Description du projet
De nouveaux biomarqueurs pour le diagnostic du cancer des ovaires
Étant donné que la plupart des patientes atteintes d’un cancer des ovaires présentent des métastases au moment du diagnostic, il est nécessaire d’identifier de nouveaux biomarqueurs pour un diagnostic rapide. Le projet KLKs4OvCa, financé par l’UE, se concentrera sur les peptidases liées à la kallicréine (KLK), une famille d’enzymes qui participent à un large éventail de processus biologiques. Les KLK étant régulées à la hausse dans le cancer des ovaires et associées à un pronostic sombre, les scientifiques cherchent à dévoiler leur rôle dans la maladie en étudiant leur activité. Les résultats du projet permettront de déterminer la valeur pronostique et thérapeutique de ces biomarqueurs et aideront à relever le défi d’un diagnostic rapide du cancer des ovaires.
Objectif
Ovarian cancer (OvCa) is one of the most fatal female gynaecological malignancies, resulting in 180,000 deaths annually. The majority of patients have metastatic disease at time of diagnosis, thus, early diagnosis of OvCa remains a challenge to our society. In addition, the low survival rates over the past decades have remained largely unchanged, evidencing the need of new therapies for OvCa. Kallikrein-related peptidases (KLKs) are a family of 14 serine proteases which form a cross activation network known as the KLK activome. KLKs show diverse tissue expression and physiological function, and aberrant KLK expression and activity has been related to several pathological conditions including skin diseases, neurodegenerative disorders and cancer. In OvCa, KLKs4,5,6 & 7 levels are upregulated and associated with its unfavourable prognosis, therefore, KLKs4,5,6 & 7 are considered potential drug targets and biomarkers for OvCa. However, KLK activity is decoupled from simple abundance, and the contribution of each KLK activity in OvCa progression remain poorly understood. In this project, I will develop selective (quenched)-Activity Based Probes ((q)-ABPs) for KLKs4,5,6 & 7 and quantify the active enzyme fraction of each KLK to determine their contribution to OvCa. Additionally, I will develop proteolysis targeting chimeras (PROTACs) which can be selectively activated by specific KLKs to unlock their potential as therapeutic targets for OvCa. This proposal aims to deliver a versatile platform to interrogate the application of KLKs4,5,6 & 7 as biomarkers and therapeutic targets for OvCa, with potential application to other KLK- and serine protease-related disorders. My participation in this proposal will allow to bring key knowledge to face the challenging objectives and receive high-quality training that will provide me with a solid and diversified groundwork to become and independent researcher in the drug discovery field.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
SW7 2AZ LONDON
Royaume-Uni