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Vulnerability of esophageal cancer to their addiction to kinase activities: evaluation and prediction of eSCC tumors responsiveness to kinase inhibitors.

Project description

Kinase inhibitors as a therapy against oesophageal cancer

Oesophageal squamous cell carcinoma (eSCC) presents with various genetic alterations that affect the activity of kinase enzymes which are involved in signalling pathways, the cell cycle or cell proliferation. However, heterogeneity associated with kinase deregulation impedes the development of a uniform anti-kinase therapy for eSCC. To support the design of novel therapeutic interventions, scientists of the EU-funded Kinaddict project will employ omics approaches to investigate how eSCC responds to kinase inhibitors. Insight into the molecular mechanisms of these responses will lead to biomarkers indicative of treatment outcome as well as combinatorial therapies.

Objective

In decades, the 5-year survival rate of several cancers has barely been improved and the esophageal squamous cell carcinoma (eSCC) is not different with a rate around 25%. In order to increase the survival, chemoradiotherapy prior surgery has become the reference for eSCC despite still a high mortality. eSCC tumors harbor a variety of genetic alterations directly or indirectly affecting the activity of kinases involved in signaling pathways, the cell cycle or the proliferation. Evidence on how eSCC tumors are addicted to such oncogenic alterations remains missing to evaluate alternative treatment modalities. The heterogeneity of eSCC tumors presenting deregulations of diverse constellations of kinases has rendered difficult the development of a unique therapeutic strategy similar to prior successes targeting EGFR or BCR-ABL. However, as the CDK4 activity lies downstream from most of the oncogenic deregulations of signalling pathways, it has been proposed to represent the therapeutic target of choice, confirmed by the first approval by the FDA/EMA of 3 CDK4/6 inhibitors to treat ER+ breast cancer. Despite this, not all tumors respond to CDK4 inhibition and long-term treatment triggers escape mechanisms. In this context, the main aim of the present proposal consists to preclinically evaluate if and how eSCC respond to inhibitors targeting kinases with an altered activity using a multi-omics approach. In this cancer, we will (1) identify the kinases with a deregulated activity associated to different genetic landscapes and determine the addiction of eSCC to their activity, (2) characterize the sensitivity of eSCC tumors to CDK4 inhibition and decipher their molecular response for effective combined targeted therapy, and (3) experimentally define the treatment modalities of eSCC in mouse models. The results will provide a strong basis to extend the study with clinicians to human tumors to determine biomarkers of responsiveness to efficient alternative therapy.

Coordinator

UNIVERSITE LIBRE DE BRUXELLES
Net EU contribution
€ 178 320,00
Address
AVENUE FRANKLIN ROOSEVELT 50
1050 Bruxelles / Brussel
Belgium

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Region
Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 178 320,00