ETMR-18. ADVANCING ETMR RESEARCH: NOVELIN VITRO ANDIN VIVO PRECLINICAL MODELS FOR DEVELOPING MORE EFFECTIVE TREATMENTS

Abstract

Abstract BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare and aggressive tumor that occurs mainly in infants under three years of age. Genetically, ETMRs are characterized by amplification and fusion of a microRNA cluster on chromosome 19 (C19MC) with TTYH1, present in ~90% of the tumors. ETMR patients still have a poor prognosis without any recent advances in treatment. A major limitation to develop more effective treatment strategies is the lack of sufficient preclinical models. METHODS Establishment of ETMR patient-derived xenograft (PDX) models and tumoroid lines, molecular characterization, high throughput in vitro drug screens, targeted drug treatments in vitro and in vivo. RESULTS We have established four new tumoroid and five new PDX ETMR models. These models faithfully recapitulate ETMR patients’ tumors based on their histological, transcriptomic, and methylome signatures. The in vitro models were derived from two patients and two PDX models and included three C19MC-amplified cell lines, of which two were a primary-relapse pair, and one a primary C19MC non-amplified model. In vivo we established the same models as PDX models subcutaneously plus an additional C19MC-amplified relapse model. High-throughput drug screening assays, using drug libraries with 225 clinically approved drugs and other small molecules, were conducted across the panel of in vitro models. Potential therapeutic candidates with promising activity in ETMR tumoroid lines identified from these screens include FGFR, XPO1, MTOR, MDM2 and topoisomerase inhibitors. CONCLUSIONS The establishment of novel preclinical models represents a significant advancement in ETMR research, offering a platform that captures the molecular complexity of the disease. The identification of several inhibitors shows the potential of these models for drug discovery and preclinical testing. Ongoing in vitro and in vivo experiments with these drugs and combinations aim to further validate their activity, moving towards the development of more effective therapies for ETMR patients.