Descripción del proyecto
Nuevos biomarcadores para el diagnóstico del cáncer ovárico
La mayoría de las pacientes con cáncer ovárico presentan metástasis en el momento del diagnóstico, por lo que se necesita identificar nuevos biomarcadores para un diagnóstico temprano. El proyecto KLKs4OvCa, financiado con fondos europeos, se centrará en las peptidasas relacionadas con la calicreína (KLK, por sus siglas en inglés), una familia de enzimas que intervienen en un amplio espectro de procesos biológicos. Dado que las KLK aumentan en el cáncer ovárico y están relacionadas con un pronóstico poco prometedor, los científicos del proyecto tienen como objetivo descubrir su papel en esta enfermedad investigando su actividad. Los resultados del proyecto determinarán el pronóstico y el valor terapéutico de estos biomarcadores y ayudarán a abordar el reto de un diagnóstico temprano del cáncer ovárico.
Objetivo
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.
Ámbito científico
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Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
SW7 2AZ LONDON
Reino Unido