Targeted Protein Degradation as a Therapeutic Strategy for the Treatment of Gastrointestinal Stromal Tumour (GIST)

Descripción del proyecto

Superar la farmacorresistencia en los tumores del estroma gastrointestinal

El tumor del estroma gastrointestinal (TEGI) es el sarcoma humano más frecuente, causado principalmente por mutaciones activadoras en el receptor tirosina quinasa KIT. Aunque los inhibidores de la quinasa proporcionan un beneficio clínico inicial, la mayoría de los pacientes recaen debido a mutaciones secundarias de KIT que confieren resistencia al fármaco. Con el apoyo de las Acciones Marie Skłodowska-Curie, el equipo del proyecto Novel GIST Therapies tiene como objetivo desarrollar una nueva estrategia terapéutica basada en la degradación dirigida de proteínas (TPD, por sus siglas en inglés). Este método funciona reclutando una proteína diana a la maquinaria de eliminación endógena, eliminándola así de una célula en lugar de limitarse a inhibir su actividad. Los investigadores establecerán y probarán la eficacia preclínica de la TPD en modelos celulares y organoides del TEGI, ofreciendo una estrategia novedosa contra los mecanismos de resistencia en el TEGI.

Objetivo

Gastrointestinal stromal tumour (GIST) is the most common subtype of sarcoma in humans and its initiation and progression is predominantly driven by constitutively activating mutations in the receptor tyrosine kinase (RTK) KIT. This dependency on KIT led to the approval of kinase inhibitors for the treatment of GIST. Inhibition of KIT activity is effective at treating GIST in the short-term however, the majority of patients eventually develop resistance. This resistance is predominantly due to the emergence of additional KIT mutations. Therefore, the development of alternative KIT targeting therapies, beyond the current state-of-the-art, is paramount for the effective treatment of GIST in the long-term. One such strategy is targeted protein degradation (TPD). TPD is based on drugs called “degraders” which are compounds that induce the proximity between a protein of interest (POI) and components of the cellular proteolytic machinery resulting in the destruction of the former. Degradation of KIT offers several benefits over inhibition, that may combat resistance in GIST. Firstly, small molecule inhibitors rely on a strong affinity for the POI to be effective whereas degraders can maintain activity when the affinity for the target is compromised by mutations. Secondly, inhibition of protein function is not a requirement for degrader activity and therefore additional ligandable sites on the POI.

In this project, I will employ a multifaceted drug discovery approach with the overarching aim of designing, identifying, and optimising degraders of KIT and investigate their effectiveness in GIST models. In order to explore the full potential of TPD in the treatment of GIST, I will pursue two different modalities of degraders: (i) bivalent (Objective 1) and (ii) monovalent (Objective 2). With a clear clinical translational goal in mind, the optimised degraders will be evaluated in various preclinical models of GIST (cellular and organoid) (Objective 3).