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Targeted inhibition of TRRAP as a strategy against aggressive brain cancer

Objectif

Patients with aggressive brain cancer have a very poor prognosis with an average life expectancy of only ~12 to 17 months. High grade brain tumors are extremely difficult to treat due to tumor cell invasion, plus resistance of tumor cells to DNA-damaging therapy. This cellular aggressiveness within brain tumors has been attributed to a subpopulation of tumor cells that possess stem cells-like features.
Unlike differentiated tumor cells, brain tumour stem cells (BTSCs) possess the ability to self-renew, to withstand DNA-damaging therapy, and to give rise to new tumor mass. Therefore, targeting BTSCs is expected to improve the efficiency of anti-brain cancer therapy. In particular, targeting pathways that sustain the undifferentiated state of BTSCs is a novel strategy to treat aggressive brain tumors. However, this approach is hampered by a poor understanding of appropriate targets promoting the BTSC phenotype.
Recently, we have demonstrated that the adapter protein TRRAP maintains BTSCs in an undifferentiated and highly tumorigenic state. Consistently, elevated expression of TRRAP in human brain tumors has a strong negative effect on patient survival. Therefore, we aim to provide a basis toward the development of an effective therapeutic strategy against the malignant function of TRRAP in BTSCs.
To this end, we will use our established BTSC assay system and BTSC in vivo models in combination with differential proteomics to characterize TRRAP protein domains and TRRAP-protein interactions that critically promote the BTSC phenotype. Moreover, we will investigate the role of TRRAP during brain tumor invasion and potential additive effects between DNA-damaging therapy and inhibition of TRRAP function in vivo.
Overall, these interrelated approaches will validate TRRAP as a brain tumor target. Ultimately, we hope to reveal and exploit the Achilles’ heel of TRRAP-dependent tumorigenesis for developing a targeted therapeutic strategy against BTSC-driven brain tumors.

Champ scientifique (EuroSciVoc)

Programme(s)

Thème(s)

Appel à propositions

FP7-PEOPLE-2011-CIG
Voir d’autres projets de cet appel

Régime de financement

MC-CIG - Support for training and career development of researcher (CIG)

Coordinateur

UNIVERSITY OF LEEDS
Contribution de l’UE
€ 100 000,00
Adresse
WOODHOUSE LANE
LS2 9JT Leeds
Royaume-Uni
Région
Yorkshire and the Humber West Yorkshire Leeds
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
Aucune donnée