Abstract 840: The ITCC-P4 consortium: Deep molecular characterization of pediatric cancer xenograft (PDX) models enable prediction of novel personalized combination treatment options for patients with childhood cancer
Authors: 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
Journal: Cancer Research (2025)

Abstract Despite advances in the understanding of the pathogenesis of pediatric cancers, first line treatment of advanced, recurrent and metastatic childhood cancer still remains chemotherapy. Omics data unraveling the molecular pathogenesis together with overall low efficacy of targeted agents in preclinical trials so far did not improve the clinical outcomes of pediatric patients. The EU-IMI-2 funded, public-private partnership project “ITCC-Pediatric Preclinical Proof-of-Concept Platform” (ITCC-P4) has built a large repertoire of more than 400 pediatric patient-derived xenograft (PDX) models, including brain, neuroblastoma, soft tissue and other rare solid pediatric cancers. Tumor and PDX omics and in vivo data are stored and analized utilizing the ITCC-P4 R2 data base (https://r2.amc.nl). Our strategy aimed to utilize deep systems biology data from human tumors and corresponding PDX models to predict more effective drug and superior drug combination treatment of neuroblastoma (NB) and rhabdomyosarcoma (RS). ITCC-P4 single mouse trial (SMT) screening in 27 PDX models from the NB and 24 RS cohort reveal overall low response rates for single targeted drugs including ALk, MDM2, CHEK, MEK kinase inhibitors and efficacy in 1 out of 3 chemotherapies only. Therefore, we conducted a SMT combination trial with already approved targeted cancer drugs in NB and RS PDX models (n=10 each), including major entity subtypes, e.g. high risk-, MYCN amplified NB and PAX3-Foxo fusion RS. In total, 10 drug combinations were compared to a control and single agent arm of up to four individual drugs. Except one drug combination, all doses and schedules were well tolerated in mice indicating absence of adverse side effects. Interestingly, similar response pattern were observed in NB and RS PDX regardless of their molecular phenotype. However, the response to single agent treatment according to RECIST criteria was low with only 20% achieving stable disease (SD) or better. In contrast, when combining these less effective single agents, we observed an additive anti-tumoral effect with 40% of PDX models responding with SD or better. Most importantly, a significant and outperforming synergistic effect with 50% complete remission and 20% stable disease was achieved with simultaneous inhibition of ALK / BCl-2 or ALK / RAF signaling, which was observed in NB and RS to similar extend. Taking together, deep molecular phenotyping together with our extensive in vivo PDX toolbox allows prediction and exploration of promising noval treatment options. Our results highlight the great potential of the ITCC-P4 portfolio and the close collaboration with internationally recognized pediatric oncologists and physicians, which enable personalized translation of specific combination treatments for childhood cancers in the near 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. The ITCC-P4 consortium: Deep molecular characterization of pediatric cancer xenograft (PDX) models enable prediction of novel personalized combination treatment options for patients with childhood cancer [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 840.