Obiettivo SummaryThe majority of metastastic solid tumours remain incurable. In-depth analysis of tumour genomes is revealing evidence for branched evolution and cancer subclonal spatial and temporal intratumour heterogeneity (ITH). Drivers of ITH such as chromosomal instability (CIN) are associated with drug resistance and poor clinical outcome. However, despite increasing knowledge of tumour diversity, there is limited insight into the mechanisms driving genomic instability and ITH or the processes that shape cancer genome evolution over time and space. Many animal tumour models fail to recapitulate patterns of genomic instability witnessed in human tumours, limiting insight into the forces that shape tumour evolution in vivo. We have found evidence for parallel subclonal evolution, resulting in the same gene or signal transduction pathway being subject to distinct inactivating or activating somatic events in different regions of the same tumour (Gerlinger NEJM 2012). These data suggest that in-depth analysis of tumour evolution may help define routes through which tumours must progress, offering opportunities for novel therapeutic approaches. We will develop new animal models of ITH, by developing knock-out strains for two suppressors of replication stress and CIN, recently identified in our laboratory (Burrell Nature 2013). These models will be used to study cancer evolution in order to decipher the impact of selection pressures, such as DNA damaging agents and cancer cytotoxics, on genomic complexity and diversity in emergent resistant subclones. In addition, through combined cancer informatics and functional genomics approaches we aim to identify novel mechanisms driving tumour heterogeneity and biological processes that permit the propagation of heterogeneous cells using novel transposon based approaches. Developments in this proposal may lead to new insight into the two forces underpinning cancer evolution and therapeutic failure, diversity and selection Campo scientifico natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsgenomes Programma(i) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) ERC-CG-2013-LS4 - ERC Consolidator Grant - Physiology, Pathophysiology and Endocrinology Invito a presentare proposte ERC-2013-CoG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-CG - ERC Consolidator Grants Istituzione ospitante THE FRANCIS CRICK INSTITUTE LIMITED Contributo UE € 1 145 438,30 Indirizzo 1 MIDLAND ROAD NW1 1AT London Regno Unito Mostra sulla mappa Regione London Inner London — West Camden and City of London Tipo di attività Research Organisations Contatto amministrativo Stéphane Maikovsky (Mr.) Ricercatore principale Robert Charles Swanton (Dr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (3) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto THE FRANCIS CRICK INSTITUTE LIMITED Regno Unito Contributo UE € 1 145 438,30 Indirizzo 1 MIDLAND ROAD NW1 1AT London Mostra sulla mappa Regione London Inner London — West Camden and City of London Tipo di attività Research Organisations Contatto amministrativo Stéphane Maikovsky (Mr.) Ricercatore principale Robert Charles Swanton (Dr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato UNIVERSITY COLLEGE LONDON Contributo UE € 854 502,40 Indirizzo GOWER STREET WC1E 6BT LONDON Mostra sulla mappa Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Malgorzata Kielbasa (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato CANCER RESEARCH UK LBG Partecipazione conclusa Regno Unito Contributo UE Nessun dato Indirizzo 2 Redman Place E20 1JQ LONDON Mostra sulla mappa Regione London Inner London — West Camden and City of London Tipo di attività Research Organisations Contatto amministrativo Justin Wilson (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
