Background: FGF-signalling pathway seems to have an important role in the progression of metastatic prostate cancer, and FGFR inhibitors have provided interesting preliminary results in preclinical studies. However, many of the currently used preclinical tumour models lack typical microenvironment and characteristics of human disease. The aim of this study was to establish patient-derived prostate cancer models and study FGFR inhibitors as potential investigational drugs.
Methods: Clinical prostate tumour specimens were collected from robotic-assisted laparoscopic radical prostatectomy operations in Turku University Hospital (Turku, Finland). Patient-derived tissues of Gleason grade 7-9 were cut into 1-2 mm3 pieces and cultured in vitro for 6 days with and without androgen supplementation. FGFR inhibitors Dovitinib, AZD4547 and BDJ398 were administered into the tissue culture medium. Viability and differentiation of cultured tissues were examined immunohistochemically by the expression of Ki-67, caspase-3, androgen receptor (AR), PSA and FGF8. Patient-derived xenograft (PDX) in vivo models were developed by implanting tissue pieces either subcutaneously or subrenally, or by digesting and then inoculating intratibially into the bone marrow cavity of nude mice.
Results: Tumour tissue maintained its viability in tissue culture and responded to testosterone exposure. Glandular epithelium degenerated when tissue grafts were grown without testosterone, as expected. FGFR-inhibitors decreased proliferation and increased apoptosis of epithelial cells in tissue culture model without having any effect on the expression of AR, PSA or FGF8. In the animal studies, tumour tissue was maintained or even expanded in all used models. Tumour-take was 25% grown in 3 passages.
Conclusion: FGFR inhibitors demonstrated anti-proliferative effects on patient-derived models in vitro. Challenging PDX prostate cancer in vivo models were successfully established utilising various tumour microenvironments. These models provide a personalised medicine tool that could be used to test the individual prostate cancer patients responses to therapy in the future.
Disclosure: Johanna Tuomela and Jussi Halleen are employees of Pharmatest Services Ltd. This work was supported by Academy of Finland.