Grant: CIHR Fellowship

Birt-Hogg-Dubé syndrome (BHD) is a predisposition to renal cell carcinoma (RCC) caused by inherited mutations of the Folliculin (FLCN) gene. The lifetime risk for BHD patients to develop RCC is approximately 20%. Timely diagnosis of BHD by DNA analysis helps timely detection of RCC, permitting nephron-sparing surgery. Nevertheless, BHD patients require life-long screening. While early discovery and resection of BHD-RCCs provides a valuable treatment option for developed countries, surgery complications may pose risks. Therapeutic treatment strategies for BHD-RCC are inadequate. Here, I aim to exploit the human-derived cancer cell models that have been developed at the Amsterdam UMC to discover and validate personalized treatment options for BHD-RCC. For the first time, I will use a recently developed technology called CRISPR screening to identify drug targets that are uniquely relevant for BHD-RCC patients. Furthermore, I will use this approach to explore a promising new drug used for hereditary RCC treatment in the VHL kidney cancer predisposition syndrome, to repurpose it for BHD therapy. I will investigate combination therapies using human BHD cancer cell line models and this work is expected to identify new, preclinically validated therapeutic options for BHD-RCC. Therapeutic strategies will be evaluated for translation to the clinic by the Amsterdam UMC urologists, medical oncologists and the Drug Rediscovery Protocol team.