Pre-Clinical Combination Targeting VEGF and PI3K in a Rare, Aggressive Mixed Endometrial Carcinoma: An Applied Case Report

Abstract We report a rare case of a young patient (VENUS 167) initially diagnosed with grade 1 endometrioid endometrial cancer, which, following endocrine treatment, presented with mixed aggressive carcinoma with three distinct histologic patterns: grade 1 endometrioid, large cell neuroendocrine, and undifferentiated carcinoma. The surgical specimen at the time of disease progression was used to establish OPTO.85, a patient-derived organoid (PDO), followed by a corresponding organoid-derived xenograft (ODX). Multi-omic analyses confirmed that OPTO.85 accurately reflected the patient’s tumor characteristics. WES analysis identified oncogenic alterations in PIK3CA, ARID1A, and CTNNB1. Further RNA-seq and ATAC-seq analyses revealed enrichment in VEGF and Wnt signaling pathways, suggesting therapeutic vulnerabilities. A high-throughput drug screen was conducted using ApexBio-Approved and Epigenetic Drug Libraries, along with Kinase Inhibitor and Tool Compound Libraries developed at the Ontario Institute of Cancer Research. The OPTO.85 PDO exhibited sensitivity to PI3K inhibitors and responsiveness to VEGF inhibition. Cediranib demonstrated synergy with BKM120, significantly reducing organoid growth. This combination also showed in vivo efficacy in the ODX model, where dual inhibitors significantly suppressed tumor growth compared to single compounds. This case exemplifies the impact of genomic profiling and patient-derived models in identifying actionable molecular changes in rare cancers with limited therapeutic options and poor prognosis. It highlights that high-throughput sequencing for individual patient tumors and generation of patient-derived models are feasible in endometrial cancer. This preclinical model may assist clinical decision and personalized therapy requiring validation in prospective studies.