bioRxiv2024
BackgroundOvarian 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 tumors 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). Methods3D tumor organoid cultures were established from paired primary OC and PDX samples. 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/taxol 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). ResultsIn 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. ConclusionThis 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. SIMPLE SUMMARYOvarian cancer (OC) remains the most lethal gynecological cancer, largely due to its late diagnosis and resistance to chemotherapy. In order to identify novel therapies to treat ovarian cancer, we need better in vitro models that represent the genetic heterogeneity of the patient population. This study evaluates patient-derived organoid models established either directly from patient samples (PDOs) or from patient samples that were first passaged in mice and are referred to as patient-derived xenograft organoids (PDXOs). For each patient, organoid response to standard chemotherapy based on organoid viability assays was compared to the patients clinical designation of platinum sensitivity, which is categorized as platinum-sensitive, platinum-resistant, or platinum-refractory based on their response to standard chemotherapy. We demonstrated that both PDOs and PDXOs accurately reflect the patients clinical designation, suggesting their utility as effective models for testing new therapies and personalizing treatment. Importantly, by providing a renewable source of patient-derived cells, PDXOs extend the utility of each sample, making organoids essential tools for developing and refining personalized treatment strategies in oncology.