Characterizing the Chemoresistant Ovarian Cancer Population using the Heterogeneous PDX

The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy across a population, but also study crucial aspects of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor’s heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. The pathways most significantly altered included Protein Kinase A signaling, GNRH signaling, and sphingosine-1-phosphate signaling. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer