Abstract A013: Functional profiling in pediatric precision medicine: global collaboration to drive clinical implementation

Abstract Background Functional precision medicine programs including ZERO (Australia), INFORM (international), and iTHER (Netherlands) combine tumor molecular profiling with ex vivo drug sensitivity profiling (DSP) to guide personalized therapy recommendations for pediatric patients. Treatment according to molecular drug targets has led to clinical benefit only in selected groups and clinical impact of integrating ex vivo tumor DSP in precision medicine programs remains unknown. Therefore, results across three programs are combined to study drug sensitivity profiles with matched solid tumors and correlate findings with clinical response data. Methods Functional profiling was performed on patient-derived viable material from high-risk, relapsed or refractory pediatric tumors after short-or long-term culture, and/or in vivo expansion. Long-term cultured and in vivo expanded samples were authenticated using short tandem repeat analysis and validated using single nucleotide polymorphism array, immunohistochemistry and/or flow cytometry. Samples were exposed to clinically relevant drug libraries. An automated data analysis pipeline was established to generate drug efficacy parameters including half-maximal inhibitory concentration (IC50) and half-maximal lethal concentrations (LC50), area under the dose-response curve value (AUC), and drug sensitivity score (DSS). In addition, tumor molecular data were established using whole-genome sequencing or whole exome sequencing and/or RNA sequencing. All data were integrated to study biomarker-drug associations and analyze correlation between ex vivo drug sensitivity and clinical response. Results Drug sensitivity screening was performed for 270 (iTHER=71; INFORM=109; ZERO=90) solid tumors. Results were collected in the R2 platform (http://r2platform.com), which allows for dedicated visualization. As a result, a powerful reference set is available, reflecting both known pharmacologic vulnerabilities, such as sensitivity of NTRK-fusion positive samples to NTRK inhibition. Additionally, tumor-type specific drug sensitivities were discovered, including sensitivity to MEK inhibitors in Wilms tumors. Moreover, in vitro non-responsiveness of heavily pre-treated samples to chemotherapy was confirmed, which potentially could avoid ineffective treatments. Clinical follow-up of a subset of patients confirmed correlation with in vitro drug sensitivity. Conclusions Our data support complementary functional profiling to omics-guided precision medicine by strengthening molecular results; identifying novel treatment options and predictive biomarkers; and avoiding ineffective treatments. Global collaboration and data sharing is essential as childhood cancer remains rare, and innovative approaches are urgently needed to improve outcome for future patients. Citation Format: Eleonora J Looze, Jie Mao, Heike Peterziel, Marlinde C Schoonbeek, Arjan Boltjes, Jan Koster, Marcel P.S. Kool, Max M Van Noesel, Olaf Witt, Paul G Ekert, Jan J Molenaar, Ina Oehme, Emmy Dolman, Karin P.S. Langenberg. Functional profiling in pediatric precision medicine: global collaboration to drive clinical implementation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A013.