Abstract
Despite increasing evidence that precision therapy targeted to the molecular drivers of a cancer has the potential to improve clinical outcomes, high-grade epithelial ovarian cancer (OC) patients are currently treated without consideration of molecular phenotype, and predictive biomarkers that could better inform treatment remain unknown. Delivery of precision therapy requires improved integration of laboratory-based models and cutting-edge clinical research, with pre-clinical models predicting patient subsets that will benefit from a particular targeted therapeutic. Patient-derived xenografts (PDXs) are renewable tumor models engrafted in mice, generated from fresh human tumors without prior in vitro exposure. PDX models allow an invaluable assessment of tumor evolution and adaptive response to therapy. PDX models have been applied to pre-clinical drug testing and biomarker identification in a number of cancers including ovarian, pancreatic, breast, and prostate cancers. These models have been shown to be biologically stable and accurately reflect the patient tumor with regards to histopathology, gene expression, genetic mutations, and therapeutic response. However, pre-clinical analyses of molecularly annotated PDX models derived from high-grade serous ovarian cancer (HG-SOC) remain limited. In vivo response to conventional and/or targeted therapeutics has only been described for very small numbers of individual HG-SOC PDX in conjunction with sparse molecular annotation and patient outcome data. Recently, two consecutive panels of epithelial OC PDX correlate in vivo platinum response with molecular aberrations and source patient clinical outcomes. These studies underpin the value of PDX models to better direct chemotherapy and predict response to targeted therapy. Tumor heterogeneity, before and following treatment, as well as the importance of multiple molecular aberrations per individual tumor underscore some of the important issues addressed in PDX models.
Highlights
Cell lines and archival tumor tissue have provided a platform for discovery and validation of novel therapeutic targets in epithelial ovarian cancer (OC)
Treatment with IL-12 or Flt-3 ligand resulted in decreased tumor growth compared to control-treated mice, with increased NK cells and necrosis in the tumors of IL-12 or Flt-3 ligand treated mice. These findings suggest an immunologic reaction in response to IL-12 and Flt-3 ligand, supporting their potential therapeutic roles in the treatment of OC [32, 33]
LIMITATIONS Probably the most noted limitation of Patient-derived xenografts (PDXs) models involves the use of immunocompromised mice, which may attenuate the impact of the tumor microenvironment on tumor growth and drug response
Summary
Cell lines and archival tumor tissue have provided a platform for discovery and validation of novel therapeutic targets in epithelial ovarian cancer (OC). The authors compared histo-pathologic features in the original patient tumor, pre-graft tissue, and post-graft tissue and found no architectural or cytological differences, nor any major differences in immunomarker expression including CK20, CK7, or WT-1 (87–91% overall concordance) This group investigated five individual sub-renal PDX models for drug response and genetic stability over subsequent passages [38]. Bankert et al generated IP PDX models from five different OC patients to examine metastasis and the microenvironment of human ovarian tumors [39] In these mice, tumor growth and spread reflect the patterns that occur clinically whereby tumors grew on surfaces within the peritoneal cavity including the omentum, spleen, ovaries, pancreas, and liver.
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