Regufe da Mota, Sergio - University of Southampton

个人简介

Dr. Sergio Regufe da Mota is a CRUK post-doctoral research fellow in Cancer Sciences group. His current research focus in attenuating androgen receptor signalling in prostate cancer that is resistant to the new generation of androgen receptor antagonists. Dr. Sergio Regufe da Mota graduated from the University of Lisbon, Portugal in 2002. He went to complete his PhD with the Institute of Tropical Medicine of the New University of Lisbon in 2009. His research was focussed on the study of the changes in the cellular proteome caused by the replication of the Hepatitis Delta Virus. He moved to the UK to join Dr Tracey Newman’s team in Southampton where he worked with biocompatible targeted nanoparticles for drug delivery to the central nervous system. In 2011 he moved to Professor Chris Proud’s group where he studied the regulation of the eukaryotic elongation factor 2 kinase and how its activity/regulation enables the cells to survive stress conditions present in a cancer setting. Currently, he works in Dr. Simon Crabb group that focus on novel molecular targets for the treatment of castration resistant prostate cancer. Recent data shows that inhibition of the lysine-specific histone demethylase 1 (LSD1) attenuates androgen receptor (AR) driven prostate cancer resistant to next generation AR antagonists.

研究领域

Therapeutic inhibition of the histone demethylase LSD1 to attenuate androgen receptor signalling in prostate cancer that is resistant to new generation AR antagonists Prostate cancer is one of the main causes of cancer related death in men. Treatment is critically reliant on androgen receptor (AR) signalling inhibition but virtually all patients become resistant to initial androgen deprivation (castration resistant prostate cancer, CRPC). Subsequent treatment options exist but the disease remains lethal (median 2-3years) after transition to CRPC. CRPC therapeutic options include the ‘new generation’ AR antagonist enzalutamide. However despite proven efficacy virtually all patients develop clinical resistance. Enzalutamide/AR antagonist resistance mechanisms include activating AR splice variants and point mutations. Lysine (K)-specific demethylase 1A (LSD1), is an epigenetic AR co-activator which modifies chromatin structure at AR target genes. Our data show that LSD1 chemical inhibition suppresses prostate cancer cell growth, synergises with AR antagonists/enzalutamide and inhibits AR signalling. Critically, in AR response element reporter assays, we have now found that LSD1 inhibition reduces activation of both wild type AR and the enzalutamide resistant variant. We therefore hypothesise that LSD1 co-activation of the AR is retained and is therapeutically targetable in CRPC despite resistance to new generation hormonal therapy.

近期论文

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Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy - Moore, Claire E.J., Wang, Xuemin, Xie, Jianling, Pickford, Jo, Barron, John, Regufe da Mota, Sergio, Versele, Matthias and Proud, Christopher G. Published:2016Publication:Cellular SignallingVolume:28, (4)Page Range:284-293doi:10.1016/j.cellsig.2016.01.005PMID:26795954 Abstract 3584: lysine specific demethylase 1 inhibition attenuates enzalutamide resistant androgen receptor V7 splice variant activation - Regufe da Mota, Sergio, Bailey, Sarah, Strivens, Rosemary A., Hayden, Annette L., Packham, Graham and Crabb, Simon J. Published:2015Publication:Cancer ResearchVolume:75Page Range:3584-3584doi:10.1158/1538-7445.am2015-3584 Elongation Factor 2 Kinase is regulated by Proline Hydroxylation and protects cells during Hypoxia - Moore, Claire E.J., Mikolajek, Halina, Regufe da Mota, Sergio, Wang, Xuemin, Kenney, Justin W., Werner, Jörn M. and Proud, Christopher G. Published:2015Publication:Molecular and Cellular BiologyVolume:35, (10)Page Range:1788-1804doi:10.1128/MCB.01457-14PMID:25755286 Regulated stability of eukaryotic elongation factor 2 kinase requires intrinsic but not ongoing activity - Wang, Xuemin, Xie, Jianling, Regufe da Mota, Sergio, Moore, Claire E. and Proud, Christopher G. Published:2015Publication:Biochemical JournalVolume:467, (2)Page Range:321-331doi:10.1042/BJ20150089PMID:25670349 Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling - Wang, X., Regufe da Mota, S., Liu, R., Moore, C. E., Xie, J., Lanucara, F., Agarwala, U., Pyr dit Ruys, S., Vertommen, D., Rider, M.H., Eyers, C.E. and Proud, C. G. Published:2014Publication:Molecular and Cellular BiologyVolume:34, (22)Page Range:4088-4103doi:10.1128/MCB.01035-14PMID:25182533