Target Therapy in Rhabdomyosarcoma: Discovering new targets and apportunities

Autor: Prada Varela, Estela Maria
Přispěvatelé: Mora Graupera, Jaume, Hernández Muñoz, Inmaculada, Agell i Jané, Neus, Universitat de Barcelona. Facultat de Medicina
Rok vydání: 2021
Předmět:
Zdroj: TDX (Tesis Doctorals en Xarxa)
TDR. Tesis Doctorales en Red
instname
Dipòsit Digital de la UB
Universidad de Barcelona
Popis: [eng] Pediatric RMS is a developmental tumor that affects patients from birth to late adolescence. RMS tumorigenesis involves the stalk of embryological myogenic processes. Classically, two main subgroups of RMS have been defined based on the histopathological features: Embryonal (ERMS) and Alveolar (ARMS). However, the molecular classification refines the subgrouping into Fusion Positive or Fusion Negative based on the occurrence of FOXO1 oncogenic translocations. The recent genetic and epigenetic landscapes of those subgroups have identified few potential druggable targets. Nowadays, the outcome of children with relapsed/refractory RMS remains very poor. In order to find new opportunities for these patients this thesis focuses on the identification of new therapeutic targets effective for RMS treatment as well as on characterizing biomarkers of response for the new targeted treatment. We initially performed a functional approach starting from IGF1R target therapies to main downstream pathways including PI3K/AKT/mTOR and MEK/ERK that we found active in primary samples as well as in patient derived models. The new IGF1/2 monoclonal antibody m708.5 was found active in a subset of RMS particularly dependent on the IGF/AKT/mTOR pathway. Interestingly, we found that the ATP-competitive pan-AKT inhibitor Ipatasertib was highly active causing tumor regression in a subset of patient derived models. We were able to classify RMS primary models and their parental samples into two subgroups: Ipatasertib- dependent and Ipatasertib non-dependent. Moreover, preclinical pharmacology corroborated the dose-dependent response of RMS to this inhibitor. Most interesting, those tumors particularly sensitive to Ipatasertib were shown to be resistant to the MEK inhibitor Trametinib. Surprisingly, the study of a mechanistically different AKT inhibitor did not recapitulate Ipatasertib efficacy in vivo. We discovered that Ipatasertib sensitivity correlated with high PRKG1 levels. We described for the first time PRKG1 gene expression as RMS specific and predictive of Ipatasertib response in vivo. The genetic signature of PRKG1 depleted RMS cells is enriched in the expression of myogenic genes, positioning for the first time PRKG1 in the landscape of RMS tumorigenesis. The potential of PRKG1 as a prognostic marker was evaluated. Ongoing studies will determine the mechanism of myogenic blocking dependent on PRKG1.
Databáze: OpenAIRE
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