Abstract 4853: A comprehensive endometrial cancer organoid biobank reveals subtype-specific transcriptional programs and therapeutic targets

Abstract Background: Endometrial cancer (EC) is a clinically and biologically heterogeneous disease with unequal outcomes, particularly among high-grade tumors that disproportionately affect racially diverse populations. Existing preclinical models incompletely capture this heterogeneity. We established a large, racially diverse EC patient-derived organoid (PDO) biobank with matched normal to define subtype-specific molecular programs and actionable vulnerabilities. Methods: Tumors and matched normal endometrium were prospectively collected (n=380). Morphologic fidelity was assessed by histology and immunophenotyping. Multi-omic profiling evaluated driver retention and defined subtype-specific transcriptional states. High-throughput drug screening identified candidate vulnerabilities. Results: A total of 319 samples were included, with a ∼93% PDO establishment rate, and matched tumor-normal PDOs generated across major EC histologies. PDOs recapitulated the key architectural and protein-expression features of their parental tumors, including TP53-abnormal serous phenotypes and mixed epithelial-mesenchymal organization in carcinosarcoma (CS). PDOs also preserved the key genomic characteristics, including TP53, PTEN, and PIK3CA alterations. Transcriptomic profiling revealed distinct subtype programs. Endometrioid PDOs showed Wnt-associated epithelial renewal with reduced apoptosis, p53, mTORC1, and inflammatory signaling. Serous PDOs displayed TP53-abnormal, MYC-and cell-cycle-enriched programs with uniformly suppressed interferon signaling. CS exhibited hybrid epithelial-mesenchymal features with activation of Hedgehog and myogenic pathways and broad suppression of NF-kB and interferon signaling. Stratification by p53 stability and MSI status defined opposing hyperproliferative versus immune-active axes. High-throughput drug screening identified class I HDAC inhibitor (romidepsin, RD) as a consistent activity signal. RD-perturbation RNA-seq in CS showed extensive remodeling at 10 nM, with downregulation of core G2-M/E2F mitotic regulators and suppression of CS-associated secreted factors, accompanied by restoration of antigen-presentation and interferon-responsive genes. Pathway analysis demonstrated coordinated suppression of mitotic modules and reactivation of cytokine and immune signaling. RD inhibited the TPX2-CDK1-KIF11 mitotic module, indicating a druggable spindle-dependency circuit in CS. Conclusions: This large, racially diverse EC PDO biobank provides a robust preclinical platform that captures EC heterogeneity and enables controlled, subtype-resolved analyses. Integrated multi-omics and functional perturbation identify a spindle-dependency axis in CS, supporting subtype-specific and ancestry-aware therapy development. Citation Format: Mali Barbi, Shalini Gupta, Santhilal Subhash, Divya Gowthaman, Arielle Katcher, Megan Gorman, Brian Yueh, Erdogan Akyildiz, Uma Mahesh, Devin Gee, Nyasha Chambwe, Charlie Chung, Marina Frimer, Gary L. Goldberg, Semir Beyaz. A comprehensive endometrial cancer organoid biobank reveals subtype-specific transcriptional programs and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4853.