Robert Rottapel

Preclinical 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. Whole-exome sequencing analysis identified oncogenic alterations in PIK3CA, ARID1A, and CTNNB1. Further RNA sequencing and assay for transposase-accessible chromatin using sequencing 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, in which dual inhibitors significantly suppressed tumor growth compared with 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. Significance: This study characterizes a rare aggressive mixed endometrial carcinoma that developed after hormonal therapy. Patient-derived organoid and xenograft models revealed actionable targets in the VEGF and PI3K pathways. Combined cediranib and BKM120 treatment showed synergistic antitumor effects in vitro and in vivo. These findings highlight the potential of integrating molecular profiling and drug testing to guide personalized therapies in rare and recurrent endometrial cancers.