ATRT-11. DEVELOPMENT OF NOVEL PRECLINICAL MODELS AND THERAPEUTIC STRATEGIES FOR ETMR

Embryonal Tumor with Multilayered Rosettes (ETMR) is a very rare, aggressive pediatric brain tumor with a dismal 5-year overall survival rate. Few genetic aberrations in miRNA clusters and processing machinery have been detected in ETMRs with 90% of ETMR patients having the C19MC amplification. ETMRs show heterogenous histopathological features, including regions of abundant neuropil, hypercellular regions with multilayered rosettes, and papillary structures resembling primitive neuroectoderm. This unique histology, together with the detection of C19MC or DICER alterations, are necessary for diagnosis. The cellular and molecular mechanisms underlying ETMR development is poorly understood, and targeted therapeutics have not been developed due to scarcity of preclinical models. To expand knowledge of ETMR biology and accelerate the design of novel, it is thus essential to develop preclinical models. We have generated a novel patient-derived ETMR cell line from a resected patient tumor sample (CTBP-03A) and created two patient-derived xenograft (PDX) models (CTBP-03A and CBTP-38). We have used these unique patient-derived cell lines to identify mechanisms driving ETMR development and progression. To identify novel therapeutic targets, we conducted high-throughput drug screening (HTDS) utilizing 2480 approved and investigational drugs, against the CBTP-03A cell line. Among the candidate drugs showing an inhibitory effect on CBTP-03, 63 compounds were selected based on their activity, CNS penetration ability, mechanism of action, and bioavailability, if known. The 63 potency-selected hits were screened in an all-versus-all format, totaling 1953 combinations. The rapidity of action of the top choice compounds used as single agent or in double and triple combination was assessed by caspase glow assay. This initial combination screen identified DNA replication stress and FGF signaling as potential new drug combinations for ETMR. We will thus describe the first combinatorial HTDS on two novel ETMR patient-derived cell lines and potential drug combination strategies for the treatment of ETMR.