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Mechanisms and Targeting Stromal Contribution to Tumour Invasion and Metastasis (STROMALIGN)
Date du début: 1 juin 2012, Date de fin: 31 mai 2017 PROJET  TERMINÉ 

"Angiogenesis inhibition has proven to be a successful anti-cancer therapeutic approach and anti-angiogenic therapies are currently approved as standard therapy in several types of cancer for their clinically validated beneficial extension of overall survival, progression-free survival and/or time-to-progression in these cancer patients. Nevertheless, in preclinical mouse models of cancer, although these therapies also show significant anti-tumour effects and overall survival benefit, these therapies are also triggering increased tumour local invasion, with more distant dissemination and emergence of metastasis (overall tumour malignization). The clinical relevance of this malignization effect in patients that are currently being treated with antiangiogenic drugs still remains elusive, but the frequent tumour relapses and acquired resistance to therapy in some patients strongly suggests this insidious event should be exhaustively evaluated.In this sense, many laboratories are rapidly advancing in the study of the molecular players and signalling pathways implicated in this event, although an important limitation of all these approaches is that they are all based on Tumour-centered studies of the causes of malignization and are not taking into account the Tumour Stroma contribution to tumour invasion and metastasis. Thus, we postulate that the tumour stroma indeed plays a critical role in malignization after anti-angiogenic therapies and its specific mechanisms should be determined in order to target these stromal components to impede tumour malignization after antiangiogenic therapies.STROMALIGN is a groundbreaking project designed to overcome these current limitations from a novel perspective: instead of focusing on the genetically instable and highly adaptive tumour cell component, we rather postulate that the tumour stroma plays a critical role in malignization after anti-angiogenic therapies and its targeting could offer significant advantages of less adaptation/resistance, and broader applicability to several different tumour types. Thus, we will initially dissect the mechanisms of stromal contribution to this malignization effect, followed by pharmacological targeting this event in transgenic and recently developed Tumorgraft mouse models of cancer, and later on applying this knowledge to the clinical setting in samples from two approved clinical studies with anti-angiogenic therapies currently ongoing at our Hospital.By starting at the biology of animal models and later on validating these findings in the clinical setting we will tackle this current biomedical challenge by finding new stromal targets of malignancy that will ultimately benefit anti-angiogenic treated patients in the clinic."