Ovarian cancer (OC) remains the deadliest gynecological cancer, primarily due to late-stage diagnosis and high rates of chemotherapy resistance and recurrence. Lack of representative preclinical models complicate the challenges of discovering effective therapies, especially for platinum-resistant OC. Patient-derived xenograft (PDX) models maintain the genetic characteristics of the original tumor and are ideal for testing candidate therapies in vivo, but their high cost limits their feasibility for high-throughput drug screening. Organoid models mimic the tumor's 3D structure and preserve intra-tumoral heterogeneity. While organoids established directly from primary patient tumors are the optimal model for personalized drug response studies, the supply of primary tissue is often limited. Patient-derived xenograft tumors can be passaged in mice and provide a renewable source of cancer cells for organoids. This study aimed to determine if PDX-derived organoids (PDXOs) can reflect patient responses to chemotherapy similarly to primary patient-derived organoids (PDOs). 3D Organoid models were established from the malignant ascites of five high grade serous ovarian cancer patients: two platinum-sensitive, two platinum-resistant, and one platinum-refractory, along with their matched PDX samples from ascites and solid tumor. Organoid viability after 72-hour treatment with paclitaxel (PTX), carboplatin (CBDCA), or their combination was compared between organoids derived directly from the patient or from the PDX models. The in vitro drug responses of PDXOs and PDOs were then compared to defined patient clinical responses: platinum-sensitive (initial response to standard platinum/paclitaxel therapy lasting > 6 months post-treatment), platinum-resistant (initial response to standard chemotherapy lasting < 6 months), or platinum-refractory (no initial response to standard chemotherapy). In drug response assays, PDXOs and PDOs demonstrated similar sensitivity to standard chemotherapy and also reliably reflected patient responses based on the clinical designation of platinum sensitivity. While organoids derived from the ascites were smaller with a denser morphology, their drug response mirrored that of the organoids derived from solid tumor. Platinum-sensitive cases exhibited significant reductions (around 50% reduction) in organoid viability when treated with carboplatin, paclitaxel, or their combination. Platinum-resistant or refractory organoids showed little to no reduction in viability with carboplatin or paclitaxel monotherapy or the combination. Organoids derived from one platinum-resistant case did show a small but significant reduction in viability with single-agent paclitaxel, suggesting that organoid models might predict response to second-line paclitaxel therapy. This study demonstrates that PDXOs respond to drugs similarly to PDOs and confirms that both models effectively mirror patient response to standard chemotherapy. This highlights the potential of PDXOs as renewable models for screening novel therapies and developing personalized strategies in OC.
Nikeghbal et al. (Tue,) studied this question.