Profiling of extracellular vesicles of metastatic urothelial cancer patients to discover protein signatures related to treatment outcome.

The prognosis of metastatic urothelial carcinoma (mUC) patients is poor, and early prediction of systemic therapy response would be valuable to improve outcome. In this exploratory study, we investigated protein profiles in sequential plasma-isolated extracellular vesicles (EVs) from a subset of mUC patients treated within a Phase I trial with vinflunine combined with sorafenib. The isolated EVs were of exosome size and expressed exosome markers CD9, TSG101 and SYND-1. We found, no association between EVs/ml plasma at baseline and progression-free survival (PFS). Protein profiling of EVs, using an antibody-based 92-plex Proximity Extension Assay on the Oncology II® platform, revealed a heterogeneous protein expression pattern. Qlucore bioinformatic analyses put forward a protein signature comprising of SYND-1, TNFSF13, FGF-BP1, TFPI-2, GZMH, ABL1 and ERBB3 to be putatively associated with PFS. Similarly, a protein signature from EVs that related to best treatment response was found, which included FR-alpha, TLR 3, TRAIL and FASLG. Several of the markers in the PFS or best treatment response signatures were also identified by a machine learning classification algorithm. In conclusion, protein profiling of EVs isolated from plasma of mUC patients shows a potential to identify protein signatures that may associate with PFS and/or treatment response.

Clinical activity of sorafenib in a previously treated advanced urothelial cancer patient.

A male patient, with advanced urothelial carcinoma, who had previously received cisplatin, was treated with sorafenib off-licence for 10.7 months. Evaluation of tumour response with computed tomography scans indicated a reduction in tumour size and necrosis of the metastases within 2 months. Progression-free survival was 10.5 months. Side effects were manageable and not beyond the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 grade 2. Molecular profiling of two of the proposed targets of sorafenib, platelet-derived growth factor receptor ß and vascular endothelial growth factor receptor 2, of the patient's tumour lesion showed high and intermediate expression levels in the tumour as compared with the surrounding non-neoplastic tissue. In contrast to previous reports, we report a clinically meaningful effect of sorafenib in a patient with advanced urothelial carcinoma. Hence, it appears that a fraction of patients with this disease are sensitive to this compound. To identify subpopulations of responders, we propose that clinical trials evaluating sorafenib and other targeted drugs should be biomarker-driven and designed with endpoints that consider the mode of action of the specific compound.