Abstract
315 Background: The prognosis for bladder cancer has not changed in 30 years. No targeted agents have been approved even though reproducible genetic abnormalities have been identified. The goal of this project was to develop and characterize a patient-derived xenograft (PDX) platform to determine the efficacy of molecularly guided targeted and chemotherapy therapy, drug re-purpose, study resistance mechanisms, and design novel therapy to overcome resistance. Methods: PDXs were developed from direct implantation of uncultured patient bladder cancer specimens into immunodeficient NSG mice. Deep sequencing in combination with computational biology was performed to characterize PDXs and identify druggable genetic aberrations that guided efficacy screening and mechanistic studies. Results: Nineteen PDXs have been established with annotated clinical information. PDXs retained morphology and 92-97% genetic aberrations of parental patient cancers. Deep sequencing revealed multiple druggable genetic aberrations, including the fibroblast growth factor receptor 3 (FGFR3) and other tyrosine kinase receptor pathways. Compared to the progression-free survival (PFS) of 9.5 days in the control arm, matched therapy with an FGFR3 inhibitor BGJ398 prolonged PFS to 18.5 days (p=2.61 X 10-6) in PDXs overexpressing FGFR3. Serial biopsies during treatment revealed reactivation of the downstream pathways coincided with development of resistance while targeting these downstream effectors reversed resistance (12 vs. 22 days, p=0.001). Efficacy studies also revealed that PDXs had differential response to chemotherapeutic drugs that could potentially guide selection of chemotherapeutic drugs for first- and second-line therapies. To determine the clinical applicability of non-myoinvasive bladder cancer, we further developed an orthotopic PDX model that mimiced disease progression to invasive and metastatic bladder cancer. Conclusions: The PDX platform allows screening for multiple targeted therapy, chemotherapy or combinations simultaneously for the most efficacious drugs or combination, and serial biopsies during treatment to study drug resistance, a task not possibly replicable at the clinical setting.
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