Abstract PR005: Conditional Reprogramming Enables Rapid Establishment of Patient-Derived Neuroendocrine Tumor Models for Functional Precision Oncology

Patient-derived organoids in pancreatic cancer: Advances and applications in precision oncology

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies owing to late diagnosis, extensive intratumoral heterogeneity, a dense desmoplastic tumor microenvironment, and limited therapeutic responsiveness. Although current treatment regimens, including FOLFIRINOX and gemcitabine plus nab-paclitaxel, have modestly improved survival, chemoresistance and the lack of reliable predictive biomarkers continue to hinder precision oncology. Conventional two-dimensional cell lines and many in vivo models do not fully recapitulate the complex architecture, cellular interactions, and biological heterogeneity of human PDAC. Patient-derived organoids (PDOs) have emerged as physiologically relevant three-dimensional models that preserve the genetic, molecular, and phenotypic characteristics of the original tumor while enabling rapid ex vivo pharmacotyping and functional therapeutic evaluation. This review summarizes recent advances in PDAC organoid technology, including tissue acquisition, organoid establishment, molecular characterization, biobanking, and integration with cancer-associated fibroblasts, immune cells, endothelial cells, CRISPR/Cas9 genome editing, assembloid systems, and microfluidic organ-on-chip platforms. We further discuss the applications of PDOs in drug screening, molecular subtype characterization, modeling therapeutic resistance, and supporting precision treatment strategies, together with emerging evidence from prospective clinical studies. Finally, we critically examine the remaining translational challenges, including culture-induced phenotypic drift, limited microenvironmental complexity, interlaboratory variability, assay standardization, and regulatory implementation. Although PDOs represent promising platforms for functional precision oncology, widespread clinical adoption will require standardized methodologies, prospective multicenter validation, and regulatory qualification before routine integration into clinical decision-making.

Multidirectional Cellular Plasticity in Ewing Sarcoma Reveals a Tumor–CAF Continuum and Novel Immunotherapeutic Targets

An integrated analysis of EwS tumor samples reveals a dynamic tumor–CAF continuum that is uniquely preserved in primary tumors and establishes a framework for identifying clinically relevant tumor-associated surface TAs, providing a foundation for the rational development of next-generation immunotherapies and precision-targeted therapies for patients with EwS.

INSM1 Regulates Neuroendocrine Plasticity and Tumor Progression in Prostate Cancer

It is demonstrated that INSM1 is consistently upregulated across NEPC patient tumors and experimental models, including both ASCL1⁺ and NEUROD1⁺ molecular subtypes, as revealed by integrated bulk and single-cell transcriptomic analyses.

DLL3-Targeted Strategies in Advanced Prostate Cancer: Current Evidence and Future Perspectives

Inhibition of androgen receptor (AR) signaling remains the cornerstone of systemic therapy for advanced prostate cancer (PC). However, a subset of aggressive tumors either arises de novo with neuroendocrine features or emerges under treatment pressure through lineage plasticity and AR independence. These lethal states are encompassed within the spectrum of aggressive-variant prostate cancer (AVPC), an umbrella term that includes both histologically confirmed neuroendocrine prostate cancer (NEPC)—comprising de novo NEPC and treatment-emergent NEPC (t-NEPC)—and clinically or molecularly defined AVPC lacking histologic confirmation but sharing neuroendocrine-like, AR-indifferent, or small-cell features. These phenotypes are characterized by rapid progression, visceral dissemination, low or discordant prostate-specific antigen (PSA) levels relative to tumor burden, and poor prognosis. Treatment options for NEPC/AVPC remain limited and largely rely on platinum-based chemotherapy, which usually provides only modest and transient benefit. This unmet need has intensified interest in lineage-associated vulnerabilities. Delta-like ligand 3 (DLL3), an inhibitory Notch ligand with restricted expression in normal adult tissues, is aberrantly upregulated in several neuroendocrine malignancies and has emerged as a clinically actionable target. In prostate cancer, DLL3 expression is enriched in neuroendocrine tumor cells, being detected in approximately 76.6% of castration-resistant NEPC compared with only 12.5% of castration-resistant adenocarcinoma, supporting its development as both a biomarker and therapeutic vulnerability. Clinical success of DLL3-targeted therapies in small-cell lung cancer further supports evaluation of DLL3-directed strategies in NEPC and related AVPC states. This review summarizes the biological rationale, translational evidence, and emerging clinical data supporting DLL3-targeted therapies in prostate cancer. Investigational platforms include antibody-drug conjugates, bispecific and trispecific T-cell engagers, and DLL3-directed radiopharmaceuticals. Early clinical studies suggest that activity is largely confined to DLL3-expressing neuroendocrine tumors, highlighting the importance of biomarker-guided patient selection. Delta-like ligand 3-directed therapies may reshape the management of DLL3-expressing prostate cancer if ongoing efforts to refine biomarkers improve patient enrichment and optimize trial design are successfully translated into clinical practice.

Integrated Patient-Derived Xenograft and Patient-Derived Cell Models Reveal Therapeutic Vulnerabilities Beyond Standard-of-Care Therapy in Endometrial Cancer

Castration-resistant prostate cancer as an adaptive tumor ecosystem: coupling tumor evolution with microenvironmental reprogramming