Abstract B006: Employing fresh tumor samples and long-term cultures for personalized drug response profiling in childhood solid cancers

Abstract Despite improved standard-of-care protocols resulting in 5-year survival rates of 80% for many childhood cancers at first diagnosis, refractory or relapsed solid tumors, including sarcomas, still have poor prognoses, necessitating improved treatment options. The international precision oncology program INFORM enrolls pediatric cancer patients for comprehensive molecular and functional analyses, including drug testing on patient-derived fresh tissue cultures. We have recently demonstrated the feasibility of drug sensitivity profiling (DSP) within a clinically relevant timeframe. In addition to immediate drug screening, we are using residual tumor tissue to establish stable long-term culture (LTC) models for as many INFORM cases and diagnoses as possible. Comparison of drug screening results between 37 fresh tissue cultures and their corresponding long-term cultures (LTCs) demonstrates the general preservation of drug sensitivity profiles and highlights outlier sensitivity to drugs targeting molecular alterations with high evidence levels. One pair of fresh tissue and long-term culture models was derived from an embryonic rhabdomyosarcoma patient who relapsed 14 months after first-line treatment according to soft-tissue sarcoma guidance. Next-generation sequencing of the fresh frozen tumor and DSP with the patient-derived fresh tissue spheroid culture of the resected relapsed tumor were conducted, and results were reported to the molecular tumor board five weeks after sample receipt. The molecular analysis identified a hotspot mutation in NRAS and CDKN2A/B deletion as actionable targets. Consistently, inhibitors of the MAPK pathway elicited an above-average response in the DSP. However, vincristine and irinotecan emerged as top hits, a result maintained in the long-term culture DSP. The patient experienced remission after 6 weeks of VIT (vincristine, irinotecan, temozolomide), making the tumor resectable and leading to a complete clinical response. Taken together, our results emphasize the clinical utility and benefit of ex vivo drug sensitivity profiling. Additionally, the INFORM LTC models expand the availability of molecularly defined models for pediatric tumor diagnoses allowing detailed functional studies e.g., of mechanisms underlying therapy-sensitivity or resistance. Citation Format: Luisa Becker, Anna Loboda, Kathrin Schramm, Robert J Autry, Monika Sparber-Sauer, Gundula Staatz, Alexandra Russo, Olaf Witt, Heike Peterziel, Ina Oehme. Employing fresh tumor samples and long-term cultures for personalized drug response profiling in childhood solid cancers [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 B006.