI and co-registered with their corresponding haematoxylin and eosin (H&E) stained images. The mass spectral data reveal tissue type-dependent lipid profiles which are consistent across the n = 110 samples (n = 107 patients) used in this study. Multivariate statistical methods were used to classify samples and identify molecular features discriminating between tissue types. Three main groups of samples (epithelial ovarian carcinoma, borderline ovarian tumours, normal ovarian stroma) were compared as were the carcinoma histotypes (serous, endometrioid, clear cell). Classification rates >84% were achieved for all analyses, and variables differing statistically between groups were determined and putatively identified. The changes noted in various lipid types help to provide a context in terms of tumour biochemistry. The classification of unseen samples demonstrates the capability of DESI-MSI to characterise ovarian samples and to overcome existing limitations in classical histopathology.
Brown R, Kandil S, Sundriyal S, et al., 2016, Synergy in reversing platinum resistance by combined inhibition of EZH2 and EHMT1/2, EUROPEAN JOURNAL OF CANCER, Vol: 69, Pages: S74-S74, ISSN: 0959-8049
Mitra A, MacIntyre D, Lee Y, et al., 2016, Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity, Blair Bell Research Society Annual Academic Meeting, Publisher: Wiley, Pages: E11-E12, ISSN: 1470-0328
Phelps DL, Balog J, El-Bahrawy M, et al., 2016, Diagnosis of borderline ovarian tumours by rapid evaporative ionisation mass spectrometry (REIMS) using the surgical intelligent knife (iKnife), Royal College of Obstetricians and Gynaecologists - Blair Bell Academic Meeting, Publisher: Wiley, Pages: e4-e4
Lanchbury J, Timms K, Reid J, et al., 2016, 3-biomarker HRD score versus individual biomarker (LOH, TAI, LST) scores in platinum treated serous ovarian cancer (SOC), ANNALS OF ONCOLOGY, Vol: 27, ISSN: 0923-7534
Flower KJ, Shenker NS, el-Bahrawy M, et al., 2016, DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer, Epigenetics, Vol: 10, Pages: 1121-1132, ISSN: 1559-2308
Germline pathogenic mutations in BRCA1 increase risk of developing breast cancer. Screening for mutations in BRCA1 frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate BRCA1-mutated from BRCA1-wild type tumors. We hypothesized that we could predict pathogenicity of variants based on DNA methylation profiles of tumors that had arisen in carriers of unclassified variants. We selected 150 FFPE breast tumor DNA samples [47 BRCA1 pathogenic mutation carriers, 65 BRCAx (BRCA1-wild type), 38 BRCA1 test variants] and analyzed a subset (n=54) using the Illumina 450K methylation platform, using the remaining samples for bisulphite pyrosequencing validation. Three validated markers (BACH2, C8orf31, and LOC654342) were combined with sequence bioinformatics in a model to predict pathogenicity of 27 variants (independent test set). Predictions were compared with standard multifactorial likelihood analysis. Prediction was consistent for c.5194-12G>A (IVS 19-12 G>A) (P>0.99); 13 variants were considered not pathogenic or likely not pathogenic using both approaches. We conclude that tumor DNA methylation data alone has potential to be used in prediction of BRCA1 variant pathogenicity but is not independent of estrogen receptor status and grade, which are used in current multifactorial models to predict pathogenicity.
French JD, Johnatty SE, Lu Y, et al., 2016, Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer, Oncotarget, Vol: 7, Pages: 6353-6368, ISSN: 1949-2553
Bonito NA, Borley J, Wilhelm-Benartzi CS, et al., 2016, Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer., Clinical Cancer Research, Vol: 22, Pages: 3097-3104, ISSN: 1557-3265
PURPOSE: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. EXPERIMENTAL DESIGN: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. RESULTS: CpG sites at contiguous genomic locations within theMSX1gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P< 0.05,q< 0.05,n= 78), have poor RECIST response (P< 0.05,q< 0.05,n= 61), and are associated with PFS in an independent cohort (n= 146). A decrease in methylation at these CpG sites correlates with decreasedMSX1gene expression.MSX1expression is associated with PFS (HR, 0.92; 95% CI, 0.85-0.99;P= 0.029;n= 309). Cisplatin-resistant ovarian cancer cell lines have reducedMSX1expression, andMSX1overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression. CONCLUSIONS: Hypomethylation of CpG sites within theMSX1gene is associated with resistant HGSOC disease at presentation and identifies expression ofMSX1as conferring platinum drug sensitivity.Clin Cancer Res; 1-8. ©2016 AACR.
Curry E, Green I, Chapman-Rothe N, et al., 2015, Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells, Clinical Epigenetics, Vol: 7, ISSN: 1868-7083
Background: Many cancers show aberrant silencing of gene expression andoverexpression of histone methyltransferases. The histone methyltransferases (HKMT)EZH2 and EHMT2 maintain the repressive chromatin histone marks H3K27 and H3K9methylation respectively, which are associated with transcriptional silencing. Althoughselective HKMT inhibitors reduce levels of individual repressive marks, removal ofH3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducingexpression of genes with multiple repressive marks.Results: We report that gene expression and inhibition of triple negative breast cancer cellgrowth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2,either by siRNA knockdown or pharmacological inhibition, rather than independently. Indeed,expression of certain genes is only induced upon dual inhibition. We sought to identifycompounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-basedassay, based on the substrate-competitive EHMT2 inhibitor BIX01294, we have identifiedproof-of-concept compounds that induce re-expression of a subset of genes consistent withdual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marksand an increase in permissive marks at the promoter and transcription start site of reexpressedgenes, while Western analysis showed reduction in global levels of H3K27me3and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma celllines with low to sub-micromolar IC50s. Biochemically, the compounds are substratecompetitive inhibitors against both EZH2 and EHMT1/2.Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is moreeffective at eliciting biological responses of gene transcription and cancer cell growthinhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.
Shenker NS, Flower KJ, Wilhelm-Benartzi C, et al., 2015, Transcriptional implications of intragenic DNA methylation in the estrogen receptor alpha gene in breast cancer cells and tissues, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: American Association for Cancer Research, ISSN: 1538-7445
He YJ, Winham SJ, Hoskins JM, et al., 2015, Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial, Pharmacogenomics Journal, Vol: 16, Pages: 243-248, ISSN: 1473-1150
Patch A-M, Christie EL, Etemadmoghadam D, et al., 2015, Whole-genome characterization of chemoresistant ovarian cancer, Nature, Vol: 521, Pages: 489-494, ISSN: 0028-0836
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
Brown R, Timms K, Paul J, et al., 2015, Homologous recombination (HR) deficiency, tumor BRCA1/2 mutations (tmBRCA) and association with response and outcome following platinum monotherapy in high grade serous ovarian cancer (HGSOC)., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Clinical Science Symposium on Predicting and Improving Adverse Outcomes in Older Adults with Cancer, Publisher: American Society of Clinical Oncology, ISSN: 0732-183X
Shenker NS, Flower KJ, Wilhelm-Benartzi CS, et al., 2015, Transcriptional implications of intragenic DNA methylation in the oestrogen receptor alpha gene in breast cancer cells and tissues., BMC Cancer, Vol: 15, Pages: 337-337, ISSN: 1471-2407
BACKGROUND: DNA methylation variability regions (MVRs) across the oestrogen receptor alpha (ESR1) gene have been identified in peripheral blood cells from breast cancer patients and healthy individuals. In contrast to promoter methylation, gene body methylation may be important in maintaining active transcription. This study aimed to assess MVRs in ESR1 in breast cancer cell lines, tumour biopsies and exfoliated epithelial cells from expressed breast milk (EBM), to determine their significance for ESR1 transcription. METHODS: DNA methylation levels in eight MVRs across ESR1 were assessed by pyrosequencing bisulphite-converted DNA from three oestrogen receptor (ER)-positive and three ER-negative breast cancer cell lines. DNA methylation and expression were assessed following treatment with DAC (1 μM), or DMSO (controls). ESR1 methylation levels were also assayed in DNA from 155 invasive ductal carcinoma biopsies provided by the Breast Cancer Campaign Tissue Bank, and validated with DNA methylation profiles from the TCGA breast tumours (n = 356 ER-pos, n = 109 ER-neg). DNA methylation was profiled in exfoliated breast epithelial cells from EBM using the Illumina 450 K (n = 36) and pyrosequencing in a further 53 donor samples. ESR1 mRNA levels were measured by qRT-PCR. RESULTS: We show that ER-positive cell lines had unmethylated ESR1 promoter regions and highly methylated intragenic regions (median, 80.45%) while ER-negative cells had methylated promoters and lower intragenic methylation levels (median, 38.62%). DAC treatment increased ESR1 expression in ER-negative cells, but significantly reduced methylation and expression of ESR1 in ER-positive cells. The ESR1 promoter was unmethylated in breast tumour biopsies with high levels of intragenic methylation, independent of ER status. However, ESR1 methylation in the strongly ER-positive EBM DNA samples were very similar to ER-positive tumour cell lines. CONCLUSION:
Flanagan JM, Brook MN, Orr N, et al., 2015, Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 24, Pages: 221-229, ISSN: 1055-9965
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- Citations: 49
Borley J, Brown R, 2015, Epigenetic mechanisms and therapeutic targets of chemotherapy resistance in epithelial ovarian cancer, ANNALS OF MEDICINE, Vol: 47, Pages: 359-369, ISSN: 0785-3890
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- Citations: 40
van der Wijst MGP, Brown R, Rots MG, 2014, Nrf2, the master redox switch: The Achilles' heel of ovarian cancer?, BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, Vol: 1846, Pages: 494-509, ISSN: 0304-419X
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- Citations: 45
Brown R, Curry E, Magnani L, et al., 2014, Poised epigenetic states and acquired drug resistance in cancer, Nature Reviews Cancer, Vol: 14, Pages: 747-753, ISSN: 1474-1768
Brown R, Fuchter M, Curry E, et al., 2014, Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells, 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: ELSEVIER SCI LTD, Pages: 179-180, ISSN: 0959-8049
Brown R, Fuchter M, Curry E, et al., 2014, 554 Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells, European Journal of Cancer, Vol: 50, Pages: 179-180, ISSN: 0959-8049
Huang H, Benzonana LL, Zhao H, et al., 2014, Prostate cancer cell malignancy via modulation of HIF-1 alpha pathway with isoflurane and propofol alone and in combination, British Journal of Cancer, Vol: 111, Pages: 1338-1349, ISSN: 1532-1827
Background: Surgery is considered to be the first line treatment for solid tumours. Recently, retrospective studies reported thatgeneral anaesthesia was associated with worse long-term cancer-free survival when compared with regional anaesthesia. This hasimportant clinical implications; however, the mechanisms underlying those observations remain unclear. We aim to investigate theeffect of anaesthetics isoflurane and propofol on prostate cancer malignancy.Methods: Prostate cancer (PC3) cell line was exposed to commonly used anaesthetic isoflurane and propofol. Malignant potentialwas assessed through evaluation of expression level of hypoxia-inducible factor-1a (HIF-1a) and its downstream effectors, cellproliferation and migration as well as development of chemoresistance.Results: We demonstrated that isoflurane, at a clinically relevant concentration induced upregulation of HIF-1a and itsdownstream effectors in PC3 cell line. Consequently, cancer cell characteristics associated with malignancy were enhanced, withan increase of proliferation and migration, as well as development of chemoresistance. Inhibition of HIF-1a neosynthesis throughupper pathway blocking by a PI-3K-Akt inhibitor or HIF-1a siRNA abolished isoflurane-induced effects. In contrast, the intravenousanaesthetic propofol inhibited HIF-1a activation induced by hypoxia or CoCl2. Propofol also prevented isoflurane-induced HIF-1aactivation, and partially reduced cancer cell malignant activities.Conclusions: Our findings suggest that modulation of HIF-1a activity by anaesthetics may affect cancer recurrence followingsurgery. If our data were to be extrapolated to the clinical setting, isoflurane but not propofol should be avoided for use in cancersurgery. Further work involving in vivo models and clinical trials is urgently needed to determine the optimal anaesthetic regimenfor cancer patients.
Hedditch EL, Gao B, Russell AJ, et al., 2014, ABCA transporter gene expression and poor outcome in epithelial ovarian cancer, JNCI: Journal of the National Cancer Institute, Vol: 106, ISSN: 0027-8874
BackgroundATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown.MethodsThe relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA–mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan–Meier analysis and log-rank tests. All statistical tests were two-sided.ResultsAssociations with outcome were observed with ABC transporters of the “A” subfamily, but not with multidrug transporters. High-level expression of ABCA1 , ABCA6 , ABCA8 , and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e−6). The combined expression pattern of ABCA1 , ABCA5 , and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration.ConclusionsExpression of ABCA transporters was associate
Block MS, Charbonneau B, Vierkant RA, et al., 2014, Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 23, Pages: 1421-1427, ISSN: 1055-9965
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Earp MA, Kelemen LE, Magliocco AM, et al., 2014, Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA, HUMAN GENETICS, Vol: 133, Pages: 481-497, ISSN: 0340-6717
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Charbonneau B, Moysich KB, Kalli KR, et al., 2014, Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome, CANCER IMMUNOLOGY RESEARCH, Vol: 2, Pages: 332-340, ISSN: 2326-6066
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- Citations: 22
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