The INCANTAR (INherited CANcer TARgeting) project focuses on understanding and developing new treatments for two rare inherited diseases, Birt–Hogg–Dubé (BHD) syndrome and Tuberous Sclerosis Complex (TSC). Both conditions can cause the formation of kidney cysts and tumors, and TSC can also affect the brain, leading to neurological symptoms.
At the center of these diseases are two proteins called TFEB and TFE3, which act as “master switches” inside cells. They control genes that manage how cells recycle their components and regulate metabolism. In healthy cells, TFEB and TFE3 are tightly controlled by another key protein complex, mTORC1, which ensures that these switches are turned on or off depending on the cell’s needs.
Our team discovered that mTORC1 can regulate TFEB and TFE3 in a previously unknown way that tunes how cells respond to different conditions. When this mechanism is disrupted, In BHD and TSC diseases, TFEB and TFE3 become permanently active, driving the uncontrolled cell growth and cyst formation seen in patients. Remarkably, experiments in mice have shown that removing TFEB entirely can prevent cysts and tumors from developing, confirming its critical role in disease progression. This led to the idea of targeting TFEB and TFE3 proteins as novel therapeutic strategies for BHD and TSC syndromes.
To this aim, the project aims to screen several compounds in order to identify drugs that can block TFEB and TFE3 activity and therefore eliminate diseased cells that show excessive activation of these proteins. The discovery of drugs that can effectively treat kidney disease in BHD and TSC patients would represent a major breakthrough. At present, there are no available therapies that can stop the formation of kidney cysts or prevent tumor growth in these conditions. Patients must therefore rely on lifelong medical monitoring and repeated surgeries, which only address the symptoms rather than the cause of the disease. By identifying new compounds that directly target the underlying molecular mechanisms, INCANTAR has the potential to transform patient care, offering the first targeted and less invasive therapeutic options for these rare but serious disorders.
The project also aims to develop novel disease models of BHD and TSC, and to this aim we proposed to generate kidney organoids, which are three-dimensional structures grown from stem cells that reproduce many aspects of human kidney. These models allow researchers to observe how TFEB and TFE3 cause disease at the cellular level and to test new treatments in a controlled laboratory setting, without the need for invasive procedures.
The impact of INCANTAR extends far beyond BHD and TSC. Because TFEB and TFE3 are also abnormally activated in several other types of cancer, our discoveries could open the way to new targeted therapies for a range of tumor types. By combining cutting-edge research tools with disease modeling and drug discovery, INCANTAR aims to transform our understanding of how these molecular pathways contribute to cancer and to pave the way for personalized, mechanism-based treatments for patients with rare and currently untreatable conditions.
