Molecular Oncology

This is embedded within the Oncology Division and is headed by Professor Michael J Seckl. The unit is focused on improving the outcome and refining the management of patients with lung cancer and gestational trophoblastic disease (GTD). The former is the commonest cancer killer and the latter is a rare but highly curable malignancy affecting pregnancy. Our research spans fundamental cancer biology through to translation into novel therapies and biomarkers that aim to help personalise healthcare for these two cancer types. Consequently, the unit has several basic and clinical science groups with networks of interaction across the UK and internationally to support this endeavour. Key team members include Drs Ana Costa-Pereira, Olivier Pardo, and Francesco Mauri working on Lung Cancer and Rosemary Fisher, Richard Harvey, Philip Savage and Neil Sebire covering the GTD area. Our research on lung cancer biology has already led to several phase I-III clinical trials of novel and known agents, whilst in GTD our national service has enabled us to become international leaders in the management of this group of disorders. Some key publications from the group are listed below:

Lung Cancer References

1. Pardo OE, Arcaro A, Salerno G, Tetley TD, Gout I, Seckl MJ. (2001). Novel cross talk between MEK and S6K2 in FGF-2 induced proliferation of SCLC cells. Oncogene. 20(52): 7658-7667.

2. Pardo OE, Arcaro A, Salerno G, Raguz S, Downward J, Seckl MJ. (2002). Fibroblast growth factor-2 induces translational regulation of Bcl-X_L and Bcl-2 via a MEK dependent pathway: correlation with resistance to etoposide induced apoptosis. J Biol Chem. 277(14): 12040-12046.

3. Arcaro A, Khanzada UK, Vanhaesebroeck B, Tetley TD, Waterfield M, Seckl MJ. (2002). Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation. EMBO J. 21(19): 5097-5108.

4. Pardo OE, Lesay A, Arcaro A, Lopes R, Ng BL, Warne PH, McNeish IA, Tetley TD, Lemoine NR, Mehmet H, Seckl MJ, Downward J. (2003). FGF-2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells. Mol Cell Biol. 23(21): 7600-7610.

5. Pardo OE, Wellbrock C, Khanzada U, Aubert M, Parker PJ, Gout I, Marais R, Downward J, Seckl MJ (2006) FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCe, B-Raf and S6K2. EMBO J. 25(13): 3078-3088.

6. Khanzada U, Pardo OE, Meier C, Downward J, Seckl MJ, Arcaro A. (2006). Potent inhibition of small cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling. Oncogene. 25(6):877-878.

7. Arcaro A, Aubert M, Espinosa del Hierro MH, Khanzada U, Angelidou S, Tetley TD, Bitterman AG Frame MC, Seckl MJ. (2007). Critical role for lipid raft-associated Src kinases in activation of P13K-Akt signalling. Cell Signal. 19(5): 1081-1092.

8. Marinov M, Ziogas A, Pardo OE, Tan LT, Lane HA, Lemoine NR, Zangemeister-Wttke U, Seckl MJ, Arcaro A. (2009). AKT/mTOR pathway activation and BCL-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001. Clin Cancer Res. 15(4): 1277-1287.

9. Pardo OE, Latigo J, Jeffery RE, Nye E, Poulson R, Spenser-Dene B, Lemoine NR, Stamp GW, Aboagye E, Seckl MJ. (2009). The FGFR inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo. Cancer Res. 69(22): 8645-8651.

10. Dhillon T, Mauri FA, Bellezza G, Cagini L, Barbareschi M, North BV, Seckl MJ. (2010). Over-expression of the Mammalian Target of Rapamycin (mTOR): a novel biomarker for poor survival in resected early stage Non-Small Cell Lung Cancer. J Thorac Onc. 5(3): 314-319.

11. Goh ETH, Pardo OE; Michael N; Niewiarowski A, Totty N, Volkova D, Tsaneva IR, Seckl MJ, Gout I. (2010). The involvement of hnRNP F in the regulation of cell proliferation via the mTOR/S6K2 pathway. J Biol Chem. 285(22): 17065-76..

12. Lara R, Mauri FA, Taylor H, Derua R, Shia A, Gray C, Nicols A, Shiner RJ, Schofield E, Bates PA, Waelkens E, Dallman M, Lamb J, Zicha D, Downward J, Seckl MJ and Pardo OE.

13. Carmo R.C., Lyons-Lewis J., Seckl M.J. and Costa-Pereira A.P. (2011). A novel requirement for Janus kinases as mediators of drug resistance induced by fibroblast growth factor-2 in human cancer cells. PLoS ONE, 6: e19861.

Gestational Trophoblastic Disease References

Lung Cancer References

Seckl MJ, Rustin GJS, Newlands ES et al. (1991) Pulmonary embolism, pulmonary hypertension and choriocarcinoma. Lancet. 338: ii; 1309-11.
Savage P, Roddie M, Seckl MJ. (1998) Choriocarcinoma and pulmonary embolism. Lancet. 352: 30.
Lo SK, Montgomery JN, Blagden S, McNeish IA, Agarwal R, Suntharalingam J, Seckl MJ, Newlands ES. (1999) Reducing incidence of headache after lumbar puncture and intrathecal cytotoxics. Lancet. 353: 2038-39.
Newlands ES, Mulholland PJ, Holden L, Seckl MJ, Rustin GJS. (2000) Etoposide and cisplatin/etoposide, methotrexate, and actinomycin-D) (EMA) chemotherapy for patients with high risk gestational trophoblastic tumours refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumours. J. Clin. Oncol. 18: 854-9.
Seckl MJ, Fisher RA, Salerno G, Rees H, Paradinas FJ, Foskett M, Newlands ES. (2000) Choriocarcinoma and partial hydatidiform moles. Lancet 356; 36-9.
Agarwal R, Strickland S, McNeish IA, Patel DC, Foskett M, Boultbee JE, Newlands ES, Seckl MJ (2002). Doppler ultrasonography of the uterine artery and the response to chemotherapy in patients with gestational trophoblastic tumors. Clin Cancer Res. 8(5): 1142-7.
McNeish IA, Strickland S, Holden L, Rustin GJS, Foskett M, Seckl MJ, Newlands ES. (2002) Low risk persistent gestational trophoblastic disease: outcome following initial treatment with low-dose methotrexate and folinic acid, 1992-2000. J Clin Oncol 20(7): 1838-44.
Sebire NJ, Foskett M, Paradinas FJ, Fisher RA, Francis RJ, Short D, Newlands ES, Seckl MJ. (2002) Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet. 359(9324): 2165-6.
Blagden SP, Foskett MA, Short D, Fuller S, Newlands ES, Seckl MJ. (2002). The effect of early pregnancy following chemotherapy on disease relapse and fetal outcome in women treated for gestational trophoblastic tumours. Br J Cancer. 86(1): 26-30.
Hodges MD, Reed HC, Seckl MJ, Newlands ES, Fisher RA (2003) Genetic refinement and physical mapping of a biparental complete hydatidiform mole locus on chromosome 19q13.4. J Med Genet 40(8): E95.
Seckl MJ, Dhillon T, Dancey G, Foskett MA, Paradinas, FJ, Rees HC, Sebire NJ, Vigushin D, Newlands ES (2004) Increased gestational age at evacuation of a complete hydatidiform mole: does it correlate with increased risk of requiring chemotherapy? J Reprod Med. 49(7): 527-30.
Seckl MJ, Gillmore R, Foskett M, Sebire NJ, Rees H, Newlands. ES, (2004) Routine terminations of Pregnancy – Should we screen for Gestational Trophoblastic Neoplasia? Lancet. 364(9435): 705-7.
Savage P, Seckl M (2005). The role of repeat uterine evacuation in trophoblast disease. Gynecol Oncol. 99(1): 251-2.
Palmieri C, Fisher RA, Sebire NJ, Lindsay I, Smith JR, McGluggage WG, Savage P, Seckl MJ (2005) Placental site trophoblastic tumour arising from a partial hydatidiform mole: the importance of b-hCG surveillance. Lancet 366: 688.
Powles T, Savage P, Short D, Young A, Pappin C, Seckl MJ.(2006) Residual lung lesions after completion of chemotherapy for gestational trophoblastic neoplasia: should we operate? Br J Cancer. 16, 949(1): 51-4.
Dhillon T, Palmieri C, Sebire NJ, Lindsay I, Newlands ES, Schmid P, Savage PM, Frank J, Seckl MJ (2006) Value of whole body 18FDG-PET to identify the active site of gestational trophoblastic neoplasia (GTN). J. Reprod. Med. 51(11): 879-87.
Mitchell H, Seckl MJ (2007) Discrepancies between commercially available immunoassays in the detection of tumour-derived hCG. Mol Cell Endocrinol. 260-262: 310-3.
Powles T, Savage PM, Stebbing J, Short D, Young A, Bower M, Pappin C, Schmid P, Seckl MJ (2007) A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia. Br J Cancer. 96(5):732-7.
Palmieri C, Dhillon T, Fisher RA, Young AM, Short D, Mitchell H, Aghajanian C, Savage PM, Newlands ES, Hancock BW, Seckl MJ (2007) Management and outcome of healthy women with a persistently elevated β-hCG. Gynecol. Oncol. 106(1): 35-43.
Sebire NJ, Foskett M, Short D, Savage P, Stewart W, Thomson M, Seckl MJ (2007) Shortened duration of human chorionic gonadotrophin surveillance following complete or partial hydatidiform mole: evidence for revised protocol of a UK regional trophoblastic disease unit. BJOG 114(6): 760-2.
Pfeffer PE, Sebire N, Lindsay I, McIndoe A, Lim A, Seckl MJ (2007) Fertility-sparing partial hysterectomy for placental-site trophoblastic tumour. Lancet Oncol. 8(8):744-6.
Ngan S, Seckl MJ (2007) Gestational Trophoblastic Neoplasia Management: An Update. Curr Opin Oncol. 19(5): 486-91.
Fisher RA, Savage PM, MacDermott C, Hook J, Sebire NJ, Lindsay I, Seckl MJ (2007) The impact of molecular genetic diagnosis on the management of women with hCG-producing malignancies. Gynaecol Oncol. 107(3): 413-9.
Wang J, Short D, Sebire NJ, Lindsay I, Newlands ES, Schmid P, Savage PM, Seckl MJ (2007) Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE). Ann Oncol. 19(9):1578-83.
Sebire N, Seckl MJ (2008) Gestational trophoblastic disease: current management of hydatidiform mole. BMJ. 337: a1193.
Patten D, Lindsay I, Fisher R A, Sebire N, Savage PM, Seckl MJ (2008) Gestational choriocarcinoma mimicking a uterine adenocarcinoma. J. Clin Oncol. 26(31): 5126-7.
Harvey RA, Pursglove HD, Schmid P, Savage PM, Mitchell HD, Seckl MJ. (2008) Human chorionic gonadotropin free beta-subunit measurement as a marker of placental site trophoblastic tumors. J Reprod Med. 53(8): 643-8.
Kerkmeijer LG, Thomas CM, Harvey R, Sweep FC, Mitchell H, Massuger LF, Seckl MJ (2009) External validation of serum hCG cutoff levels for prediction of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease. Br J Cancer. 100(6): 979-84.
Wang C, Dixon P, Decordova S, Hodges M, Sebire N, Ozalp S, Fallahian M, Sensi A, Ashrafi F, Repiska V, Zhao J, Xiang Y, Savage P, Seckl M, Fisher R (2009) Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine rich region. J Med Genet. 46(8): 569-75.
Schmid P, Nagai Y, Agarwal R, Hancock BW, Savage PM, Sebire NJ, Lindsay I, Wells M, Fisher RA, Short D, Newlands ES, Wischnewsky MB, Seckl MJ (2009) Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet. 374(9683): 6-7.
McGrath S, Short D, Harvey R, Schmid P, Savage PM, Seckl MJ (2010) The management and outcome of women with post-hydatidiform mole ‘low-risk’ gestational trophoblastic neoplasia, but hCG levels in excess of 100,000 IU/L (2010). Br. J Cancer. 102(5): 810.4.
Seckl MJ, Sebire NJ and Berkowitz R (2010) Gestational trophoblastic disease. Lancet. 376(9742): 717-29.
Harvey RA, Mitchell HDC, Stenman U-H, Blankenstein MA, Nustad K, Stieber P, Stewart W, Savage PM, Seckl MJ, Braunstein GD (2010) Differences in total human chorionic gonadotrophin (hCG) immunoassays’ analytical specificity and ability to measure hCG from gestational trophoblastic disease and germ cell tumour patients. J Reprod Med. 55(7-8): 285-95.
Alifrangis C, Seckl MJ (2010) Genetics of gestational trophoblastic neoplasia: an update for the clinician. Future Oncol. 6(12): 1915-23.
Alifrangis C, Evans R, Williams J, Seckl MJ (2011) An unusual gum lesion with a positive pregnancy test. Br Med J. (In press).