Abstract 1202: Molecular profiles and drug response of ITCC-P4 patient-derived xenograft pediatric cancer models for target identification and prediction of targeted therapies

Abstract Highly variable clinical outcomes, tumor heterogeneity with low mutational burden and lack of personalized therapy options remain a great challenge for the treatment of pediatric cancers. For more powerful preclinical testing in pediatric cancers the EU-(IMI-2) funded public-private partnership “ITCC-Pediatric Preclinical Proof-of-Concept Platform” (ITCC-P4) was built to establish a large repertoire of patient-derived xenograft (PDX) models. Over 400 PDX models representing central nervous system, bone- and soft tissue pediatric cancers were developed and deeply analyzed via multi-omics together with their corresponding human tumor counterparts. Meanwhile, a cohort of more than 250 PDX models was characterized for their response against standard-of-care (SoC) and targeted drugs in preclinical tests. Here we report our in vivo testing data for 27 neuroblastoma (NB) and 24 rhabdomyosarcomas (RS) and 9 Ewing sarcomas (EWS). Design of experiments contain a subset of three SoC chemotherapies and six targeted drugs, specifically customized for each indication by leading and internationally recognized pediatric oncologists. All molecular and drug-testing data obtained by the consortium are available via the R2 genomics analysis and visualization platform (https://r2.amc.nl). Not surprisingly and corresponding with clinical observations, best response rate indicated by RECIST criteria was still achieved with SoC chemotherapy in all three indications. In RS and EWS PDX single or combined chemotherapy induced remission of tumors in only 10% of tested models. Stable disease was detected in 40-50% of the EWS and RS cohort whereas the remaining 50% progressed under SoC. Treatment with targeted agents did not significantly improve response rates. Only few targeted drugs achieved stable disease or better in 10-15% of cases, including MDM2 inhibition in EWS, and inhibition of CDK or VEGFR2 in RS models. Compared to RS and EWS, chemotherapy induced significantly higher RECIST response rates in NB models achieving 20-40% complete remission with Topotecan and 40-60% stable disease with SoC in combination. Most interestingly, our screen identified MDM2 (25% SD or better) and CHEK1 (60% SD or better) as potential target pathways for antitumor therapy. Not surprisingly, high Alk expression correlated with preclinical outcome in vivo, but only in a limited subset of PDX. In three NB models belonging to highest Alk expressing PDX, a complete remission was achieved with Alk-inhibition. The ITCC-P4 R2 molecular phenotyping and drug testing data repository developed for preclinical oncology can be used as powerful tool for target identification and validation. Compiled data enable target-oriented PDX model selection and proof-of-concept studies to improve childhood cancer therapy in the future. Citation Format: Dennis Gürgen, Apurva Gopisetty, Eva-Maria Rief, Aniello Federico, Danny A. Zwijnenburg, Marcel Kool, Alexandra Saint-Charles, Gudrun Schleiermacher, Gilles Vassal, Jan J. Koster, Stefan M. Pfister, Jens Hoffmann. Molecular profiles and drug response of ITCC-P4 patient-derived xenograft pediatric cancer models for target identification and prediction of targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1202.