Imperial College London

ProfessorCharlesCoombes

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Medical Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2135c.coombes

 
 
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Assistant

 

Mrs Suzy Ford +44 (0)20 7594 2135

 
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Location

 

145ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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932 results found

Rushton AJ, Nteliopoulos G, Shaw JA, Coombes RCet al., 2021, A Review of Circulating Tumour Cell Enrichment Technologies, CANCERS, Vol: 13

Journal article

Sava GP, Fan H, Coombes RC, Buluwela L, Ali Set al., 2020, CDK7 inhibitors as anticancer drugs, Cancer and Metastasis Reviews, Vol: 39, Pages: 805-823, ISSN: 0167-7659

Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.

Journal article

Kalofonou M, Malpartida-Cardenas K, Alexandrou G, Rodriguez-Manzano J, Yu L-S, Miscourides N, Allsopp R, LT Gleason K, Goddard K, Fernandez-Garcia D, Page K, Georgiou P, Ali S, Coombes RC, Shaw J, Toumazou Cet al., 2020, A novel hotspot specific isothermal amplification method for detection of thecommon PIK3CA p.H1047R breast cancer mutation, Scientific Reports, Vol: 10, ISSN: 2045-2322

Breast cancer (BC) is a common cancer in women worldwide. Despite advances in treatment, up to 30% of women eventually relapse and die of metastatic breast cancer. Liquid biopsy analysis of circulating cell-free DNA fragments in the patients’ blood can monitor clonality and evolving mutations as a surrogate for tumour biopsy. Next generation sequencing platforms and digital droplet PCR can be used to profile circulating tumour DNA from liquid biopsies; however, they are expensive and time consuming for clinical use. Here, we report a novel strategy with proof-of-concept data that supports the usage of loop-mediated isothermal amplification (LAMP) to detect PIK3CA c.3140 A > G (H1047R), a prevalent BC missense mutation that is attributed to BC tumour growth. Allele-specific primers were designed and optimized to detect the p.H1047R variant following the USS-sbLAMP method. The assay was developed with synthetic DNA templates and validated with DNA from two breast cancer cell-lines and two patient tumour tissue samples through a qPCR instrument and finally piloted on an ISFET enabled microchip. This work sets a foundation for BC mutational profiling on a Lab-on-Chip device, to help the early detection of patient relapse and to monitor efficacy of systemic therapies for personalised cancer patient management.

Journal article

Sava G, Fan H, Fisher R, Coombes R, Buluwela L, Ali Set al., 2020, ABC transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942., Oncogene, Vol: 39, Pages: 651-663, ISSN: 0950-9232

The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was up-regulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.

Journal article

Fernandez-Garcia D, Hills A, Page K, Hastings RK, Toghill B, Goddard KS, Ion C, Ogle O, Boydell AR, Gleason K, Rutherford M, Lim A, Guttery DS, Coombes RC, Shaw JAet al., 2019, Plasma cell-free DNA (cfDNA) as a predictive and prognostic marker in patients with metastatic breast cancer, Breast Cancer Research, Vol: 21, Pages: 1-13, ISSN: 1465-542X

BackgroundBreast cancer (BC) is the most common cancer in women, and despite the introduction of new screening programmes, therapies and monitoring technologies, there is still a need to develop more useful tests for monitoring treatment response and to inform clinical decision making.The purpose of this study was to compare circulating cell-free DNA (cfDNA) and circulating tumour cells (CTCs) with conventional breast cancer blood biomarkers (CA15-3 and alkaline phosphatase (AP)) as predictors of response to treatment and prognosis in patients with metastatic breast cancer (MBC).MethodsOne hundred ninety-four female patients with radiologically confirmed MBC were recruited to the study. Total cfDNA levels were determined by qPCR and compared with CELLSEARCH® CTC counts and CA15-3 and alkaline phosphatase (AP) values. Blood biomarker data were compared with conventional tumour markers, treatment(s) and response as assessed by RECIST and survival.Non-parametric statistical hypothesis tests were used to examine differences, correlation analysis and linear regression to determine correlation and to describe its effects, logistic regression and receiver operating characteristic curve (ROC curve) to estimate the strength of the relationship between biomarkers and clinical outcomes and value normalization against standard deviation to make biomarker values comparable. Kaplan–Meier estimator and Cox regression models were used to assess survival. Univariate and multivariate models were performed where appropriate.ResultsMultivariate analysis showed that both the amount of total cfDNA (p value = 0.024, HR = 1.199, CI = 1.024–1.405) and the number of CTCs (p value = 0.001, HR = 1.243, CI = 1.088–1.421) are predictors of overall survival (OS), whereas total cfDNA levels is the sole predictor for progression-free survival (PFS) (p value = 0.042, HR =&th

Journal article

Joseph C, Al-Izzi S, Alsaleem M, Kurozumi S, Toss MS, Arshad M, Goh FQ, Alshankyty IM, Aleskandarany MA, Ali S, Ellis IO, Mongan NP, Green AR, Rakha EAet al., 2019, Retinoid X receptor gamma (RXRG) is an independent prognostic biomarker in ER-positive invasive breast cancer., British Journal of Cancer, Vol: 121, Pages: 776-785, ISSN: 0007-0920

BACKGROUND: Retinoid X Receptor Gamma (RXRG) is a member of the nuclear receptor superfamily and plays a role in tumour suppression. This study aims to explore the prognostic significance of RXRG in breast cancer. METHODS: Primary breast cancer tissue microarrays (n = 923) were immuno-stained for RXRG protein and correlated with clinicopathological features, and patient outcome. RESULTS: Nuclear RXRG expression was significantly associated with smaller tumour size (p = 0.036), lower grade (p < 0.001), lobular histology (p = 0.016), lower Nottingham Prognostic Index (p = 0.04) and longer breast cancer-specific survival (p < 0.001), and longer time to distant metastasis (p = 0.002). RXRG expression showed positive association with oestrogen receptor (ER)-related biomarkers: GATA3, FOXA1, STAT3 and MED7 (all p < 0.001) and a negative correlation with the Ki67 proliferation marker. Multivariate analysis demonstrated RXRG protein as an independent predictor of longer breast cancer-specific survival and distant metastasis-free survival. In the external validation cohorts, RXRG expression was associated with improved patients' outcome (p = 0.025). In ER-positive tumours, high expression of RXRG was associated with better patient outcome regardless of adjuvant systemic therapy. ER signalling pathway was the top predicted master regulator of RXRG protein expression (p = 0.005). CONCLUSION: This study provides evidence for the prognostic value of RXRG in breast cancer particularly the ER-positive tumours.

Journal article

Hong SP, Lombardo Y, Chan TE, Corleone G, Rotmensz N, Magnani L, Bravaccini S, Rocca A, Pruneri G, McEwen KR, Coombes RC, Barozzi Iet al., 2019, Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy, Nature Communications, Vol: 10, ISSN: 2041-1723

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

Journal article

Perone Y, Farrugia AJ, Rodriguez-Meira A, Gyorffy B, Ion C, Uggetti A, Chronopoulos A, Marrazzo P, Faronato M, Shousha S, Davies C, Steel JH, Patel N, Del Rio Hernandez A, Coombes C, Pruneri G, Lim A, Calvo F, Magnani Let al., 2019, SREBP1 drives keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ER alpha breast cancer (vol 10, 2115, 2019), NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723

Journal article

Nguyen VTM, Barozzi I, Faronato M, Lombardo Y, Steel JH, Patel N, Darbre P, Castellano L, Gyorffy B, Woodley L, Rodriguez-Meira A, Patten DK, Vircillo V, Periyasamy M, Ali S, Frige G, Minucci S, Coombes RC, Magnani Let al., 2019, Author Correction: Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion, Nature Communications, Vol: 10, ISSN: 2041-1723

Journal article

Ruenraroengsak P, Kiryushko D, Theodorou IG, Klosowski MM, Taylor ER, Niriella T, Palmieri C, Yagüe E, Ryan MP, Coombes RC, Xie F, Porter AEet al., 2019, Frizzled-7-targeted delivery of zinc oxide nanoparticles to drug-resistant breast cancer cells, Nanoscale, Vol: 11, Pages: 12858-12870, ISSN: 2040-3364

There is a need for novel strategies to treat aggressive breast cancer subtypes and overcome drug resistance. ZnO nanoparticles (NPs) have potential in cancer therapy due to their ability to potently and selectively induce cancer cell apoptosis. Here, we tested the in vitro chemotherapeutic efficacy of ZnONPs loaded via a mesoporous silica nanolayer (MSN) towards drug-sensitive breast cancer cells (MCF-7: estrogen receptor-positive, CAL51: triple-negative) and their drug-resistant counterparts (MCF-7TX, CALDOX). ZnO-MSNs were coated on to gold nanostars (AuNSs) for future imaging capabilities in the NIR-II range. Electron and confocal microscopy showed that MSN-ZnO-AuNSs accumulated close to the plasma membrane and were internalized by cells. High-resolution electron microscopy showed that MSN coating degraded outside the cells, releasing ZnONPs that interacted with cell membranes. MSN-ZnO-AuNSs efficiently reduced the viability of all cell lines, and CAL51/CALDOX cells were more susceptible than MCF7/MCF-7-TX cells. MSN-ZnO-AuNSs were then conjugated with the antibody to Frizzled-7 (FZD-7), the receptor upregulated by several breast cancer cells. We used the disulphide (S-S) linker that could be cleaved with a high concentration of glutathione normally observed within cancer cells, releasing Zn2+ into the cytoplasm. FZD-7 targeting resulted in approximately three-fold amplified toxicity of MSN-ZnO-AuNSs towards the MCF-7TX drug-resistant cell line with the highest FZD-7 expression. This study shows that ZnO-MSs are promising tools to treat triple-negative and drug-resistant breast cancers and highlights the potential clinical utility of FZD-7 for delivery of nanomedicines and imaging probes specifically to these cancer types.

Journal article

Coombes RC, Page K, Salari R, Hastings RK, Armstrong A, Ahmed S, Ali S, Cleator S, Kenny L, Stebbing J, Rutherford M, Sethi H, Boydell A, Swenerton R, Fernandez-Garcia D, Gleason KLT, Goddard K, Guttery DS, Assaf ZJ, Wu H-T, Natarajan P, Moore DA, Primrose L, Dashner S, Tin AS, Balcioglu M, Srinivasan R, Shchegrova SV, Olson A, Hafez D, Billings P, Aleshin A, Rehman F, Toghill BJ, Hills A, Louie MC, Lin C-HJ, Zimmermann BG, Shaw JAet al., 2019, Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence, Clinical Cancer Research, Vol: 25, Pages: 4255-4263, ISSN: 1078-0432

Purpose: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer.Experimental Design: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X).Results: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5–24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling.Conclusions: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.

Journal article

Perone Y, Farrugia AJ, Meira AR, Győrffy B, Ion C, Uggetti A, Chronopoulos A, Marrazzo P, Faronato M, Shousha S, Davies C, Steel JH, Patel N, del Rio Hernandez A, Coombes C, Pruneri G, Lim A, Calvo F, Magnani Let al., 2019, SREBP1 drives Keratin 80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer, Nature Communications, Vol: 10, ISSN: 2041-1723

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

Journal article

Szijgyarto Z, Flach KD, Opdam M, Palmieri C, Linn SC, Wesseling J, Ali S, Bliss JM, Cheang MCU, Zwart W, Coombes RCet al., 2019, Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)-PathIES, Breast Cancer Research and Treatment, Vol: 175, Pages: 149-163, ISSN: 0167-6806

PurposeThe prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES).MethodsOf the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini–Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (pBH).ResultsPhospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (pBH = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (pBH > 0.05 for all).ConclusionsThis PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.

Journal article

Mahmud Z, Asaduzzaman M, Kumar U, Masrour N, Jugov R, Coombes RC, Shousha S, Hu Y, Lam EW-F, Yagüe Eet al., 2019, Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases, Biochemical Pharmacology, Vol: 163, Pages: 391-403, ISSN: 0006-2952

E-cadherin transcriptional activator EP300 is down-regulated in metaplastic breast carcinoma, a rare form of triple negative and E-cadherin-negative aggressive breast cancer with a poor clinical outcome. In order to shed light on the regulation of E-cadherin by EP300 in breast cancer we analyzed by immunohistochemistry 41 cases of invasive breast cancer with both E-cadherinhigh and E-cadherinlow expression levels, together with 20 non-malignant breast tissues. EP300 and E-cadherin showed a positive correlation in both non-malignant and cancer cases and both markers together were better predictors of lymph node metastasis than E-cadherin alone. These data support a metastasis suppressor role for EP300 in breast cancer. However, some reports suggest an oncogenic role for EP300. We generated a breast cancer cell model to study E-cadherin-independent effects of EP300 by over-expression of EP300 in HS578T cells which have E-cadherin promoter hypermethylated. In this cell system, EP300 led to up-regulation of mesenchymal (vimentin, Snail, Slug, Zeb1) and stemness (ALDH+ and CD44high/CD24low) markers, increases in migration, invasion, anchorage-independent growth and drug resistance. Genome-wide expression profiling identified aldo-keto reductases AKR1C1-3 as effectors of stemness and drug resistance, since their pharmacological inhibition with flufenamic acid restored both doxorubicin and paclitaxel sensitivity and diminished mammosphere formation. Thus, in cells with a permissive E-cadherin promoter, EP300 acts as a tumour/metastasis supressor by up-regulating E-cadherin expression, maintenance of the epithelial phenotype and avoidance of an epithelial-to-mesenchymal transition. In cells in which the E-cadherin promoter is hypermethylated, EP300 functions as an oncogene via up-regulation of aldo-keto reductases. This offers the rationale of using current aldo-keto reductase inhibitors in breast cancer treatment.

Journal article

Anderson RL, Balasas T, Callaghan J, Coombes RC, Evans J, Hall JA, Kinrade S, Jones D, Jones PS, Jones R, Marshall JF, Panico MB, Shaw JA, Steeg PS, Sullivan M, Tong W, Westwell AD, Ritchie JWA, Berg R, Drysdale M, Eccles S, Elvin P, Harris A, Ireson C, Machesky L, McLeod R, Muschel R, Newell H, Pittman M, Roman B, Santos C, Sibson N, Smith A, Waddell Iet al., 2019, A framework for the development of effective anti-metastatic agents, NATURE REVIEWS CLINICAL ONCOLOGY, Vol: 16, Pages: 185-204, ISSN: 1759-4774

Journal article

Coombes RC, Armstrong A, Ahmed S, Page K, Hastings RK, Salari R, Sethi H, Boydell A-R, Shchegrova SV, Fernandez-Garcia D, Gleason KL, Goddard K, Guttery DS, Assaf ZJ, Balcioglu M, Moore DA, Primrose L, Navarro SL, Aleshin A, Rehman F, Toghill BJ, Louie MC, Zimmermann BG, Lin C-HJ, Shaw JAet al., 2019, Early detection of residual breast cancer through a robust, scalable and personalized analysis of circulating tumour DNA (ctDNA) antedates overt metastatic recurrence, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Theodorou I, Ruenraroengsak P, Carter D, Jiang Q, Yague E, Aboagye E, Coombes RC, Porter AE, Ryan M, Xie Fet al., 2019, Towards multiplexed near-infrared cellular imaging using gold nanostar arrays with tunable fluorescence enhancement, Nanoscale, Vol: 11, Pages: 2079-2088, ISSN: 2040-3364

Sensitive detection of disease biomarkers expressed by human cells is critical to the development of novel diagnostic and therapeutic methods. Here we report that plasmonic arrays based on gold nanostar (AuNS) monolayers enable up to 19-fold fluorescence enhancement for cellular imaging in the near-infrared (NIR) biological window, allowing the application of low quantum yield fluorophores for sensitive cellular imaging. The high fluorescence enhancement together with low autofluorescence interference in this wavelength range enable higher signal-to-noise ratio compared to other diagnostic modalities. Using AuNSs of different geometries and therefore controllable electric field enhancement, cellular imaging with tunable enhancement factors is achieved, which may be useful for the development of multicolour and multiplexed platforms for a panel of biomarkers, allowing to distinguish different subcell populations at the single cell level. Finally, the uptake of AuNSs within HeLa cells and their high biocompatibility, pave the way for novel high-performance in vitro and in vivo diagnostic platforms.

Journal article

Sokol ES, Feng YX, Jin DX, Basudan A, Lee AV, Atkinson JM, Chen J, Stephens PJ, Frampton GM, Gupta PB, Ross JS, Chung JH, Oesterreich S, Ali SM, Hartmaier RJet al., 2019, Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer., Ann Oncol, Vol: 30, Pages: 115-123

Background: Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed. Patients and methods: Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes. Results: Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P < 0.027] and are frequently polyclonal in ctDNA assays. Assessment of paired specimens shows that NF1 alterations arise in the setting of acquired resistance. An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4-hydroxy tamoxifen. Our study further identified a significant increase in tumor mutational burden (TMB) in mILCs relative to breast ILCs or metastatic IDCs (8.9% >20 mutations/mb; P < 0.001). Most TMB-high mILCs harbor an APOBEC trinucleotide signature (14/16; 88%). Conclusions: This study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibit

Journal article

Dubash SR, Merchant S, Heinzmann K, Mauri F, Lavdas I, Inglese M, Kozlowski K, Rama N, Masrour N, Steel JF, Thornton A, Lim AK, Lewanski C, Cleator S, Coombes RC, Kenny L, Aboagye EOet al., 2018, Clinical translation of [F-18]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 2285-2299, ISSN: 1619-7070

BackgroundEffective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy.ResultsBreast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes.ConclusionThis study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.

Journal article

Theodorou I, Jiang Q, Malms L, Xie X, Coombes RC, Aboagye E, Porter AE, Ryan M, Xie Fet al., 2018, Fluorescence enhancement from single gold nanostars: towards ultra-bright emission in the first and second near-infrared biological windows, Nanoscale, Vol: 10, Pages: 15854-15864, ISSN: 2040-3364

Gold nanostars (AuNSs) are promising agents for the development of high-performance diagnostic devices, by enabling metal enhanced fluorescence (MEF) in the physiological near-infrared (NIR) and second near-infrared (NIR-II) windows. The local electric field near their sharp tips and between their branches can be enhanced by several orders of magnitude, holding great promise for large fluorescence enhancements from single AuNS particles, rather than relying on interparticle coupling in nanoparticle substrates. Here, guided by electric field simulations, two different types of AuNSs with controlled morphologies and plasmonic responses in the NIR and NIR-II regions are used to investigate the mechanism of MEF from colloidal AuNSs. Fluorophore conjugation to AuNSs allows significant fluorescence enhancement of up to 30 times in the NIR window, and up to 4-fold enhancement in the NIR-II region. Together with other inherent advantages of AuNSs, including their multispike morphology offering easy access to cell membranes and their large surface area providing flexible multifunctionality, AuNS are promising for the development of in vivo imaging applications. Using time-resolved fluorescence measurements to deconvolute semi-quantitatively excitation enhancement from emission enhancement, we show that a combination of enhanced excitation and an increased radiative decay rate, both contribute to the observed large enhancement. In accordance to our electric field modelling, however, excitation enhancement is the component that varies most with particle morphology. These findings provide important insights into the mechanism of MEF from AuNSs, and can be used to further guide particle design for high contrast enhancement, enabling the development of MEF biodetection technologies.

Journal article

Blok EJ, Engels CC, Dekker-Ensink G, Kranenbarg EM-K, Putter H, Smit VTHBM, Liefers G-J, Morden JP, Bliss JM, Coombes RC, Bartlett JMS, Kroep JR, van de Velde CJH, Kuppen PJKet al., 2018, Exploration of tumour-infiltrating lymphocytes as a predictive biomarker for adjuvant endocrine therapy in early breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 171, Pages: 65-74, ISSN: 0167-6806

Journal article

Patten DK, Corleone G, Győrffy B, Perone Y, Slaven N, Barozzi I, Erdős E, Saiakhova A, Goddard K, Vingiani A, Shousha S, Pongor LS, Hadjiminas DJ, Schiavon G, Barry P, Palmieri C, Coombes RC, Scacheri P, Pruneri G, Magnani Let al., 2018, Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer, Nature Medicine, Vol: 24, Pages: 1469-1480, ISSN: 1078-8956

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

Journal article

Shaw JA, Page K, Fernandez-Garcia D, Hills A, Boydell AR, Primrose L, Toghill B, Hastings RK, Gleeson K, Rosales BM, Goddard K, Guttery DS, Ali S, Coombes RCet al., 2018, Circulating tumor DNA for early detection and intervention in breast cancer: ctDNA profiles discriminate between healthy women in a true cancer screening setting and disease-free women on follow up, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Ainscow EK, Leishman A, Sullivan E, Li B, Gallagher W, Peall A, Clark K, Thomson S, Ali S, Coombes RC, Bahl Aet al., 2018, CT7001: An orally bioavailable CDK7 inhibitor is a potential therapy for breast, small-cell lung and haematological cancers, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Amrania H, Woodley-Barker L, Goddard K, Rosales B, Shousha S, Thomas G, McFarlane T, Sroya M, Wilhelm-Benartzi C, Phillips CCet al., 2018, Mid-infrared imaging in breast cancer tissue: an objective measure of grading breast cancer biopsies, Convergent Science Physicsl Oncology, Vol: 4, ISSN: 2057-1739

Introduction: -The majority of cancers are diagnosedusingexcised biopsy specimens. These are graded, using a gold-standard histopathology protocol based onhaemotoxylin and eosin (“H+E”)chemical staining. Howeverthe grading is done by eye and if the same biopsy is graded by differentpractitioners, they typically only agree ~70% of the time. The resultingovertreatment problem constitutes a massive unmet need worldwide.Objective:-Ournew ‘Digistain’technology, uses mid-infrared imaging to mapthe fractional concentration of nucleic acids, i.e. the nuclear-to-cytoplasmic chemical ratio (NCR) across an unstained biopsy section. It allows a quantitative “Digistain index” (DI) score, corresponding to the NCR, to be reproducibly extracted from an objective physical measurement of a cancer. Our objective here is to evaluate itspotential for aiding cancer diagnosis for the first time. We correlate the DI scores with H+E grades in a double-blind clinical pilot trial.Methods:-Two adjacent slices were taken from 75 breast cancer FFPE blocks; one was graded with the standard H+E protocol, and also used to define a “Region of Interest” (RoI). Digistain was then used to acquire a DI value averaged over the corresponding RoI on the other (unstained) sliceand theresults werestatistically analysed.Results:-We find the DI score correlates significantly (p=0.0007) with tumorgradein a way that promises to significantly reduce the inherent subjectivity and variability in biopsy grading.Discussion: The NCR is elevated by increased mitotic activity because cells divide when they are youngerand, on average, becomesmaller asthe disease progresses. Also, extra DNA and RNA is generated as thenuclear transcription machinery goes awry and nuclear pleomorphism occurs. Both effects make the NCR a recognized biomarker for a wide range of tumors

Journal article

Hindley JW, Elani Y, McGilvery CM, Ali S, Bevan CL, Law R, Ces Oet al., 2018, Light-triggered enzymatic reactions in nested vesicle reactors, Nature Communications, Vol: 9, Pages: 1-6, ISSN: 2041-1723

Cell-sized vesicles have tremendous potential both as miniaturised pL reaction vessels and in bottom-up synthetic biology as chassis for artificial cells. In both these areas the introduction of light-responsive modules affords increased functionality, for example, to initiate enzymatic reactions in the vesicle interior with spatiotemporal control. Here we report a system composed of nested vesicles where the inner compartments act as phototransducers, responding to ultraviolet irradiation through diacetylene polymerisation-induced pore formation to initiate enzymatic reactions. The controlled release and hydrolysis of a fluorogenic β-galactosidase substrate in the external compartment is demonstrated, where the rate of reaction can be modulated by varying ultraviolet exposure time. Such cell-like nested microreactor structures could be utilised in fields from biocatalysis through to drug delivery.

Journal article

Ali S, Patel H, Periyasamy M, Sava G, Bondke A, Slafer BW, Kroll SHB, Barbazanges MV, Starkey RG, Ottaviani S, Harrod AE, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes Cet al., 2018, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment, Molecular Cancer Therapeutics, ISSN: 1535-7163

Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.

Journal article

Ali SN, Jayasena CN, Sam AH, 2018, Which patients with gynaecomastia require more detailed investigation?, CLINICAL ENDOCRINOLOGY, Vol: 88, Pages: 360-363, ISSN: 0300-0664

Gynaecomastia may be due to medication, chronic liver or kidney disease, hypogonadism (primary or secondary to pituitary disease) or hyperthyroidism. Having excluded these aetiologies, it is imperative to be vigilant for underlying malignancy causing gynaecomastia. These include human chorionic gonadotrophin‐secreting testicular and extratesticular tumours and oestrogen‐secreting testicular tumours and feminising adrenal tumours.

Journal article

Coombes RC, Tovey H, Kilburn L, Mansi J, Palmieri C, Bartlett J, Hicks J, Makris A, Evans A, Loibl S, Denkert C, Murray E, Grieve R, Coleman R, Schmidt M, Klare P, Rezai M, Rautenberg B, Klutinus N, Rhein U, Mousa K, Ricardo-Vitorino S, von Minckwitz G, Bliss Jet al., 2018, A phase III multicentre double blind randomised trial of celecoxib versus placebo in primary breast cancer patients (REACT - Randomised EuropeAn celecoxib trial), San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

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