Imperial College London

ProfessorMichaelSeckl

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Molecular Cancer Medicine
 
 
 
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Contact

 

+44 (0)20 3311 1421m.seckl

 
 
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Location

 

08Cyclotron buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

289 results found

Braga A, Berkowitz RS, Seckl MJ, 2021, Gestational trophoblastic neoplasia: one size does not fit all - Authors' reply., Lancet Oncol, Vol: 22

Journal article

Blay J-Y, Casali P, Bouvier C, Dehais C, Galloway I, Gietema J, Halámková J, Hindi N, Idbaih A, Kinloch E, Klümpen H-J, Kolarova T, Kopeckova K, Lovey J, Magalhaes M, Oselin K, Piperno-Neumann S, Ravnsbaek A, Rogasik M, Safwat A, Scheipl S, Seckl M, Taylor J, Temnyk M, Trama A, Urbonas M, Wartenberg M, Weinman A, EURACAN Networket al., 2021, European Reference Network for rare adult solid cancers, statement and integration to health care systems of member states: a position paper of the ERN EURACAN, ESMO Open, Vol: 6, ISSN: 2059-7029

Journal article

Braga A, Paiva G, Ghorani E, Freitas F, Velarde LGC, Kaur B, Unsworth N, Lozano-Kuehne J, Esteves APVDS, Filho JR, Amim Jr J, Aguiar X, Sarwar N, Elias KM, Horowitz NS, Berkowitz RS, Seckl MJet al., 2021, Predictors for single-agent resistance in FIGO score 5 or 6 gestational trophoblastic neoplasia: a multicentre, retrospective, cohort study, LANCET ONCOLOGY, Vol: 22, Pages: 1188-1198, ISSN: 1470-2045

Journal article

Pardo O, Chrysostomou S, Roy R, Prischi F, Thamlikitkul L, Chapman KL, Mufti U, Peach R, Ding L, Hancock D, Moore C, Molina-Arcas M, Mauri F, Pinato DJ, Abrahams JM, Ottaviani S, Castellano L, Giamas G, Pascoe J, Moonamale D, Pirrie S, Gaunt C, Billingham L, Steven NM, Cullen M, Hrouda D, Winkler M, Post J, Cohen P, Salpeter SJ, Bar V, Zundelevich A, Golan S, Leibovici D, Lara R, Klug DR, Yaliraki SN, Barahona M, Wang Y, Downward J, Skehel JM, Ali MMU, Seckl MJet al., 2021, Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer, Science Translational Medicine, Vol: 13, ISSN: 1946-6234

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Journal article

Seckl MJ, Ghorani E, 2021, Progress to international harmonisation of care and future developments, BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY, Vol: 74, Pages: 159-167, ISSN: 1521-6934

Journal article

Bergamini A, Sarwar N, Ferrandina G, Scarfone G, Short D, Aguiar X, Camnasio C, Kaur B, Savage PM, Cormio G, Lim A, Pignata S, Mangili G, Seckl MJet al., 2021, Response to letter entitled: Re: Can we replace adjuvant chemotherapy with surveillance for stage IA-C immature ovarian teratomas of any grade? An international multicenter analysis, EUROPEAN JOURNAL OF CANCER, Vol: 152, Pages: 257-258, ISSN: 0959-8049

Journal article

Cortes-Charry R, Hennah L, Froeling FEM, Short D, Aguiar X, Tin T, Harvey R, Unsworth N, Kaur B, Savage P, Sarwar N, Seckl MJet al., 2021, Increasing the human chorionic gonadotrophin cut-off to <= 1000 IU/l for starting actinomycin D in post-molar gestational trophoblastic neoplasia developing resistance to methotrexate spares more women multi-agent chemotherapy, ESMO OPEN, Vol: 6

Journal article

Bouchard-Fortier G, Ghorani E, Short D, Aguiar X, Harvey R, Unsworth N, Kaur B, Sarwar N, Seckl MJet al., 2020, Following chemotherapy for gestational trophoblastic neoplasia, do residual lung lesions increase the risk of relapse?, GYNECOLOGIC ONCOLOGY, Vol: 158, Pages: 698-701, ISSN: 0090-8258

Journal article

Bergamini A, Sarwar N, Ferrandina G, Scarfone G, Short D, Aguiar X, Camnasio C, Kaur B, Savage PM, Cormio G, Lim A, Pignata S, Mangili G, Seckl MJet al., 2020, Can we replace adjuvant chemotherapy with surveillance for stage IA-C immature ovarian teratomas of any grade? an international multicenter analysis, EUROPEAN JOURNAL OF CANCER, Vol: 137, Pages: 136-143, ISSN: 0959-8049

Journal article

Lok C, van Tromme N, Massuger L, Golfie F, Seckl Met al., 2020, Practical clinical guidelines of the EOTTD for treatment and referral of gestational trophoblastic disease, EUROPEAN JOURNAL OF CANCER, Vol: 130, Pages: 228-240, ISSN: 0959-8049

Journal article

Balachandran K, Salawu A, Ghorani E, Kaur B, Sebire NJ, Short D, Harvey R, Hancock B, Tidy J, Singh K, Sarwar N, Winter MC, Seckl MJet al., 2019, When to stop human chorionic gonadotrophin (hCG) surveillance after treatment with chemotherapy for gestational trophoblastic neoplasia (GTN): A national analysis on over 4,000 patients, GYNECOLOGIC ONCOLOGY, Vol: 155, Pages: 8-12, ISSN: 0090-8258

Journal article

Froeling FEM, Ramaswami R, Papanastasopoulos P, Kaur B, Sebire NJ, Short D, Fisher RA, Sarwar N, Wells M, Singh K, Ellis L, Horsman JM, Winter MC, Tidy J, Hancock BW, Seckl MJet al., 2019, Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours, BRITISH JOURNAL OF CANCER, Vol: 120, Pages: 587-594, ISSN: 0007-0920

Journal article

Frijstein MM, Lok CAR, Short D, Singh K, Fisher RA, Hancock BW, Tidy JA, Sarwar N, Kanfer E, Winter MC, Savage PM, Seckl MJet al., 2019, The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia, EUROPEAN JOURNAL OF CANCER, Vol: 109, Pages: 162-171, ISSN: 0959-8049

Journal article

Ngan HYS, Seckl MJ, Berkowitz RS, Xiang Y, Golfier F, Sekharan PK, Lurain JR, Massuger Let al., 2018, Update on the diagnosis and management of gestational trophoblastic disease, INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS, Vol: 143, Pages: 79-85, ISSN: 0020-7292

Journal article

Braga A, Biscaro A, do Amaral Giordani JM, Viggiano M, Elias KM, Berkowitz RS, Seckl MJet al., 2018, Does a human chorionic gonadotropin level of over 20,000 IU/L four weeks after uterine evacuation for complete hydatidiform mole constitute an indication for chemotherapy for gestational trophoblastic neoplasia?, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 223, Pages: 50-55, ISSN: 0301-2115

Journal article

Cormio G, Seckl MJ, Loizzi V, Resta L, Cicinelli Eet al., 2018, Increased human Chorionic Gonadotropin levels five years before diagnosis of an ovarian dysgerminoma, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 220, Pages: 138-139, ISSN: 0301-2115

Journal article

Coyle C, Short D, Jackson L, Sebire NJ, Kaur B, Harvey R, Savage PM, Seckl MJet al., 2017, What is the optimal duration of human chorionic gonadotrophin surveillance following evacuation of a molar pregnancy? A retrospective analysis on over 20,000 consecutive patients., Gynecologic Oncology, Vol: 148, Pages: 254-257, ISSN: 0090-8258

OBJECTIVE: To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal human chorionic gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines. METHODS: The Charing Cross Hospital Trophoblast Disease Centre database was screened to identify all registered cases of hydatidiform mole (HM) between 1980 and 2009. RESULTS: We identified 20,144 cases of HM, comprising 8400 CHM, 9586 PHM, and 2158 cases of unclassified hydatidiform mole (UHM). Twenty-nine cases (20 CHM, 3 PHM and 6 UHM) developed pGTN after the first normal hCG. For CHM the risk of pGTN at the point of hCG normalisation was 1 in 406, and fell rapidly in the first six months of monitoring. For PHM the risk of pGTN at the point of hCG normalisation was 1 in 3195. Women with CHM where hCG normalisation occurred beyond 56days after uterine evacuation of molar tissue were found to have a 3.8-fold higher risk of pGTN. CONCLUSIONS: Our results show that pGTN can occur after hCG normalisation following PHM but the risk is extremely low. Women with CHM have a comparatively higher risk of pGTN after hCG normalisation. Those with CHM where hCG normalises within 56days have a lower risk of pGTN. We have revised the current UK hCG surveillance protocol for PHM to a single additional confirmatory normal urine hCG measurement one month after first normalisation. The protocol for CHM remains unchanged.

Journal article

Ghorani E, Kaur B, Fisher RA, Short D, Joneborg U, Carlson JW, Akarca A, Marafioti T, Quezada SA, Sarwar N, Seckl MJet al., 2017, Pembrolizumab is effective for drugresistant gestational trophoblastic neoplasia, Lancet, Vol: 390, Pages: 2343-2345, ISSN: 0140-6736

Journal article

Roy R, Pardo O, Seckl M, Huang Yet al., 2017, Emerging roles of hnRNPA1 inmodulating malignanttransformation, Wiley Interdisciplinary Reviews: RNA, Vol: 8, ISSN: 1757-7004

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes such as processing of heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, RNA splicing, transactivation of gene expression, and modulation of protein translation. hnRNPA1 is the most abundant and ubiquitously expressed member of this protein family and has been shown to be involved in multiple molecular events driving malignant transformation. In addition to selective mRNA splicing events promoting expression of specific protein variants, hnRNPA1 regulates the gene expression and translation of several key players associated with tumorigenesis and cancer progression. Here, we will summarize our current knowledge of the involvement of hnRNPA1 in cancer, including its roles in regulating cell proliferation, invasiveness, metabolism, adaptation to stress and immortalization.

Journal article

Singh K, Warnock C, Ireson J, Strickland S, Short D, Seckl MJ, Hancock BWet al., 2017, Experiences of Women With Gestational Trophoblastic Neoplasia Treated With High-Dose Chemotherapy and Stem Cell Transplantation: A Qualitative Study, ONCOLOGY NURSING FORUM, Vol: 44, Pages: 375-383, ISSN: 0190-535X

Journal article

Eysbouts YK, Ottevanger PB, Massuger LFAG, IntHout J, Short D, Harvey R, Kaur B, Sebire NJ, Sarwar N, Sweep FCGJ, Seckl MJet al., 2017, Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset, Annals of Oncology, Vol: 28, Pages: 1856-1861, ISSN: 0923-7534

BackgroundWorldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible.Patients and methodsBetween January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified.ResultsOf the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5–10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7–44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0–16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3–3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9–12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4–30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system.ConclusionOur s

Journal article

Seckl MJ, Ottensmeier CH, Cullen M, Schmid P, Ngai Y, Muthukumar D, Thompson J, Harden S, Middleton G, Fife KM, Crosse B, Taylor P, Nash S, Hackshaw Aet al., 2017, Multicenter, phase III, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in small-cell lung cancer (LUNGSTAR), Journal of Clinical Oncology, Vol: 35, Pages: 1506-1514, ISSN: 0732-183X

PurposeTreating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies showthat statins exert additive effects with agents, such as cisplatin, to impair tumor growth, andobservational studies suggest that statins combined with anticancer therapies delay relapse andprolong life in several cancer types. To our knowledge, we report the first large, randomized,placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer,specifically SCLC.Patients and MethodsPatients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 wererandomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles ofetoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerabletoxicity. Primary end point was overall survival (OS), and secondary end points were progressionfreesurvival (PFS), response rate, and toxicity.ResultsEight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median ageof recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease.There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in allpatients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2%(95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01(95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. Themedian PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, forextensive disease. Adverse events were similar between groups.ConclusionPravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients.Our conclusions are the same as those found in all four much smaller, randomized, placebocontrolledtr

Journal article

Li H, Stokes W, Chater E, Roy R, de Bruin E, Hu Y, Liu Z, Smit EF, Heynen GJJE, Downward J, Seckl MJS, Wang Y, Tang H, Pardo OEet al., 2016, Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer, Cell Discovery, Vol: 2, ISSN: 2056-5968

Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.

Journal article

Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GY, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM, Zamorano JL, Aboyans V, Achenbach S, Agewall S, Badimon L, Barón-Esquivias G, Baumgartner H, Bax JJ, Bueno H, Carerj S, Dean V, Erol Ç, Fitzsimons D, Gaemperli O, Kirchhof P, Kolh P, Lancellotti P, Lip GY, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Roffi M, Torbicki A, Vaz Carneiro A, Windecker S, AuthorsTask Force Members, ESC Committee for Practice Guidelines CPGet al., 2016, 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC), European Journal of Heart Failure, Vol: 19, Pages: 9-42, ISSN: 1879-0844

Journal article

Zhao S, Sebire NJ, Kaur B, Seckl MJ, Fisher RAet al., 2016, Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance., Gynecologic Oncology, ISSN: 1095-6859

OBJECTIVE: To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies. METHODS: The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of tumour tissue microdissected from formalin-fixed, paraffin-embedded blocks. RESULTS: The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p<0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p<0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin. CONCLUSIONS: PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles.

Journal article

Tyebally S, Ghorani E, Kaur B, Sturdy A, Khokhar A, Fisher R, Seckl M, Price Let al., 2016, A case of progressive breathlessness post partum, Thorax, Vol: 71, Pages: 871-872, ISSN: 1468-3296

Journal article

Ghorani E, Ramaswami R, Smith RJ, Savage PM, Seckl MJet al., 2016, Anti-Mullerian hormone in patients treated with chemotherapy for gestational trophoblastic neoplasia does not predict short-term fertility, Journal of Reproductive Medicine, Vol: 61, Pages: 205-209, ISSN: 0024-7758

OBJECTIVE: Serum anti-Müllerian hormone (AMH) is an emerging indicator of ovarian reserve which may be predictive of reproductive capacity. Although AMH levels decline with chemotherapy, little is known about the relevance of this to subsequent fertility, and we set out to evaluate this association in patients with gestational trophoblastic neoplasia (GTN).STUDY DESIGN: The GTN database of our national referral center was screened from 2008–2012 for patients undergoing AMH testing, and subsequent fertility outcomes were reviewed.RESULTS: Of 470 treated patients, 3 underwent AMH testing for evaluation of potential subfertility 4–13 months following multiagent chemotherapy, with levels ranging from 0.07–4.62 pmol/L. All 3 were counseled by independent fertility specialists of the low probability of subsequent conception but went on to initiate spontaneously conceived pregnancies within 2–9 months, resulting in healthy infants.CONCLUSION: Low serum AMH is not a reliable predictor of reduced short-term fertility postchemotherapy for GTN and should be interpreted with caution when counseling patients in this setting.

Journal article

Eagles N, Sebire NJ, Short D, Savage PM, Seckl MJ, Fisher RAet al., 2016, Correction to: "Risk of recurrent molar pregnancies following complete and partial hydatidiform moles", Human Reproduction, Vol: 31, Pages: 1379-1379, ISSN: 1460-2350

Journal article

Ke H, Masoumi KC, Ahlqvist K, Seckl MJ, Rydell-Tormanen K, Massoumi Ret al., 2016, Nemo-like kinase regulates the expression of vascular endothelial growth factor (VEGF) lein alveolar epithelial cells, Scientific Reports, Vol: 6, ISSN: 2045-2322

Journal article

Jiao L, Ghorani E, Sebire NJ, Seckl MJet al., 2016, Intraplacental choriocarcinoma: Systematic review and management guidance, Gynecologic Oncology, ISSN: 1095-6859

Journal article

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