Abstract
Simple SummaryIn the conventional treatment of gynecologic malignancies, most patients receive similar ‘one-size-fits-all’ treatment. However, it is increasingly clear that standard therapies do not work in every patient, and it would be very helpful to have pretreatment predictive assays to provide more personalized regimens. In this study, we describe the routine, successful establishment of patient-derived organoid models (PDOs) of endometrial and ovarian cancer tissues from consenting patients and provide an example of how information from drug screening in PDOs may be a useful predictor of patient response to therapy.Developing reliable experimental models that can predict clinical response before treating the patient is a high priority in gynecologic cancer research, especially in advanced or recurrent endometrial and ovarian cancers. Patient-derived organoids (PDOs) represent such an opportunity. Herein, we describe our successful creation of 43 tumor organoid cultures and nine adjacent normal tissue organoid cultures derived from patients with endometrial or ovarian cancer. From an initial set of 45 tumor tissues and seven ascites fluid samples harvested at surgery, 83% grew as organoids. Drug sensitivity testing and organoid cell viability assays were performed in 19 PDOs, a process that was accomplished within seven days of obtaining the initial surgical tumor sample. Sufficient numbers of cells were obtained to facilitate testing of the most commonly used agents for ovarian and endometrial cancer. The models reflected a range of sensitivity to platinum-containing chemotherapy as well as other relevant agents. One PDO from a patient treated prior to surgery with neoadjuvant trastuzumab successfully predicted the patient’s postoperative chemotherapy and trastuzumab resistance. In addition, the PDO drug sensitivity assay identified alternative treatment options that are currently used in the second-line setting. Our findings suggest that PDOs could be used as a preclinical platform for personalized cancer therapy for gynecologic cancer patients.
Highlights
Ovarian cancer is the fifth leading cause of death of women from cancer worldwide [1]
In addition to research models to identify biomarkers of response to novel therapeutics or combinatorial regimens, we propose that patient-derived organoids (PDOs) hold great promise as valuable preclinical models which can provide insights into drug responses that are case-specific
As an example of the power of PDOs to predict clinical outcomes, we present a case in which the PDO results reflected patient resistance to standard therapy, something we argue could be predicted upfront in the future using the PDO method for screening
Summary
Ovarian cancer is the fifth leading cause of death of women from cancer worldwide [1]. A class of targeted agents used in ovarian cancer is PARP inhibitors, which are most effective for patients with germline or somatic mutations in BRCA1/2 [11] In both preclinical studies and translational studies of completed clinical trials, our group has recently reported that mutations in the tumor suppressor TP53 predict the benefit of adding the antiangiogenic compound bevacizumab to chemotherapy upfront in advanced endometrial cancer [4,12]. PDOs can grow with high efficiency in a short period of time which is much faster than generating a patient-derived xenograft (PDX model), enabling a priori prediction of responsiveness to chemotherapy, with the potential to substitute other regimens if primary resistance is demonstrated [21]. As an example of the power of PDOs to predict clinical outcomes, we present a case in which the PDO results reflected patient resistance to standard therapy, something we argue could be predicted upfront in the future using the PDO method for screening
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