Development of a novel patient-derived preclinical model from malignant effusions in patients with tyrosine kinase inhibitor resistant clear cell renal cell carcinoma.

Abstract

445 Background: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood and there is a need to develop new therapeutic options overcoming them. Methods: To develop a preclinical model that predicts clinical activity of novel agents.We established patient-derived cell (PDC) and xenograft (PDX) models from malignant effusions (n = 15) or surgical specimen (n = 4).Genomic features of the PDX model were compared with those of the primary tumor. Drug effects of cell viability were then tested with PDC and PDX models. Results: Successful PDCs, defined as cells that maintained growth following 2 passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. Conclusions: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations. We show that novel preclinical models are developed using malignant effusions derived from patients with kidney cancer. The preclinical models can be used to test anti-tumor activity of novel therapeutics. The preclinical model we developed can be used to interrogate sensitivity to targeted agents based on genomic alterations. The PDC model from malignant effusions of patients was successfully converted to a PDX model, and represents an important and feasible platform for future cancer research.