Project acronym OVER-HER2
Project OVErcoming Resistance to anti-HER2 therapy
Researcher (PI) Jose Manuel Baselga Torres
Host Institution (HI) FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary HER2 is a membrane receptor tyrosine kinase overexpressed in 30% of breast tumors and results in an aggressive clinical course. Anti-HER2 therapies including monoclonal antibodies (trastuzumab) and small-molecule tyrosine kinase inhibitors (lapatinib) are active and have improved survival of patients with HER2 overexpressing breast cancer. However, the emergence of primary or acquired resistance to these agents limits their efficacy. We have previously identified mechanisms of resistance to anti-HER2 therapies such as the co-expression of a truncated form of HER2 that correlates with trastuzumab resistance or the presence of downstream oncogenic mutations of PI3K or PTEN loss that result in resistance to lapatinib . Not surprisingly, PI3K/mTOR inhibitors overcome lapatinib resistance in the later example. Building on our results to date, this proposal is aimed at identifying novel mechanisms of resistance to anti-HER2 agents and to devise therapeutic strategies to revert it. To uncover such mechanisms, we have generated cancer cells with acquired resistance to lapatinib or trastuzumab by continuous exposure to increasing concentrations of these agents. We will perform genome wide screens, including shRNA libraries, gene expression and SNPs arrays, to discover candidate genes responsible for decreased sensitivity to anti-HER2 agents. To overcome anti-HER2 therapy resistance we will study several therapeutic strategies, such as combinations of different anti-HER2 compounds and the use of alternative agents targeting downstream/parallel pathways. Among the novel targeted therapies, we plan to study the use of PI3K, Akt, CDK2 and Hsp90 inhibitors, for which we will also start resistance-screens. It is anticipated that any promising preclinical leads will stimulate trial design and conduct for subsequent evaluation and confirmation in the clinic.
Summary
HER2 is a membrane receptor tyrosine kinase overexpressed in 30% of breast tumors and results in an aggressive clinical course. Anti-HER2 therapies including monoclonal antibodies (trastuzumab) and small-molecule tyrosine kinase inhibitors (lapatinib) are active and have improved survival of patients with HER2 overexpressing breast cancer. However, the emergence of primary or acquired resistance to these agents limits their efficacy. We have previously identified mechanisms of resistance to anti-HER2 therapies such as the co-expression of a truncated form of HER2 that correlates with trastuzumab resistance or the presence of downstream oncogenic mutations of PI3K or PTEN loss that result in resistance to lapatinib . Not surprisingly, PI3K/mTOR inhibitors overcome lapatinib resistance in the later example. Building on our results to date, this proposal is aimed at identifying novel mechanisms of resistance to anti-HER2 agents and to devise therapeutic strategies to revert it. To uncover such mechanisms, we have generated cancer cells with acquired resistance to lapatinib or trastuzumab by continuous exposure to increasing concentrations of these agents. We will perform genome wide screens, including shRNA libraries, gene expression and SNPs arrays, to discover candidate genes responsible for decreased sensitivity to anti-HER2 agents. To overcome anti-HER2 therapy resistance we will study several therapeutic strategies, such as combinations of different anti-HER2 compounds and the use of alternative agents targeting downstream/parallel pathways. Among the novel targeted therapies, we plan to study the use of PI3K, Akt, CDK2 and Hsp90 inhibitors, for which we will also start resistance-screens. It is anticipated that any promising preclinical leads will stimulate trial design and conduct for subsequent evaluation and confirmation in the clinic.
Max ERC Funding
1 666 700 €
Duration
Start date: 2011-01-01, End date: 2014-12-31
Project acronym RAS AHEAD
Project Ras Genes in Health and Disease
Researcher (PI) Mariano Barbacid Montalban
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Ras genes are some of the best-studied genes in biomedical research due to their central role in mitogenic signaling and their oncogenic activation in one third of all human tumors. More recently, Ras genes have also been implicated in developmental disorders including Costello and Noonan syndromes. In spite of this wealth of information, we still do not know the role of Ras proteins in adult homeostasis and, more importantly, how their misregulation affects human health. The latter is of paramount importance in order to develop efficacious therapies against tumors carrying Ras oncogenes - an achievement that could save thousands of lives worldwide. We propose to address these issues using genetic approaches in mouse models. We aim to systemically ablate all Ras genes in adult mice as well as in selective tissues to understand their role in normal homeostasis. We also propose to characterize mouse models for developmental disorders induced by hyperactive Ras proteins. These models should help us to better understand these human disorders as well as tools to test potential therapeutic strategies. Finally, we propose to use K-Ras driven mouse tumor models for human PDA and NSCLC to address key questions that may be directly translated to the clinic. In the case of PDA, we propose to study the contribution of the inflammatory response induced by pancreatitis to tumor development. In the case of NCSLC, we propose to isolate cancer initiating cells in an attempt to reveal the earliest events in tumor development. Moreover, we intend to use this tumor model to validate druggable Ras downstream effectors as therapeutic targets. The results derived from these studies should provide key information to design forthcoming clinical trials that will benefit cancer patients.
Summary
Ras genes are some of the best-studied genes in biomedical research due to their central role in mitogenic signaling and their oncogenic activation in one third of all human tumors. More recently, Ras genes have also been implicated in developmental disorders including Costello and Noonan syndromes. In spite of this wealth of information, we still do not know the role of Ras proteins in adult homeostasis and, more importantly, how their misregulation affects human health. The latter is of paramount importance in order to develop efficacious therapies against tumors carrying Ras oncogenes - an achievement that could save thousands of lives worldwide. We propose to address these issues using genetic approaches in mouse models. We aim to systemically ablate all Ras genes in adult mice as well as in selective tissues to understand their role in normal homeostasis. We also propose to characterize mouse models for developmental disorders induced by hyperactive Ras proteins. These models should help us to better understand these human disorders as well as tools to test potential therapeutic strategies. Finally, we propose to use K-Ras driven mouse tumor models for human PDA and NSCLC to address key questions that may be directly translated to the clinic. In the case of PDA, we propose to study the contribution of the inflammatory response induced by pancreatitis to tumor development. In the case of NCSLC, we propose to isolate cancer initiating cells in an attempt to reveal the earliest events in tumor development. Moreover, we intend to use this tumor model to validate druggable Ras downstream effectors as therapeutic targets. The results derived from these studies should provide key information to design forthcoming clinical trials that will benefit cancer patients.
Max ERC Funding
2 496 192 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym THE LAST SONG
Project The Last Song of the Troubadours: Linguistic Codification and Construction of a Literary Canon in the Crown of Aragon (14th and 15th centuries)
Researcher (PI) Anna Alberni Jorda
Host Institution (HI) UNIVERSITAT DE BARCELONA
Call Details Starting Grant (StG), SH5, ERC-2009-StG
Summary This project aims at the edition, study and interpretation of the troubadour poetry written in the Crown of Aragon between the 14th and 15th centuries, with special attention to its reception by a learned public of connoisseurs haunted by the myth of courtly love and its associated culture in the late medieval period. While Italy, France and the rest of the Iberian Peninsula were already moving towards Humanism, in the Crown of Aragon the prestige of the poetic universe created by the troubadours managed to make its way into the 15th century, and was adapted to new cultural fashions through a particular process of appropriation and re-codification that is unique in Europe. The purpose of this project is to enlarge and deepen our knowledge of a linguistic and literary heritage that functioned as a vertebrate agent in medieval aesthetics and poetics and well into the Modern Age. By exploring the paths of this re-codification process, working simultaneously at a linguistic, literary and historical level, we will be able to grasp new aspects of a canon that has been determinant in subsequent artistic movements, namely Spanish Renaissance poetry and the highly innovative discourse undertaken by the Catalan poet Ausiàs March, through which the long autumn of the Middle Ages is finally concluded, giving entrance to Modern poetry in the Iberian peninsula. The project will thus inquire into the question of how the aesthetic and linguistic code of the troubadours shaped the mentality of courtly society, establishing an intellectual and stylistic background in which the literary culture of Europe is deeply rooted. Part of the results of the research will be displayed in a critical digital edition, including codicological, linguistic, literary and historical data that will make the texts express themselves in order to permit a full comprehension of the corpus considered.
Summary
This project aims at the edition, study and interpretation of the troubadour poetry written in the Crown of Aragon between the 14th and 15th centuries, with special attention to its reception by a learned public of connoisseurs haunted by the myth of courtly love and its associated culture in the late medieval period. While Italy, France and the rest of the Iberian Peninsula were already moving towards Humanism, in the Crown of Aragon the prestige of the poetic universe created by the troubadours managed to make its way into the 15th century, and was adapted to new cultural fashions through a particular process of appropriation and re-codification that is unique in Europe. The purpose of this project is to enlarge and deepen our knowledge of a linguistic and literary heritage that functioned as a vertebrate agent in medieval aesthetics and poetics and well into the Modern Age. By exploring the paths of this re-codification process, working simultaneously at a linguistic, literary and historical level, we will be able to grasp new aspects of a canon that has been determinant in subsequent artistic movements, namely Spanish Renaissance poetry and the highly innovative discourse undertaken by the Catalan poet Ausiàs March, through which the long autumn of the Middle Ages is finally concluded, giving entrance to Modern poetry in the Iberian peninsula. The project will thus inquire into the question of how the aesthetic and linguistic code of the troubadours shaped the mentality of courtly society, establishing an intellectual and stylistic background in which the literary culture of Europe is deeply rooted. Part of the results of the research will be displayed in a critical digital edition, including codicological, linguistic, literary and historical data that will make the texts express themselves in order to permit a full comprehension of the corpus considered.
Max ERC Funding
436 200 €
Duration
Start date: 2009-11-01, End date: 2013-06-30
