Imperial College London

ProfessorNagyHabib

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Hepatobiliary Surgery
 
 
 
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Contact

 

+44 (0)20 3313 8574nagy.habib

 
 
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Assistant

 

Mrs Benita White +44 (0)7960 986 387

 
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Location

 

BN1/18 B BlockHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

490 results found

Andrikakou P, Reebye V, Vasconcelos D, Yoon S, Voutila J, George AJT, Swiderski P, Habib R, Catley M, Blakey D, Habib NA, Rossi JJ, Huang K-Wet al., 2022, Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome., Nucleic Acid Ther

Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism. SIRT1 saRNA significantly increased SIRT1 messenger RNA (mRNA) and protein levels in both lipopolysaccharide-stimulated and nonstimulated macrophages. SIRT1 saRNA significantly decreased inflammatory-like responses, by reducing mRNA levels of key inflammatory cytokines, such as Tumor Necrosis Factor alpha, Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and chemokines Monocyte Chemoattractant Protein-1 and keratinocyte chemoattractant. SIRT1 overexpression also significantly reduced phosphorylation of nuclear factor-κB and c-Jun N-terminal kinase, both key signaling molecules for the inflammatory pathway. To investigate the therapeutic effect of SIRT1 upregulation, we treated a high-fat diet model with SIRT1 saRNA conjugated to a transferrin receptor aptamer for delivery to the liver and cellular internalization. Animals in the SIRT1 saRNA treatment arm demonstrated significantly decreased weight gain with a significant reduction in white adipose tissue, triglycerides, fasting glucose levels, and intracellular lipid accumulation. These suggest treatment-induced changes to lipid and glucose metabolism in the animals. The results of this study demonstrate that targeted activation of SIRT1 by saRNAs is a potential strategy to reverse MetS.

Journal article

da Costa AC, Martins CR, Habib N, 2022, Hepatic Endometriosis, JOURNAL OF GASTROINTESTINAL SURGERY, ISSN: 1091-255X

Journal article

Xiong Y, Ke R, Zhang Q, Lan W, Yuan W, Chan KNI, Roussel T, Jiang Y, Wu J, Liu S, Wong AST, Shim JS, Zhang X, Xie R, Dusetti N, Iovanna J, Habib N, Peng L, Lee LTOet al., 2022, Small Activating RNA Modulation of the G Protein-Coupled Receptor for Cancer Treatment, ADVANCED SCIENCE

Journal article

Antonowicz S, Abbassi-Ghadi N, Bodai Z, Wiggins T, Markar S, Boshier P, Goh YM, Adam M, Lu H, Kudo H, Rosini F, Goldin R, Moralli D, Green C, Peters C, Habib N, Gabra H, Fitzgerald R, Takats Z, Hanna Get al., 2021, The smell of oesophageal adenocarcinoma: opportunities for tests and treatments, Publisher: OXFORD UNIV PRESS, ISSN: 0007-1323

Conference paper

McLean KA, Kamarajah SK, Chaudhry D, Gujjuri RR, Raubenheimer K, Trout I, AlAmeer E, Creagh-Brown B, Harrison EM, Nepogodiev D, Roslani AC, Li E, Pata F, Ramos-De la Medina A, van Ramshorst GH, Sayyed R, Simoes J, Smart N, Bhangu A, Glasbey JC, Khaw RA, Ahmed W, Akhbari M, Baker D, Borakati A, Mills E, Murray V, Thavayogan R, Yasin I, Glasbey J, Ridley W, Sarrami M, Zhang G, Egoroff N, Pockney P, Richards T, Edwards M, Lee M, Pinkney T, Pearse R, Vohra R, Sohrabi C, Jamieson A, Nguyen M, Rahman A, English C, Tincknell L, Kakodkar P, Kwek I, Punjabi N, Burns J, Varghese S, Erotocritou M, McGuckin S, Vayalapra S, Dominguez E, Moneim J, Bhatia S, Kouli O, Salehi M, Tan HL, Yoong A, Zhu L, Seale B, Nowinka Z, Patel N, Chrisp B, Harris J, Maleyko I, Muneeb F, Gough M, James CE, Skan O, Chowdhury A, Rebuffa N, Khan H, Down B, Fatimah HQ, Siaw-Acheampong K, Benson RA, Bywater E, Dawson BE, Evans JP, Heritage E, Jones CS, Khatri C, Keatley JM, Knight A, Lawday S, Mann HS, Marson EJ, Mckay SC, Mills EC, Pellino G, Picciochi M, Taylor EH, Tiwari A, Simoes JFF, Trout IM, Venn ML, Wilkin RJW, Smart NJ, Minaya-Bravo A, Gallo G, Moug S, Di Saverio S, Vallance A, Vimalchandran D, Griffiths EA, Evans RPT, Townend P, Roberts K, McKay S, Isaac J, Satoi S, Edwards J, Coonar AS, Marchbank A, Caruana EJ, Layton GR, Patel A, Brunelli A, Ford S, Desai A, Gronchi A, Fiore M, Almond M, Tirotta F, Dumitra S, Kolias A, Price SJ, Fountain DM, Jenkinson MD, Hutchinson P, Marcus HJ, Piper RJ, Lippa L, Servadei F, Esene I, Freyschlag C, Neville I, Rosseau G, Schaller K, Demetriades AK, Robertson F, Alamri A, Shaw R, Schache AG, Winter SC, Ho M, Nankivell P, Biel JR, Batstone M, Ganly I, Vidya R, Wilkins A, Singh JK, Thekinkattil D, Sundar S, Fotopoulou C, Leung E, Khan T, Chiva L, Sehouli J, Fagotti A, Cohen P, Gutelkin M, Ghebre R, Konney T, Pareja R, Bristow R, Dowdy S, Rajkumar STS, Ng J, Fujiwara K, Stewart GD, Lamb B, Narahari K, McNeill A, Colquhoun A, McGrath J, Bromage S, Barod R, Kasiviset al., 2021, Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 1448-1464, ISSN: 0007-1323

Journal article

Hashimoto A, Sarker D, Reebye V, Jarvis S, Sodergren MH, Kossenkov A, Sanseviero E, Raulf N, Vasara J, Andrikakou P, Meyer T, Huang K-W, Plummer R, Chee CE, Spalding D, Pai M, Khan S, Pinato DJ, Sharma R, Basu B, Palmer D, Ma Y-T, Evans J, Habib R, Martirosyan A, Elasri N, Reynaud A, Rossi JJ, Cobbold M, Habib NA, Gabrilovich DIet al., 2021, Upregulation of C/EBP alpha Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer, CLINICAL CANCER RESEARCH, Vol: 27, Pages: 5961-5978, ISSN: 1078-0432

Journal article

Desai K, Lawrence PV, Wadsworth C, Mangal N, Habib N, Sadanandam A, Sodergren Met al., 2021, Characterization of longitudinally collected fine needle aspiration biopsies of pancreatic ductal adenocarcinoma upon endoscopic ultrasound guided radiofrequency ablation., Publisher: AMER ASSOC CANCER RESEARCH, Pages: 68-69, ISSN: 0008-5472

Conference paper

Tan CP, Sinigaglia L, Gomez V, Nicholls J, Habib NAet al., 2021, RNA Activation-A Novel Approach to Therapeutically Upregulate Gene Transcription, MOLECULES, Vol: 26

Journal article

Plummer R, Sodergren M, Pinato D, Sarker D, Reebye V, Spalding D, Raulf N, Sinigaglia L, Talbot T, Cortellini A, D'Alessio A, Tchakov I, Habib R, Rossi J, Habib Net al., 2021, A PHASE 1 STUDY OF MYELOID MODULATING AGENT MTL-CEBPA IN COMBINATION WITH PEMBROLIZUMAB IN ADULT PATIENTS WITH ADVANCED SOLID TUMOURS, Publisher: BMJ PUBLISHING GROUP, Pages: A545-A545

Conference paper

Glasbey J, Ademuyiwa A, Adisa A, AlAmeer E, Arnaud AP, Ayasra F, Azevedo J, Minaya-Bravo A, Costas-Chavarri A, Edwards J, Elhadi M, Fiore M, Fotopoulou C, Gallo G, Ghosh D, Griffiths EA, Harrison E, Hutchinson P, Lawani I, Lawday S, Lederhuber H, Leventoglu S, Li E, Gomes GMA, Mann H, Marson EJ, Martin J, Mazingi D, McLean K, Modolo M, Moore R, Morton D, Ntirenganya F, Pata F, Picciochi M, Pockney P, Ramos-De la Medina A, Roberts K, Roslani AC, Kottayasamy Seenivasagam R, Shaw R, Simões JFF, Smart N, Stewart GD, Sullivan R, Sundar S, Tabiri S, Taylor EH, Vidya R, Nepogodiev D, Bhangu A, Glasbey JC, McLean K, Nepogodiev D, Harrison E, Bhangu AA, Nepogodiev D, Siaw-Acheampong K, Benson RA, Bywater E, Chaudhry D, Dawson BE, Evans JP, Glasbey JC, Gujjuri RR, Heritage E, Jones CS, Kamarajah SK, Khatri C, Khaw RA, Keatley JM, Knight A, Lawday S, Li E, Mann HS, Marson EJ, McLean KA, Mckay SC, Mills EC, Pellino G, Picciochi M, Taylor EH, Tiwari A, Simoes JFF, Trout IM, Venn ML, Wilkin RJW, Bhangu A, Glasbey JC, Smart NJ, Minaya-Bravo A, Evans JP, Gallo G, Moug S, Pata F, Pockney P, Di Saverio S, Vallance A, Vimalchandran D, Griffiths EA, Kamarajah SK, Evans RPT, Townend P, Roberts K, McKay S, Isaac J, Satoi S, Edwards J, Coonar AS, Marchbank A, Caruana EJ, Layton GR, Patel A, Brunelli A, Ford S, Desai A, Gronchi A, Fiore M, Almond M, Tirotta F, Dumitra S, Kolias A, Price SJ, Fountain DM, Jenkinson MD, Hutchinson P, Marcus HJ, Piper RJ, Lippa L, Servadei F, Esene I, Freyschlag C, Neville I, Rosseau G, Schaller K, Demetriades AK, Robertson F, Alamri A, Shaw R, Schache AG, Winter SC, Ho M, Nankivell P, Rey Biel J, Batstone M, Ganly I, Vidya R, Wilkins A, Singh JK, Thekinkattil D, Sundar S, Fotopoulou C, Leung EYL, Khan T, Chiva L, Sehouli J, Fagotti A, Cohen P, Gutelkin M, Ghebre R, Konney T, Pareja R, Bristow R, Dowdy S, Shylasree TS, Kottayasamy Seenivasagam R, Ng J, Fujiwara K, Stewart GD, Lamb B, Narahari K, McNeill A, Colquhoun A, McGrath JS, Bromage S, Barod R, Kasivisvaet al., 2021, Effect of COVID-19 pandemic lockdowns on planned cancer surgery for 15 tumour types in 61 countries: an international, prospective, cohort study, The Lancet Oncology, Vol: 22, Pages: 1507-1517, ISSN: 1470-2045

BackgroundSurgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction.MethodsThis international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926.FindingsOf eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notif

Journal article

Huang K-W, Tan CP, Reebye V, Chee CE, Zacharoulis D, Habib R, Blakey DC, Rossi JJ, Habib N, Sodergren MHet al., 2021, MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22

Journal article

Mangal N, Erridge S, Habib N, Sadanandam A, Reebye V, Sodergren MHet al., 2021, Cannabinoids in the landscape of cancer, Journal of Cancer Research and Clinical Oncology, Vol: 147, Pages: 2507-2534, ISSN: 0171-5216

IntroductionCannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. There is a growing body of evidence from cell culture and animal studies in support of cannabinoids possessing anticancer properties.MethodA database search of peer reviewed articles published in English as full texts between January 1970 and April 2021 in Google Scholar, MEDLINE, PubMed and Web of Science was undertaken. References of relevant literature were searched to identify additional studies to construct a narrative literature review of oncological effects of cannabinoids in pre-clinical and clinical studies in various cancer types.ResultsPhyto-, endogenous and synthetic cannabinoids demonstrated antitumour effects both in vitro and in vivo. However, these effects are dependent on cancer type, the concentration and preparation of the cannabinoid and the abundance of receptor targets. The mechanism of action of synthetic cannabinoids, (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has mainly been described via the traditional cannabinoid receptors; CB1 and CB2, but reports have also indicated evidence of activity through GPR55, TRPM8 and other ion channels including TRPA1, TRPV1 and TRPV2.ConclusionCannabinoids have shown to be efficacious both as a single agent and in combination with antineoplastic drugs. These effects have occurred through various receptors and ligands and modulation of signalling pathways involved in hallmarks of cancer pathology. There is a need for further studies to characterise its mode of action at the molecular level and to delineate efficacious dosage and route of administration in addition to synergistic regimes.

Journal article

COVIDSurg Collaborative Co-authors, 2021, Machine learning risk prediction of mortality for patients undergoing surgery with perioperative SARS-CoV-2: the COVIDSurg mortality score, British Journal of Surgery, Vol: 108, Pages: 1274-1292, ISSN: 0007-1323

Since the beginning of the COVID-19 pandemic tens of millions of operations have been cancelled1 as a result of excessive postoperative pulmonary complications (51.2 per cent) and mortality rates (23.8 per cent) in patients with perioperative SARS-CoV-2 infection2. There is an urgent need to restart surgery safely in order to minimize the impact of untreated non-communicable disease.As rates of SARS-CoV-2 infection in elective surgery patients range from 1–9 per cent3–8, vaccination is expected to take years to implement globally9 and preoperative screening is likely to lead to increasing numbers of SARS-CoV-2-positive patients, perioperative SARS-CoV-2 infection will remain a challenge for the foreseeable future.To inform consent and shared decision-making, a robust, globally applicable score is needed to predict individualized mortality risk for patients with perioperative SARS-CoV-2 infection. The authors aimed to develop and validate a machine learning-based risk score to predict postoperative mortality risk in patients with perioperative SARS-CoV-2 infection.

Journal article

Mizandari M, Azrumelashvili T, Keshavarz P, Habib Net al., 2021, Image-Guided Percutaneous Pancreatic Duct Drainage: A 10-Year Observational Study, JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY, Vol: 32, Pages: 1075-+, ISSN: 1051-0443

Journal article

Pinato D, Cortellini A, Sukumaran A, Cole T, Pai M, Habib N, Spalding D, Sodergren M, Martinez M, Dhillon T, Tait P, Thomas R, Ward C, Kocher H, Yip V, Slater S, Sharma Ret al., 2021, PRIME-HCC: Phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma, BMC Cancer, Vol: 21, ISSN: 1471-2407

BackgroundAfter liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209–040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3–4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC.MethodsThe study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC.DiscussionThe results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcom

Journal article

Antonowicz S, Bodai Z, Wiggins T, Markar SR, Boshier PR, Goh YM, Adam ME, Lu H, Kudo H, Rosini F, Goldin R, Moralli D, Green CM, Peters CJ, Habib N, Gabra H, Fitzgerald RC, Takats Z, Hanna GBet al., 2021, Endogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma, Nature Communications, Vol: 12, ISSN: 2041-1723

Volatile aldehydes are enriched in esophageal adenocarcinoma (EAC) patients’ breath and could improve early diagnosis, however the mechanisms of their production are unknown. Here, we show that weak aldehyde detoxification characterizes EAC, which is sufficient to cause endogenous aldehyde accumulation in vitro. Two aldehyde groups are significantly enriched in EAC biopsies and adjacent tissue: (i) short-chain alkanals, and (ii) medium-chain alkanals, including decanal. The short-chain alkanals form DNA-adducts, which demonstrates genotoxicity and confirms inadequate detoxification. Metformin, a putative aldehyde scavenger, reduces this toxicity. Tissue and breath concentrations of the medium-chain alkanal decanal are correlated, and increased decanal is linked to reduced ALDH3A2 expression, TP53 deletion, and adverse clinical features. Thus, we present a model for increased exhaled aldehydes based on endogenous accumulation from reduced detoxification, which also causes therapeutically actionable genotoxicity. These results support EAC early diagnosis trials using exhaled aldehyde analysis.

Journal article

Glasbey JC, Omar O, Nepogodiev D, Minaya-Bravo A, Bankhead-Kendall BK, Fiore M, Futaba K, Gabre-Kidan A, Gujjuri RR, Isik A, Kaafarani HMA, Kamarajah SK, Li E, Loeffler MW, McLean KA, Outani O, Ntirenganya F, Satoi S, Shaw R, Simoes JFF, Stewart GD, Tabiri S, Trout IM, Bhangu AA, Glasbey JC, Omar O, Bhangu AA, Siaw-Acheampong K, Benson RA, Bywater E, Chaudhry D, Dawson BE, Evans JP, Glasbey JC, Gujjuri RR, Heritage E, Jones CS, Kamarajah SK, Khatri C, Khaw RA, Keatley JM, Knight A, Lawday S, Li E, Mann HS, Marson EJ, McLean KA, Mckay SC, Mills EC, Nepogodiev D, Pellino G, Picciochi M, Taylor EH, Tiwari A, Simoes JFF, Trout IM, Venn ML, Wilkin RJW, Bhangu A, Glasbey JC, Smart NJ, Minaya-Bravo A, Evans JP, Gallo G, Moug S, Pata F, Pockney P, Di Saverio S, Vallance A, Vimalchandran D, Griffiths EA, Kamarajah SK, Evans RPT, Townend P, Roberts K, McKay S, Isaac J, Satoi S, Edwards J, Coonar AS, Marchbank A, Caruana EJ, Layton GR, Patel A, Brunelli A, Ford S, Desai A, Gronchi A, Fiore M, Almond M, Tirotta F, Dumitra S, Kolias A, Price SJ, Fountain DM, Jenkinson MD, Hutchinson P, Marcus HJ, Piper RJ, Lippa L, Servadei F, Esene I, Freyschlag C, Neville I, Rosseau G, Schaller K, Demetriades AK, Robertson F, Alamri A, Shaw R, Schache AG, Winter SC, Ho M, Nankivell P, Biel JR, Batstone M, Ganly I, Vidya R, Wilkins A, Singh JK, Thekinkattil D, Sundar S, Fotopoulou C, Leung E, Khan T, Chiva L, Sehouli J, Fagotti A, Cohen P, Gutelkin M, Ghebre R, Konney T, Pareja R, Bristow R, Dowdy S, Rajkumar STS, Ng J, Fujiwara K, Stewart GD, Lamb B, Narahari K, McNeill A, Colquhoun A, McGrath J, Bromage S, Barod R, Kasivisvanathan V, Klatte T, Simoes JFF, Abbott TEF, Abukhalaf S, Adamina M, Ademuyiwa AO, Agarwal A, Akkulak M, Alameer E, Alderson D, Alakaloko F, Albertsmeiers M, Alser O, Alshaar M, Alshryda S, Arnaud AP, Augestad KM, Ayasra F, Azevedo J, Bankhead-Kendall BK, Barlow E, Beard D, Benson RA, Blanco-Colino R, Brar A, Minaya-Bravo A, Breen KA, Bretherton C, Buarque IL, Burke J, Caruet al., 2021, Preoperative nasopharyngeal swab testing and postoperative pulmonary complications in patients undergoing elective surgery during the SARS-CoV-2 pandemic, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 88-96, ISSN: 0007-1323

Journal article

Gavriilidis P, Sutcliffe RP, Roberts KJ, Pai M, Spalding D, Habib N, Jiao LR, Sodergren MHet al., 2020, No difference in mortality among ALPPS, two-staged hepatectomy, and portal vein embolization/ligation: A systematic review by updated traditional and network meta-analyses, HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL, Vol: 19, Pages: 411-419, ISSN: 1499-3872

Journal article

Debacker AJ, Voutila J, Catley M, Blakey D, Habib Net al., 2020, Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug, MOLECULAR THERAPY, Vol: 28, Pages: 1759-1771, ISSN: 1525-0016

Journal article

Sodergren MH, Mangal N, Wasan H, Sadanandam A, Balachandran VP, Jiao LR, Habib Net al., 2020, Immunological combination treatment holds the key to improving survival in pancreatic cancer, JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, Vol: 146, Pages: 2897-2911, ISSN: 0171-5216

Journal article

Sarker D, Plummer R, Meyer T, Sodergren MH, Basu B, Chee CE, Huang K-W, Palmer DH, Ma YT, Evans TRJ, Spalding DRC, Pai M, Sharma R, Pinato DJ, Spicer J, Hunter S, Kwatra V, Nicholls JP, Collin D, Nutbrown R, Glenny H, Fairbairn S, Reebye V, Voutila J, Dorman S, Andrikakou P, Lloyd P, Felstead S, Vasara J, Habib R, Wood C, Saetrom P, Huber HE, Blakey DC, Rossi JJ, Habib Net al., 2020, MTL-CEBPA, a small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label, phase I trial, Clinical Cancer Research, Vol: 26, Pages: 3936-3946, ISSN: 1078-0432

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Journal article

Kumar J, Habib NAGY, Huang KAI, Warwick JANE, MAURO P, ARASARADNAM Ret al., 2020, Immunological basis of genesis of hepatocellular carcinoma: unique challenges and potential opportunities through immunomodulation, Vaccines, Vol: 8, ISSN: 2076-393X

A majority of hepatocellular carcinoma (HCC) develops in the setting of persistent chronic inflammation as immunological mechanisms have been shown to play a vital role in the initiation, growth and progression of tumours. The index review has been intended to highlight ongoing immunological changes in the hepatic parenchyma responsible for the genesis and progression of HCC. The in-situ vaccine effect of radiofrequency (RF) is through generation tumour-associated antigens (TAAs), following necrosis and apoptosis of tumour cells, which not only re-activates the antitumour immune response but can also act in synergism with checkpoint inhibitors to generate a superlative effect with intent to treat primary cancer and distant metastasis. An improved understanding of oncogenic responses of immune cells and their integration into signaling pathways of the tumour microenvironment will help in modulating the antitumour immune response. Finally, we analyzed contemporary literature and summarised the recent advances made in the field of targeted immunotherapy involving checkpoint inhibitors along with RF application with the intent to reinstate antitumour immunity and outline future directives in very early and early stages of HCC.

Journal article

Sarker D, Sodergren M, Plummer ER, Basu B, Meyer T, Huang K-W, Evans TRJ, Spalding D, Ma YT, Palmer DH, Chee CE, Pinato DJ, Reebye V, McVeigh D, Raulf N, Vasara J, Andrikakou P, Habib R, Blakey D, Habib NAet al., 2020, Phase Ib dose escalation and cohort expansion study of the novel myeloid differentiating agent MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

da Costa AC, Sodergren M, Jayant K, Santa Cruz F, Spalding D, Pai M, Habib Net al., 2020, Radiofrequency combined with immunomodulation for hepatocellular carcinoma: State of the art and innovations, WORLD JOURNAL OF GASTROENTEROLOGY, Vol: 26, Pages: 2040-2048, ISSN: 1007-9327

Journal article

Jayant K, Habib N, Huang KW, Warwick J, Arasaradnam Ret al., 2020, Recent Advances: The Imbalance of Immune Cells and Cytokines in the Pathogenesis of Hepatocellular Carcinoma, DIAGNOSTICS, Vol: 10

Journal article

Reebye V, Vasara J, Raulf N, Hashimoto A, Jarvis S, Andrikakou P, Habib R, Blakey D, Gabrilovich D, Rossi J, Habib Net al., 2020, Therapeutic saRNAstargeting CEBPA in Myeloid Cells. A potential Immunomodulatoryswitch for Anticancer Therapy, 23rd Annual Meeting of the American-Society-for-Gene-and-Cell-Therapy, Publisher: CELL PRESS, Pages: 51-52, ISSN: 1525-0016

Conference paper

Huang K-W, Reebye V, Czysz K, Ciriello S, Dorman S, Reccia I, Lai H-S, Peng L, Kostomitsopoulos N, Nicholls J, Habib RS, Tomalia DA, Saetrom P, Wilkes E, Cutillas P, Rossi JJ, Habib NAet al., 2020, Liver activation of hepatocellular nuclear factor-4 alpha by small activating RNA rescues dyslipidemia and improves metabolic profile, Molecular Therapy : Nucleic Acids, Vol: 19, Pages: 361-370, ISSN: 2162-2531

Non-alcoholic fatty liver disease (NAFLD) culminates in insulin resistance and metabolic syndrome. Because there are no approved pharmacological treatment agents for non-alcoholic steatohepatitis (NASH) and NAFLD, different signaling pathways are under investigation for drug development with the focus on metabolic pathways. Hepatocyte nuclear factor 4-alpha (HNF4A) is at the center of a complex transcriptional network where its disruption is directly linked to glucose and lipid metabolism. Resetting HNF4A expression in NAFLD is therefore crucial for re-establishing normal liver function. Here, small activating RNA (saRNA) specific for upregulating HNF4A was injected into rats fed a high-fat diet for 16 weeks. Intravenous delivery was carried out using 5-(G5)-triethanolamine-core polyamidoamine (PAMAM) dendrimers. We observed a significant reduction in liver triglyceride, increased high-density lipoprotein/low-density lipoprotein (HDL/LDL) ratio, and decreased white adipose tissue/body weight ratio, all parameters to suggest that HNF4A-saRNA treatment induced a favorable metabolic profile. Proteomic analysis showed significant regulation of genes involved in sphingolipid metabolism, fatty acid β-oxidation, ketogenesis, detoxification of reactive oxygen species, and lipid transport. We demonstrate that HNF4A activation by oligonucleotide therapy may represent a novel single agent for the treatment of NAFLD and insulin resistance.

Journal article

Clift A, Frilling A, Braat A, Alsafi A, Wasan H, Al-Nahhas A, Thomas R, Drymousis P, Habib N, Tait Pet al., 2020, Radioembolization for Neuroendocrine Liver Metastases: An Institutional Case Series, Systematic Review and Meta-Analysis, 17th Annual European-Neuroendocrine-Tumor-Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 223-223, ISSN: 0028-3835

Conference paper

Sarker D, Sodergren M, Plummer ER, Basu B, Meyer T, Huang K-W, Evans TRJ, Spalding D, Ma YT, Palmer DH, Chee CE, Pinato DJ, Reebye V, McVeigh D, Raulf N, Vasara J, Andrikakou P, Habib R, Blakey D, Habib NAet al., 2020, First-in-human phase I trial of small activating RNA (saRNA) oligonucleotide MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC), Gastrointestinal Cancers Symposium of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Yoon S, Huang K-W, Andrikakou P, Vasconcelos D, Swiderski P, Reebye V, Sodergren M, Habib N, Rossi JJet al., 2019, Targeted delivery of C/EBP alpha-saRNA by RNA aptamers shows anti-tumor effects in a mouse model of advanced PDAC, Molecular Therapy : Nucleic Acids, Vol: 18, Pages: 142-154, ISSN: 2162-2531

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies; it preferentially metastasizes to the liver and is the main cause of death from this disease. In previous studies, small activating RNA against CCAAT/enhancer-binding protein-α (C/EBPα-saRNA) demonstrated efficacy of PDAC in a local subcutaneous tumor model. In this study, we focused on the efficacy of C/EBPα-saRNA in advanced stage PDAC. For targeted delivery, we selected a new anti-transferrin receptor aptamer (TR14), which demonstrated a high binding affinity to target proteins. The TR14 aptamer was internalized with clathrin-mediated endocytosis, distributed in early endosome, late endosome, and lysosome subcellularly. To investigate its anti-tumor effects to advanced PDAC, we conjugated C/EBPα-saRNA to TR14. Treatment of pancreatic cancer cells with the conjugates upregulated expression of C/EBPα and its downstream target p21, and inhibited cell proliferation. For in vivo assays, we established an advanced PDAC mouse model by engrafting luciferase reporter-PANC-1 cells directly into the livers of non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. After treatment of aptamer-C/EBPα conjugates, we observed significant reduction of tumor growth in this advanced PDAC mouse model. Combinational treatment of the conjugates with gemcitabine also demonstrated enhanced anti-tumor effects in advanced PDAC. This suggests that aptamer-C/EBPα conjugates could be used as an adjuvant, along with other conventional anti-cancer drugs in advanced PDAC. In conclusion, targeted delivery of C/EBPα-saRNAs by aptamers might have potential therapeutic effects in advanced PDAC.

Journal article

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