Abstract
Background: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missing. Patients and Methods: In vitro drug screening of tumor-derived short-term cultures obtained from seven patients with clear cell RCC was performed. For one patient, a patient-derived xenograft (PDX) mouse model was established for in vivo validation experiments. Drug effects were further investigated in established RCC cell lines. Results: The proteasome inhibitor carfilzomib was among the top hits identified in three of four patients in which an in vitro drug screening could be performed successfully. Carfilzomib also showed significant acute and long-term cytotoxicity in established RCC cell lines. The in vivo antitumoral activity of carfilzomib was confirmed in a same-patient PDX model. The cytotoxicity of carfilzomib was found to correlate with the level of accumulation of ubiquitinated proteins. Conclusions: In this proof-of-concept study, we show that patient-individualized in vitro drug screening and preclinical validation is feasible. However, the fact that carfilzomib failed to deliver a clinical benefit in RCC patients in a recent phase II trial unrelated to the present study underscores the complexities and limitations of this strategy.
Highlights
Metastatic renal cell carcinoma (RCC) has a poor prognosis with 5-year survival rates between 8% and 12% [1,2]
The proteasome inhibitor carfilzomib was a hit in three of the four successful drug screens, with reduction in tumor cell viability ranging from a 0.19-fold to a 0.28-fold change (RCC001, RCC008, and RCC024; Table 1)
We investigated whether carfilzomib has acute antitumoral activity in estab lished RCC cell lines as well as non-cancerous, kidney-derived HEK293 cells
Summary
Metastatic renal cell carcinoma (RCC) has a poor prognosis with 5-year survival rates between 8% and 12% [1,2]. Advanced RCC is characterized by a high degree of genomic and functional intratumoral heterogeneity [6,7] Under selection pressure, such as systemic anti-cancer therapy, tumor heterogeneity may promote clonal evolution and, the outgrowth of treatment-resistant tumor cell populations [8]. Patient-individualized tumor models and drug screening may help to overcome these uncertainties. This strategy can include cell culture models directly derived from the patient’s tumor tissue, such as short-term cultures or organoids, as well as patient-derived xenograft (PDX) models [12]. The fact that carfilzomib failed to deliver a clinical benefit in RCC patients in a recent phase II trial unrelated to the present study underscores the complexities and limitations of this strategy
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