Abstract 7203: Systematic pan-cancer functional patient stratification to advance therapy personalization in rare solid tumors

Abstract Introduction: To date, comprehensive omics sequencing has greatly advanced cancer therapies and precision oncology. However, rare cancers remain challenging due to unique genetic profiles and low prevalence, limiting molecular mechanism-oriented treatment strategies. Comprehensive precision oncology programs enable molecularly informed treatments, benefiting many patients with advanced rare cancers. Nevertheless, therapeutic target selection remains complex, particularly in cases with no or multiple targetable alterations. To improve patient stratification for rare cancers, we developed a high-throughput drug testing strategy that rapidly identifies actionable therapeutic vulnerabilities to support molecular sequencing-based target identification in precision oncology. Methods: We developed a workflow to generate 3D patient-derived cancer models (PCM) and conduct drug sensitivity testing (DST) from viable patient tissues. Tumor tissue was processed into 3D short-term (ST-PCM) or expandable 3D long-term PCM (LT-PCM), such as organoids and spheroids. Dissociated PCM were seeded on pre-spotted drug test plates containing 87 FDA-approved or clinical trial drugs in five concentrations. Cell viability and drug sensitivity scores (DSS) were assessed after 72 hours for hit identification, followed by discussion in a molecular tumor board. Results: DSS correlation in replicates across entities and PCM types showed consistent hit classification with low variance (∼2.3-8.3%). High DSS values for mutation-targeting drugs validated assay sensitivity, while lack of response in controls confirmed specificity. Screening of >100 PCMs (76 from precision oncology patients) from 17 distinct rare and common tumor entities, including sarcomas, CUP, and others, revealed high feasibility: all LT-PCMs and 97% of ST-PCMs derived from surgical specimens allowed partial or full DST. Despite limited material from small biopsies, i.e., fine needle biopsies, successful screening of drug subsets was achieved in 78% of cases with direct seeding as ST-PCM. Additionally, 24 patient samples were screened after tumor cell expansion in LT-PCM, further expanding the cohort of patients eligible for functional testing. Among all tested PCMs, 91% responded to at least one of the tested drugs ex vivo (range 1-38, median 8). Molecular analysis linked pathway alterations with a higher likelihood of pathway inhibitor response. Importantly, preliminary analysis suggests concordance between ex vivo predictions for drug sensitivity and patient responses. Conclusion: We established a robust DST strategy that identifies potential therapeutic vulnerabilities to guide personalized treatment recommendations in precision oncology. This approach, feasible even with limited material, has the potential to enhance treatment decision-making and improve outcomes for adults with rare solid tumors. Citation Format: Jasmina Paluncic, Zunamys I. Carrero, Juliana Schulz, Attila Jady, Claudia Dagostino, Sára Hrabovská, Lino Möhrmann, Irina Kerle, Maximilian Werner, Dorothea Hanf, Maria Gabriela Pereira dos Santos, Elinor Young, Jessica Pablik, Ivona Mateska, Heike Peterziel, Daniel E. Stange, Alexander A. Wurm, Ina Oehme, Vivek Venkataramani, Christoph Heilig, Simon Kreutzfeldt, Benjamin Schmidt, Peter Horak, Stephan Richter, Jürgen Weitz, Klaus-Dieter Schaser, Daniela Richter, Stefan Froehling, Christoph Heining, Hanno Glimm, Claudia R. Ball. Systematic pan-cancer functional patient stratification to advance therapy personalization in rare solid tumors [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 7203.