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CORDIS

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

Projektbeschreibung

Die Rolle von aberranter Glykosylierung bei zielgerichteter Brustkrebstherapie

Die Progression von Krebs durch Therapieresistenzen verhindert eine erfolgreiche Behandlung nahezu vollständig. Durch die Entwicklung von zielgerichteten Therapien, zum Beispiel mit Hilfe von Trastuzumab, hat sich die Behandlung von Patientinnen mit dem HER2-positiven Brustkrebs grundlegend verändert. Die aberrante Glykosylierung von Proteinen scheint mit mehreren Prozessen zusammenzuhängen, wie unter anderem Invasion, Angiogenese und Modulation der Immunantwort. Der HER2-Rezeptor ist stark glykosyliert und Angriffspunkt gängiger Antikörperbehandlungen, wie zum Beispiel mit Trastuzumab. Forschungsziel des EU-finanzierten Projekts ROSETTA ist es nun, die Rolle der Glykosylierung bei der Entstehung von Resistenzen gegen jene Therapien zu entschlüsseln, die am HER2-Rezeptor ansetzen. Das Projekt hat das Potenzial, neue Marker für die Reaktion auf Therapien sowie neue therapeutische Optionen zur Verbesserung der gängigen Behandlungsmethoden zu finden.

Ziel

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.

Koordinator

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Netto-EU-Beitrag
€ 175 572,48
Adresse
DR MOLEWATERPLEIN 40
3015 GD Rotterdam
Niederlande

Auf der Karte ansehen

Region
West-Nederland Zuid-Holland Groot-Rijnmond
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 175 572,48