Periodic Reporting for period 1 - INCANTAR (TARGETING INHERITED CANCER SYNDROMES)
Período documentado: 2023-09-01 hasta 2026-02-28
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.
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.
During this reporting period, our team made significant progress toward understanding and treating two rare genetic diseases: Birt–Hogg–Dubé (BHD) syndrome and Tuberous Sclerosis Complex (TSC). Both conditions are linked to the abnormal activation of the proteins TFEB and TFE3, which regulate genes involved in cell growth and metabolism.
After testing several compounds, we identified a drug candidate that can block TFEB activity. This compound showed strong anti-tumor effects in cell models of BHD and TSC, significantly reducing cancer cell growth. To test this compound in animals, we also generated a new mouse model of BHD disease, which better recapitulated the patients renal disease, compared to the previously generated models. This innovative model mimics important features of the human condition, including cyst formation and kidney tumors, but allows the disease to progress slowly enough for drug testing. Initial experiments using this model showed promising results: treatment with the compound reduced kidney cysts, improved kidney function, and lowered levels of tumor-related markers.
In parallel, we developed 3D kidney organoids of BHD and TSC syndromes. These are highly reliable culture models to study kidney pathology. These organoids reproduced key features of each disease, such as cyst formation. Their analyses revealed major differences in how these organoids develop and function, helping us understand how the diseases begin and progress.
We also generated new mouse models to study the brain effects of TSC. These models will help us explore whether targeting TFEB or TFE3 genes could improve neurological symptoms in TSC.
Together, these achievements establish a strong experimental foundation for developing new treatments for BHD and TSC, and for discovering shared molecular mechanisms that could be targeted across related kidney and brain diseases.
After testing several compounds, we identified a drug candidate that can block TFEB activity. This compound showed strong anti-tumor effects in cell models of BHD and TSC, significantly reducing cancer cell growth. To test this compound in animals, we also generated a new mouse model of BHD disease, which better recapitulated the patients renal disease, compared to the previously generated models. This innovative model mimics important features of the human condition, including cyst formation and kidney tumors, but allows the disease to progress slowly enough for drug testing. Initial experiments using this model showed promising results: treatment with the compound reduced kidney cysts, improved kidney function, and lowered levels of tumor-related markers.
In parallel, we developed 3D kidney organoids of BHD and TSC syndromes. These are highly reliable culture models to study kidney pathology. These organoids reproduced key features of each disease, such as cyst formation. Their analyses revealed major differences in how these organoids develop and function, helping us understand how the diseases begin and progress.
We also generated new mouse models to study the brain effects of TSC. These models will help us explore whether targeting TFEB or TFE3 genes could improve neurological symptoms in TSC.
Together, these achievements establish a strong experimental foundation for developing new treatments for BHD and TSC, and for discovering shared molecular mechanisms that could be targeted across related kidney and brain diseases.
The outcomes of this project have broad implications for both rare disease research and renal oncology. Our research led to the identification of a promising drug compound that can block TFEB activity in both BHD and TSC disease models. These results provide a foundation for the development of new treatments targeting the TFEB/TFE3 pathway, which could benefit patients affected by BHD, TSC, and related kidney cancers.
The new BHD and TSC disease models (both mouse and kidney organoid) will also serve as valuable tools for the wider scientific community, accelerating the translation of laboratory discoveries into clinical applications. In the long term, this work could lead to personalized therapeutic strategies, reduce the need for invasive surgeries, and improve quality of life for patients.
Beyond their immediate use in the development of treatments for BHD and TSC, these discoveries may also foster the understanding of general mechanisms of cyst formation, cellular metabolism, and tumor growth, offering insights relevant to more common kidney diseases. Importantly, the project also fostered a strong network of interdisciplinary collaboration between molecular biologists, clinicians, and drug discovery experts, building capacity for future translational work in Europe.
To ensure that these advances can lead to tangible patient benefits, several steps are necessary. Further preclinical studies are required to confirm the safety, efficacy, and pharmacological profile of the identified compound. Optimization and formulation work will be needed to improve its stability and delivery for potential use in humans. Finally, engagement with industrial partners and biotechnology companies will be essential to support compound scaling, toxicology testing, and clinical trial readiness. All these steps will require dedicated funding, and regulatory guidance to pave the way for commercialization and eventual patient access.
The new BHD and TSC disease models (both mouse and kidney organoid) will also serve as valuable tools for the wider scientific community, accelerating the translation of laboratory discoveries into clinical applications. In the long term, this work could lead to personalized therapeutic strategies, reduce the need for invasive surgeries, and improve quality of life for patients.
Beyond their immediate use in the development of treatments for BHD and TSC, these discoveries may also foster the understanding of general mechanisms of cyst formation, cellular metabolism, and tumor growth, offering insights relevant to more common kidney diseases. Importantly, the project also fostered a strong network of interdisciplinary collaboration between molecular biologists, clinicians, and drug discovery experts, building capacity for future translational work in Europe.
To ensure that these advances can lead to tangible patient benefits, several steps are necessary. Further preclinical studies are required to confirm the safety, efficacy, and pharmacological profile of the identified compound. Optimization and formulation work will be needed to improve its stability and delivery for potential use in humans. Finally, engagement with industrial partners and biotechnology companies will be essential to support compound scaling, toxicology testing, and clinical trial readiness. All these steps will require dedicated funding, and regulatory guidance to pave the way for commercialization and eventual patient access.