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Deciphering the Role of aberrant glycOSylation in the rEsponse to Targeted TherApies for breast cancer

Description du projet

Le rôle de la glycosylation aberrante dans le traitement ciblé du cancer du sein

La résistance à la thérapie qui entraine la progression du cancer constitue un obstacle majeur à la réussite du traitement. Le développement de traitements ciblés tels que le trastuzumab a révolutionné le traitement des patientes atteintes d’un cancer du sein HER2+ («human epidermal growth factor receptor 2 positive»). Un lien a été établi entre la glycosylation aberrante des protéines et de multiples processus incluant l’invasion, l’angiogenèse et la modulation de l’immunoréaction. Le récepteur HER2 est lourdement glycosylé, et il constitue la cible des traitements actuels à base d’anticorps, dont le trastuzumab. L’objectif de recherche du projet ROSETTA, financé par l’UE, consiste à déchiffrer le rôle de la glycosylation dans le développement d’une résistance aux traitements ciblant HER2. Le projet est en mesure d’identifier les nouveaux marqueurs de réponse aux traitements et de découvrir de nouvelles alternatives thérapeutiques visant à améliorer les traitements actuels.

Objectif

Resistance and cancer progression remain a major obstacle to the successful treatment of cancer. In HER2+ breast cancer, the development of targeted therapies such as trastuzumab, has revolutionized the treatment for these cancer patients. However, a significant number of patients develop resistance. In this realm, my previous work focused on understanding the crosstalk of interconnected signaling pathways in HER2+ cancer cells that drive tumorigenesis and undermine the efficacy of current treatments.
The research goal of this proposal is to provide a new focus to the challenge of resistance by deciphering the role of glycosylation in driving resistance to HER2-targeted therapies. Aberrant glycosylation of proteins is a hallmark in cancer and has been linked to multiple processes such as invasion, angiogenesis and modulation of the immune response. The receptor HER2, the main driver of HER2+ cancers, is heavily glycosylated and is the target of current antibody-based treatments, including trastuzumab. In this scenario, this proposal aims to (1) identify glycosylation-related genes associated with incomplete pathological response to trastuzumab to (2) dissect their role on trastuzumab binding and (3) assess their impact in the response to trastuzumab mediated by immune cells. This research plan will be accomplished combining the analysis of clinical data from tumor biopsies, the use of trastuzumab-resistant tumor-derived breast cancer cell lines and, the implementation and imaging of 3D heterotypic cultures of cancer cell line-derived spheroids and immune cells. Thus, this proposal addresses a largely unexplored layer of complexity in cancer biology – the role of glycosylation in resistance to targeted therapies – and holds the potential to identify new markers of response to therapies and open the path to new therapeutic options for the improvement of current treatments.

Coordinateur

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Contribution nette de l'UE
€ 175 572,48
Adresse
DR MOLEWATERPLEIN 40
3015 GD Rotterdam
Pays-Bas

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Région
West-Nederland Zuid-Holland Groot-Rijnmond
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 175 572,48