Renal disease in tuberous sclerosis complex: pathogenesis and therapy

Area of Science:

• Genetics and Molecular Biology
• Oncology
• Nephrology

Background:

• Tuberous sclerosis complex (TSC) is an autosomal dominant disorder.
• It is characterized by hamartomatous tumors in multiple organs, including the brain, heart, skin, lungs, and kidneys.
• Neurological and renal manifestations are common, with mutations in TSC1 and TSC2 genes underlying the disease.

Purpose of the Study:

• To review recent advances in Tuberous Sclerosis Complex (TSC) research.
• To highlight critical knowledge gaps in understanding TSC pathogenesis and treatment.
• To emphasize the need for strategies to eliminate, not just suppress, TSC-associated tumors.

Main Methods:

• Review of current literature on Tuberous Sclerosis Complex (TSC).
• Analysis of clinical trial data for mTORC1 inhibitors in TSC.
• Identification of unresolved questions in TSC research.

Main Results:

• Inactivating mutations in TSC1/TSC2 lead to dysregulated mTORC1 signaling.
• mTORC1 inhibitors reduce angiomyolipoma size but do not prevent regrowth.
• Several critical knowledge gaps remain, including factors driving aggressive renal cell carcinoma (RCC), mechanisms of cystogenesis, long-term effects of mTORC1 inhibition, and angiomyolipoma cell of origin.

Conclusions:

• Current therapies for TSC-associated tumors, like angiomyolipomas, offer only temporary suppression.
• Further research is essential to identify the cell of origin for angiomyolipomas and understand the factors contributing to aggressive renal cell carcinoma (RCC).
• Addressing these knowledge gaps is crucial for developing curative strategies for Tuberous Sclerosis Complex.