Patient-Derived Xenografts of High-Grade Serous Ovarian Cancer Subtype as a Powerful Tool in Pre-Clinical Research

SIMPLE SUMMARY: Patient-derived xenografts (PDXs) have gained popularity as a model system in anti-cancer drug development. PDXs are established by the transfer of patient tumors directly into mice without prior in vitro manipulation, assuming that these models closely resemble patient tumors. However, recent reports have shown that tumor evolution can result in genomic alterations of PDXs, emphasizing the need to assess the extent of genetic drift in PDX models. To address this need, we developed a method to interrogate genetic drift in a panel of ovarian cancer PDXs using SNP genotyping. We demonstrated that PDX models retain molecular and histological characteristics of the original patients’ tumors even following multiple passages in mice. Further, we showed that these models faithfully recapitulate the therapeutic response of their corresponding patients. Overall, validated patient-derived models of ovarian cancer are valuable tools to facilitate translation of new therapies from pre-clinical studies to patients. ABSTRACT: (1) Background. PDX models have become the preferred tool in research laboratories seeking to improve development and pre-clinical testing of new drugs. PDXs have been shown to capture the cellular and molecular characteristics of human tumors better than simpler cell line-based models. More recently, however, hints that PDXs may change their characteristics over time have begun to emerge, emphasizing the need for comprehensive analysis of PDX evolution. (2) Methods. We established a panel of high-grade serous ovarian carcinoma (HGSOC) PDXs and developed and validated a 300-SNP signature that can be successfully utilized to assess genetic drift across PDX passages and detect PDX contamination with lymphoproliferative tissues. In addition, we performed a detailed histological characterization and functional assessment of multiple PDX passages. (3) Results. Our data show that the PDXs remain largely stable throughout propagation, with marginal genetic drift at the time of PDX initiation and adaptation to mouse host. Importantly, our PDX lines retained the major histological characteristics of the original patients’ tumors even after multiple passages in mice, demonstrating a strong concordance with the clinical responses of their corresponding patients. (4) Conclusions. Our data underline the value of defined HGSOC PDXs as a pre-clinical tumor model.