Tuberous sclerosis complex (TSC)

Clinical features of TSC. 

Tuberous sclerosis complex (TSC) is a rare genetic disease, caused by mutational inactivation of either the TSC1 or TSC2 tumor suppressor gene. TSC affects multiple organs including the brain, heart, kidney, lung and skin.

Genetics of TSC. 

Individuals with TSC have inactivating germline loss-of-function mutations in TSC1 or TSC2.  The TSC1 and TSC2 genes are tumor suppressor genes. Tumors, including renal angiomyolipomas, facial angiofibromas, and pulmonary lymphangioleiomyomatosis (LAM), develop after somatic “second hit” inactivation of the remaining wild-type allele of TSC1 or TSC2.

Biochemical function of the TSC proteins.

The TSC protein complex integrates signals from the cellular environment, including growth factors and nutrients to regulate the activity of mechanistic/mammalian target of rapamycin complex 1 (mTORC1). mTORC1 controls numerous essential metabolic processes, including protein and lipid synthesis, glycolysis/ATP production, lysosome and mitochondrial biogenesis and autophagy

Current treatment of TSC. 

Sirolimus (Rapamycin), an mTORC1 inhibitor, is FDA-approved for the treatment of LAM, and everolimus, which is similar to sirolimus and also inhibits mTORC1, is FDA-approved for the treatment of certain manifestations of TSC, including angiomyolipomas and subependymal giant cell astrocytomas.  Sirolimus and everolimus are referred to as “Rapalogs.”

Why are new treatments for TSC a priority? 

Rapalogs (sirolimus/Rapamycin and everolimus) partially shrink TSC tumors, but do not eliminate them.  The tumors grow back when the drugs are stopped.  Therefore, many individuals with TSC and LAM need lifelong therapy.  This highlights the unmet clinical need for treatments that induce long term disease-free remissions.

Role of the Henske Lab in TSC research. 

The Henske Lab has been dedicated to understanding the signaling pathways implicated in TSC and its many manifestations. In 1998, Dr. Henske was the first to report the physical interaction between the TSC1 and TSC2 proteins, which is fundamental to our understanding of  TSC. Since then, her research has expanded into the role of autophagy, nutrient uptake, lysosomes, and miRNA in the pathogenesis of TSC.  She is also committed to identifying cellular pathways and drugs that will lead to the elimination of tumors in individuals with TSC and a cure for TSC.