Targeting TFEB transcription factor as a novel therapeutic approach for the treatment of Birt-Hogg-Dube’- associated kidney cancer
Worldwide Cancer Research
Telethon Institute Of Genetics And Medicine
Birt-Hogg-Dube’ is a hereditary cancer syndrome, due to loss of function mutations in the gene encoding Folliculin and characterized by benign skin tumors, lung and kidney cysts and renal cell carcinoma. Renal tumors represent the most severe manifestation of the disease and to date surgery is the only available therapeutic intervention. The design of effective targeted therapies depend on a better understanding of the primary cellular pathways in which folliculin serves as tumor suppressor. We recently found that depletion of TFEB in a kidney-specific mouse model of BHD syndrome fully rescued cystogenesis suggesting a key role of TFEB in Folliculin dependent pathologies. Encouraged by these findings, in this grant application we propose to understand the contribute of TFEB to the development of kidney tumors in Flcn heterozygous mice, which faithfully recapitulate kidney pathologies in BHD disease. In addition, we aimed at dissecting the TFEB downstream pathways responsible for tumor growth in BHD patients and functionally characterize a novel mechanism of regulation of TFEB localization, which could represent a novel therapeutic strategy for the treatment of BHD renal tumors.
2.1 Biological and endogenous factors