Imperial College London

ProfessorSimakAli

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

181 results found

HART STEPHEN GB, ALI SIMAK GB, PUFONG BORIS T GB, PORTER ANDREW C G GB, BULUWELA LAKI GB, VAINIKKA SATU GB, JENKINSON JOHN D GB, KANDA PATRICK GBet al., 2023, Control of gene expression using a complex of an oligonucleotide and a regulatory peptide, US2005136040

Patent

Allsopp R, Alexandrou G, Toumazou C, Ali S, Coombes C, Kalofonou M, Shaw Jet al., 2022, A comparison between Mini-loop mediated isothermal amplification and polymerase spiral reaction for selective amplification of short template DNA, bioRxiv

Journal article

Li Z, McGinn O, Wu Y, Bahreini A, Priedigkeit NM, Ding K, Onkar S, Lampenfeld C, Sartorius CA, Miller L, Rosenzweig M, Cohen O, Wagle N, Richer JK, Muller WJ, Buluwela L, Ali S, Bruno TC, Vignali DAA, Fang Y, Zhu L, Tseng GC, Gertz J, Atkinson JM, Lee A, Oesterreich Set al., 2022, ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation, NATURE COMMUNICATIONS, Vol: 13, ISSN: 0008-5472

Journal article

Li Z, Wu Y, Yates ME, Tasdemir N, Bahreini A, Chen J, Levine KM, Priedigkeit NM, Nasrazadani A, Ali S, Buluwela L, Arnesen S, Gertz J, Richer JK, Troness B, El-Ashry D, Zhang Q, Gerratana L, Zhang Y, Cristofanilli M, Montanez MA, Sundd P, Wallace CT, Watkins SC, Fumagalli C, Guerini-Rocco E, Zhu L, Tseng GC, Wagle N, Carroll JS, Jank P, Denkert C, Karsten MM, Blohmer J-U, Park BH, Lucas PC, Atkinson JM, Lee A, Oesterreich Set al., 2022, Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis, CANCER RESEARCH, Vol: 82, Pages: 1321-1339, ISSN: 0008-5472

Journal article

Baker SC, Mason AS, Slip RG, Skinner KT, Macdonald A, Masood O, Harris RS, Fenton TR, Periyasamy M, Ali S, Southgate Jet al., 2022, Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer, ONCOGENE, Vol: 41, Pages: 2139-2151, ISSN: 0950-9232

Journal article

Howell SJ, Kenny LM, Lord S, Krebs MG, Arkenau T, Baird R, MacPherson IR, Bahl A, Clack G, Ainscow E, Barrett AGM, Dickinson PA, Fuchter MJ, Lehnert M, Ali S, McIntosh S, Coombes Cet al., 2022, A clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC), San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Mayayo-Peralta I, Faggion B, Hoekman L, Morris B, Lieftink C, Goldsbrough I, Buluwela L, Siefert JC, Post H, Altelaar M, Beijersbergen R, Ali S, Zwart W, Prekovic Set al., 2021, Ribociclib induces broad chemotherapy resistance and EGFR dependency in ESR1 wildtype and mutant breast cancer, Cancers, Vol: 13, ISSN: 2072-6694

While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene mutations occurring in 15–40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment

Journal article

Page K, Martinson LJ, Fernandez-Garcia D, Hills A, Gleason KLT, Gray MC, Rushton AJ, Nteliopoulos G, Hastings RK, Goddard K, Ions C, Parmar V, Primrose L, Openshaw MR, Guttery DS, Palmieri C, Ali S, Stebbing J, Coombes RC, Shaw JAet al., 2021, Circulating tumor DNA profiling from breast cancer screening through to metastatic disease, JCO Precision Oncology, Vol: 5, Pages: 1768-1776, ISSN: 2473-4284

PURPOSE: We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer. MATERIALS AND METHODS: Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform. RESULTS: One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1, TP53, and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations. CONCLUSION: We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1, TP53, and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs.

Journal article

Kumar U, Hu Y, Masrour N, Castellanos-Uribe M, Harrod A, May ST, Ali S, Speirs V, Charles Coombes R, Yagüe Eet al., 2021, MicroRNA-495/TGF-β/FOXC1 axis regulates multidrug resistance in metaplastic breast cancer cells, Biochemical Pharmacology, Vol: 192, Pages: 1-15, ISSN: 0006-2952

Triple-negative metaplastic breast carcinoma (MBC) poses a significant treatment challenge due to lack of targeted therapies and chemotherapy resistance. We isolated a novel MBC cell line, BAS, which showed a molecular and phenotypic profile different from the only other metaplastic cell model, HS578T cells. To gain insight behind chemotherapeutic resistance, we generated doxorubicin (HS-DOX, BAS-DOX) and paclitaxel (HS-TX, BAS-TX) resistant derivatives of both cell lines. Drug sensitivity assays indicated a truly multidrug resistant (MDR) phenotype. Both BAS-DOX and BAS-TX showed up-regulation of FOXC1 and its experimental down-regulation re-sensitized cells to doxorubicin and paclitaxel. Experimental modulation of FOXC1 expression in MCF-7 and MDA-MB-231 cells corroborated its role in MDR. Genome-wide expression analyses identified gene expression signatures characterized by up-regulation of TGFB2, which encodes cytokine TGF-β2, in both BAS-DOX and BAS-TX cells. Pharmacological inhibition of the TGF-β pathway with galunisertib led to down-regulation of FOXC1 and increase in drug sensitivity in both BAS-DOX and BAS-TX cells. MicroRNA (miR) expression analyses identified high endogenous miR-495-3p levels in BAS cells that were downregulated in both BAS MDR cells. Transient expression of miR-495-3p mimic in BAS-DOX and BAS-TX cells caused downregulation of TGFB2 and FOXC1 and re-sensitized cells to doxorubicin and paclitaxel, whereas miR-495-3p inhibition in BAS cells led to increase in resistance to both drugs and up-regulation of TGFB2 and FOXC1. Together, these data suggest interplay between miR-495-3p, TGF-β2 and FOXC1 regulating MDR in MBC and open the exploration of novel therapeutic strategies.

Journal article

Alexandrou G, Moser N, Mantikas K-T, Rodriguez-Manzano J, Ali S, Coombes RC, Shaw J, Georgiou P, Toumazou C, Kalofonou Met al., 2021, Detection of Multiple Breast Cancer ESR1 mutations on an ISFET based Lab-on-Chip Platform., IEEE Trans Biomed Circuits Syst, Vol: PP

ESR1 mutations are important biomarkers in metastatic breast cancer. Specifically, p.E380Q and p.Y537S mu- tations arise in response to hormonal therapies given to patients with hormone receptor positive (HR+) breast cancer (BC). This paper demonstrates the efficacy of an ISFET based CMOS integrated Lab-on-Chip (LoC) system, coupled with variant- specific isothermal amplification chemistries, for detection and discrimination of wild type (WT) from mutant (MT) copies of the ESR1 gene. Hormonal resistant cancers often lead to increased chances of metastatic disease which leads to high mortality rates, especially in low-income regions and areas with low healthcare coverage. Design and optimization of bespoke primers was carried out and tested on a qPCR instrument and then benchmarked versus the LoC platform. Assays for detection of p.Y537S and p.E380Q were developed and tested on the LoC platform, achieving amplification in under 25 minutes and sensitivity of down to 1000 copies of DNA per reaction for both target assays. The LoC system hereby presented, is cheaper and smaller than other standard industry equivalent technologies such as qPCR and sequencing. The LoC platform proposed, has the potential to be used at a breast cancer point-of-care testing setting, offering mutational tracking of circulating tumour DNA in liquid biopsies to assist patient stratification and metastatic monitoring.

Journal article

Baker SC, Mason AS, Slip RG, Skinner KT, Macdonald A, Masood O, Harris RS, Fenton TR, Periyasamy M, Ali S, Southgate Jet al., 2021, BK polyomavirus (BKPyV) is a risk factor for bladder cancer through induction of APOBEC3-mediated genomic damage

<jats:title>Abstract</jats:title><jats:p>Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. BK polyomavirus (BKPyV) is a common childhood infection that can be reactivated in the adult kidney leading to viruria. Here we used a mitotically-quiescent, differentiated, normal human urothelial <jats:italic>in vitro</jats:italic> model to study BKPyV infection. BKPyV infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry into the cell cycle via inhibition of Retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, which combined to push urothelial cells from G0 into an arrested G2 cell cycle state. The single-stranded DNA displacement loops formed during BKPyV-infection, provide a substrate for APOBEC3 enzymes where they interacted with LT-Ag. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations, including transplant patients and the elderly.</jats:p>

Journal article

Greber BJ, Remis J, Ali S, Nogales Eet al., 2021, 2.5 angstrom-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942, Biophysical Journal, Vol: 120, Pages: 677-686, ISSN: 0006-3495

The human CDK-activating kinase (CAK), composed of CDK7, cyclin H, and MAT1, is involved in the control of transcription initiation and the cell cycle. Because of these activities, it has been identified as a promising target for cancer chemotherapy. A number of CDK7 inhibitors have entered clinical trials, among them ICEC0942 (also known as CT7001). Structural information can aid in improving the affinity and specificity of such drugs or drug candidates, reducing side effects in patients. Here, we have determined the structure of the human CAK in complex with ICEC0942 at 2.5 Å-resolution using cryogenic electron microscopy. Our structure reveals conformational differences of ICEC0942 compared with previous X-ray crystal structures of the CDK2-bound complex, and highlights the critical ability of cryogenic electron microscopy to resolve structures of drug-bound protein complexes without the need to crystalize the protein target

Journal article

Li Z, Wu Y, Yates ME, Tasdemir N, Bahreini A, Chen J, Levine KM, Priedigkeit NM, Ali S, Buluwela L, Arnesen S, Gertz J, Richer JK, Troness B, El-Ashry D, Zhang Q, Gerratana L, Zhang Y, Cristofanilli M, Montanez MA, Sundd P, Wallace CT, Watkins SC, Zhu L, Tseng GC, Wagle N, Carroll JS, Jank P, Denkert C, Karsten MM, Blohmer J-U, Park BH, Lucas PC, Atkinson JM, Lee AV, Oesterreich Set al., 2021, Hotspot <i>ESR1</i> mutations are multimodal and contextual drivers of breast cancer metastasis

<jats:title>Abstract</jats:title><jats:p>Constitutively active estrogen receptor-α (ER/<jats:italic>ESR1</jats:italic>) mutations have been identified in approximately one third of ER+ metastatic breast cancer. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of <jats:italic>ESR1</jats:italic> mutations exclusively in distant, but not local recurrences. In concordance with transcriptomic profiling of <jats:italic>ESR1</jats:italic> mutant tumors, genome-edited Y537S and D538G cell models have a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the <jats:italic>TIMP3/MMP</jats:italic> axis, which functionally confers enhanced cell-cell contacts while decreased cell-ECM adhesion. Context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as vulnerability. Mutant ESR1 exhibits non-canonical regulation of several metastatic pathways including secondary transactivation and <jats:italic>de novo</jats:italic> FOXA1-driven chromatin remodeling. Collectively, our data supports evidence for <jats:italic>ESR1</jats:italic> mutation-driven metastases and provides insight for future preclinical therapeutic strategies.</jats:p><jats:sec><jats:title>Significance</jats:title><jats:p>Context and allele-dependent transcriptome and cistrome reprogramming in genome-edited <jats:italic>ESR1</jats:italic> mutation cell models elicit diverse metastatic phenotypes, including but not limited to alterations in cell adhesion and migration. The gain-of-function mutations can be pharmacologically targeted, and thus may be key components of novel therapeutic treatment strategies for ER-mutant metastatic breast cancer.</jats:p></jats:sec>

Journal article

Li Z, Wu Y, Bahreini A, Priedigkeit NM, Ding K, Sartorius CA, Miller L, Rosenzweig M, Wagle N, Richer JK, Muller WJ, Buluwela L, Ali S, Fang Y, Zhu L, Tseng GC, Gertz J, Atkinson JM, Lee AV, Oesterreich Set al., 2020, <i>ESR1</i>mutant breast cancers show elevated basal cytokeratins and immune activation

<jats:title>Abstract</jats:title><jats:p>Estrogen receptor alpha (ER/<jats:italic>ESR1</jats:italic>) is mutated in 30-40% of endocrine resistant ER-positive (ER+) breast cancer.<jats:italic>ESR1</jats:italic>mutations cause ligand-independent growth and increased metastasis<jats:italic>in vivo</jats:italic>and<jats:italic>in vitro</jats:italic>. Despite the distinct clinical features and changes in therapeutic response associated with<jats:italic>ESR1</jats:italic>mutations, there are no data about their potential role in intrinsic subtype switching. Applying four luminal and basal gene set pairs,<jats:italic>ESR1</jats:italic>mutant cell models and clinical samples showed a significant enrichment of basal subtype markers. Among them, the six basal cytokeratins (BCKs) were the most enriched genes. Induction of BCKs was independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated topological associated domain at the<jats:italic>KRT14/16/17</jats:italic>genomic region. Unexpectedly, high<jats:italic>BCK</jats:italic>expression in ER+ primary breast cancer is associated with good prognosis, and these tumors show enriched activation of a number of immune pathways, a distinctive feature shared with<jats:italic>ESR1</jats:italic>mutant tumors. S100A8 and S100A9 were among the most highly induced immune mediators shared between high-<jats:italic>BCK</jats:italic>s ER+ and<jats:italic>ESR1</jats:italic>mutant tumors, and single-cell RNA-seq analysis inferred their involvement in paracrine crosstalk between epithelial and stromal cells. Collectively, these observations demonstrate that<jats:italic>ESR1</jats:italic>mutant tumors gain basal features with induction of basal cytokeratins via epigenetic mechanisms in rare subpopulation of cells. This

Journal article

Giannoudis A, Malki MI, Rudraraju B, Mohhamed H, Menon S, Liloglou T, Ali S, Carroll JS, Palmieri Cet al., 2020, Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer, Breast Cancer Research, Vol: 22, Pages: 1-17, ISSN: 1465-542X

BackgroundActivating transcription factor-2 (ATF2), a member of the leucine zipper family of DNA binding proteins, has been implicated as a tumour suppressor in breast cancer. However, its exact role in breast cancer endocrine resistance is still unclear. We have previously shown that silencing of ATF2 leads to a loss in the growth-inhibitory effects of tamoxifen in the oestrogen receptor (ER)-positive, tamoxifen-sensitive MCF7 cell line and highlighted that this multi-faceted transcription factor is key to the effects of tamoxifen in an endocrine sensitive model. In this work, we explored further the in vitro role of ATF2 in defining the resistance to endocrine treatment.Materials and methodsWe knocked down ATF2 in TAMR, LCC2 and LCC9 tamoxifen-resistant breast cancer cell lines as well as the parental tamoxifen sensitive MCF7 cell line and investigated the effects on growth, colony formation and cell migration. We also performed a microarray gene expression profiling (Illumina Human HT12_v4) to explore alterations in gene expression between MCF7 and TAMRs after ATF2 silencing and confirmed gene expression changes by quantitative RT-PCR.ResultsBy silencing ATF2, we observed a significant growth reduction of TAMR, LCC2 and LCC9 with no such effect observed with the parental MCF7 cells. ATF2 silencing was also associated with a significant inhibition of TAMR, LCC2 and LCC9 cell migration and colony formation. Interestingly, knockdown of ATF2 enhanced the levels of ER and ER-regulated genes, TFF1, GREB1, NCOA3 and PGR, in TAMR cells both at RNA and protein levels. Microarray gene expression identified a number of genes known to mediate tamoxifen resistance, to be differentially regulated by ATF2 in TAMR in relation to the parental MCF7 cells. Moreover, differential pathway analysis confirmed enhanced ER activity after ATF2 knockdown in TAMR cells.ConclusionThese data demonstrate that ATF2 silencing may overcome endocrine resistance and highlights further the dual role

Journal article

Sava GP, Ali S, 2020, Developing themes in targeted therapies for hormone receptor–positive breast cancer, Current Opinion in Endocrine and Metabolic Research, Vol: 15, Pages: 15-23, ISSN: 2451-9650

Journal article

Periyasamy M, Singh A, Gemma C, Farzan R, Allsopp R, Shaw J, Charmasz S, Young L, Cunnea P, Coombes R, Gyorffy B, Buluwela L, Ali Set al., 2020, Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK directed activation of NF-κB, Oncogene, Vol: 15 December 2020, Pages: 1077-1090, ISSN: 0950-9232

The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression. Here, we investigate A3B expression upon treatment with chemotherapeutic drugs that activate p53, including 5-fluorouracil, etoposide and cisplatin. Contrary to expectation, these drugs induced A3B expression and concomitant cellular cytosine deaminase activity. A3B induction was p53-independent, as chemotherapy drugs stimulated A3B expression in p53 mutant cells. These drugs commonly activate ATM, ATR and DNA-PKcs. Using specific inhibitors and gene knockdowns, we show that activation of DNA-PKcs and ATM by chemotherapeutic drugs promotes NF-kB activity, with consequent recruitment of NF-kB to the A3B gene promoter to drive A3B expression. Further, we find that A3B knockdown re-sensitises resistant cells to cisplatin, and A3B knockout enhances sensitivity to chemotherapy drugs. Our data highlight a role for A3B in resistance to chemotherapy and indicate that stimulation of A3B expression by activation of DNA repair and NF-kB pathways could promote cancer mutations and expedite chemoresistance.

Journal article

Palinkas HL, Bekesi A, Rona G, Pongor L, Papp G, Tihanyi G, Holub E, Poti A, Gemma C, Ali S, Morten MJ, Rothenberg E, Pagano M, Szuts D, Gyorffy B, Vertessy BGet al., 2020, Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments, eLife, Vol: 9, Pages: 1-37, ISSN: 2050-084X

Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug treatments in human cancer cell line models derived from HCT116. We developed a straightforward U-DNA sequencing method (U-DNA-Seq) that was combined with in situ super-resolution imaging. Using a novel robust analysis pipeline, we found broad regions with elevated probability of uracil occurrence both in treated and non-treated cells. Correlation with chromatin markers and other genomic features shows that non-treated cells possess uracil in the late replicating constitutive heterochromatic regions, while drug treatment induced a shift of incorporated uracil towards segments that are normally more active/functional. Data were corroborated by colocalization studies via dSTORM microscopy. This approach can be applied to study the dynamic spatio-temporal nature of genomic uracil.

Journal article

Uriz-Huarte A, Date A, Ang H, Ali S, Brady HJM, Fuchter MJet al., 2020, The transcriptional repressor REV-ERB as a novel target for disease, Bioorganic & Medicinal Chemistry Letters, Vol: 30, Pages: 127395-127395, ISSN: 0960-894X

REV-ERB is a member of the nuclear receptor superfamily of transcription factors involved in the regulation of many physiological processes, from circadian rhythm, to immune function and metabolism. Accordingly, REV-ERB has been considered as a promising, but difficult drug target for the treatment of numerous diseases. Here, we concisely review current understanding of the function of REV-ERB, modulation by endogenous factors and synthetic ligands, and the involvement of REV-ERB in select human diseases. Particular focus is placed on the medicinal chemistry of synthetic REV-ERB ligands, which demonstrates the need for higher quality ligands to aid in robust validation of this exciting target.

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

Kumar R, Clarke R, Ali S, 2020, Preface, CANCER AND METASTASIS REVIEWS, Vol: 39, Pages: 579-579, ISSN: 0167-7659

Journal article

Ali S, Balachandran K, O'Malley B, 2020, 90 Years of progesterone: Ninety years of progesterone: the 'other' ovarian hormone, Journal of Molecular Endocrinology, Vol: 65, Pages: E1-E4, ISSN: 0952-5041

Journal article

Flach KD, Periyasamy M, Jadhav A, Dorjsuren D, Siefert JC, Hickey TE, Opdam M, Patel H, Canisius S, Wilson DM, Collier MD, Prekovic S, Nieuwland M, Kluin RJC, Zakharov A, Wesseling J, Wessels LFA, Linn SC, Tilley WD, Simeonov A, Ali S, Zwart Wet al., 2020, Endonuclease FEN1 coregulates ER alpha activity and provides a novel drug interface in tamoxifen-resistant breast cancer, Cancer Research, Vol: 80, Pages: 1914-1926, ISSN: 0008-5472

Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex vivo–cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof of principle for FEN1 blockade in tamoxifen-resistant breast cancer.

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

Pálinkás HL, Békési A, Róna G, Pongor L, Tihanyi G, Holub E, Póti Á, Gemma C, Ali S, Morten MJ, Rothenberg E, Pagano M, Szüts D, Győrffy B, Vértessy BGet al., 2020, Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments, Publisher: eLife Sciences Publications Ltd

<jats:title>ABSTRACT</jats:title><jats:p>Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug-treatment in human cancer cell-line HCT116. We developed a straightforward U-DNA sequencing method (U-DNA-Seq) that was combined with <jats:italic>in situ</jats:italic> super-resolution imaging. Using a novel robust analysis pipeline, we found broad regions with elevated probability of uracil occurrence both in treated and non-treated cells. Correlation with chromatin markers and other genomic features shows that non-treated cells possess uracil in the late replicating constitutive heterochromatic regions, while drug treatment induced a shift of incorporated uracil towards more active/functional segments. Data were corroborated by colocalization studies via dSTORM microscopy. This approach can also be applied to study the dynamic <jats:italic>spatio-temporal</jats:italic> nature of genomic uracil.</jats:p>

Working paper

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

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

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

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

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

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