Biologics: Targets and Therapy Dovepress Everolimus in the Treatment of Subependymal Giant Cell Astrocytomas, Angiomyolipomas, and Pulmonary and Skin Lesions Associated with Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by inactivating mutations in either the TSC1 or TSC2 genes. It is characterized by the development of multiple, benign tumors in several organs throughout the body. Lesions occur in the brain, kidneys, heart, liver, lungs, and skin and result in seizures and epilepsy, mental retardation, autism, and renal and pulmonary organ system dysfunction, as well as other complications. Elucidation of the molecular pathways and etiological factors responsible for causing TSC has led to a paradigm shift in the management and treatment of the disease. TSC1 or TSC2 mutations lead to constitutive upregulation of the mammalian target of rapamycin pathway, which affects many cellular processes involved in tumor growth. By targeting mammalian target of rapamycin with everolimus, an orally active rapamycin derivative, clinically meaningful and statistically significant reductions in tumor burden have been achieved for the main brain (subependymal giant cell astrocytoma) and renal manifestations (angiomyolipoma) associated with TSC. This review provides an overview of TSC, everolimus, and the clinical trials that led to its approval for the treatment of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma. Epidemiology and etiology of sub ependymal giant cell astrocytomas, angiomyolipomas, skin lesions, and lymphangioleio myomatosis associated with tuberous sclerosis complex Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with an approximate birth incidence of 1:6,000 newborns. Up to 1 million people worldwide are affected. 4 Although TSC can be inherited, approximately two-thirds of all cases are sporadic. 5 Patients with TSC have a severely debilitating disorder that is associated with multiple benign tumors (hamartomas), most commonly in the brain, kidney, lungs, and skin. 4,6 Common symptoms include seizures (90%); renal tumors, also known as angiomyolipomas (up to 80%); skin lesions, ie, ash leaf macules and cutaneous fibromas (∼70%); pulmonary involvement, specifically lymphangioleio-myomatosis (LAM) (#40%); autism and autism spectrum disorders (30%–40%); and neurocognitive impairments (50%–60%), which often occur in individuals with a normal intelligence quotient.