Abstract 530: A personalized HGSC organoid platform for repurposing lysosomal death inducing drugs

Abstract Introduction: Among the gynecological malignancies, the most prevalent and lethal is the high-grade serous ovarian cancer (HGSC), accounting for 70-80% of ovarian cancer mortality. Tumor evolution studies suggests that high molecular heterogeneity prevails long before treatment intervention, evincing that patients would not benefit from a universal treatment but would rather benefit personalized treatments. Here, we established a prospective HGSC patient-derived tumor organoid biobank, where we are testing lysosome-targeting FDA approved medicines, to evaluate their cytotoxicity as standard treatment alternatives and/or supplements. Materials and Methods: HGSC patient tissues from various anatomical sites (multiregional) and different courses of treatment (longitudinal) were grown as long-term 3D tumor organoid cultures (PDOs). Relevant biomarker proteins were qualitative and quantitative evaluated via immunofluorescent labeling and drug profiling was studied via cytotoxicity assays, measurement of proliferative index and lysosomal membrane permeabilization using 3D high-throughput high-content imaging and image analysis. Genomic and transcriptomic data were derived from whole-genome sequencing, whole exome sequencing and RNA sequencing of the organoid cultures and corresponding parental tumors. PDX models were used for in vivo drug testing. Results and Discussion: Organoids were established as self-renewable, robust cultures with stemness-like characteristics that mirrored the genomic profile of the parental tissue, thus being ideal model systems for preclinical studies. We identified a cohort of 22 samples derived from 17 patients and tested sensitivity towards clinically approved lysosomal-targeting drugs. Samples were categorized as sensitive or non-sensitive to the treatment and gene-expression analysis indicated a pathway possibly involved in the resistance mechanism of the non-sensitive group. Inhibition of this pathway enhanced the initially observed cytotoxicity. Treatment efficiently inhibited the growth of engrafted sensitive samples in vivo. Conclusion: To maximize survival potential of HGSC patients, functional drug testing on patient-derived cancer models is essential. Here, our platform is a powerful tool to study a broad spectrum of alternative drug combinations to accordingly direct clinical decisions. It also gives the possibility to investigate intensively the mechanisms that lie behind the onset and the refractory of the HGSC. Citation Format: Aikaterini Skorda, Benita Sophie Rasmussen, Marie Lund Bay, Daria Afedeva, Anna Røssberg Lauridsen, Yilin Li, Elina Valkonen, Ahmad Abdul-Al, Mar Casasnovas Ventura, Lorenzo Fuso, Jaume Roca Arias, Wojciech Senkowski, Krister Wennerberg, Olli Carpen, Anni Virtanen, Alexandra Lahtinen, Jaana Oikkonen, Johanna Hynninen, Sampsa Hautaniemi, Tuula Anneli Kallunki. A personalized HGSC organoid platform for repurposing lysosomal death inducing drugs [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 530.