Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex

Abstract

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.

Keywords: angiomyolipomas; everolimus; facial angiofibromas; lymphangioleiomyomatosis; subependymal giant cell astrocytoma; tuberous sclerosis complex.

Figure 1

Computed tomography scan demonstrating acute presentation of bilateral subependymal giant cell astrocytomas with marked obstructive hydrocephalus. After emergency surgical resection, the patient with tuberous sclerosis complex was left blind and mentally retarded.

Figure 2

Renal computed tomography scan demonstrating significant angiomyolipomata burden in both kidneys of a patient with tuberous sclerosis complex.

Figure 3

Examples of tuberous sclerosis complex-associated skin lesions: (A) angiofibromas and (B) shagreen patches and ash leaf macules.

Figure 4

Chest computed tomography scan showing parenchymal destruction associated with lymphangioleiomyomatosis in a patient with tuberous sclerosis complex.

Figure 5

The mammalian target of rapamycin signaling pathway. Note: Franz DN et al. Journal of Child Neurology. 28(5):602–607, Copyright © 2013 by Sage. Reprinted by Permission of SAGE Publications. Abbreviations: 4E-BP1, 4E binding protein 1; Abl, Abelson kinase; Akt, protein kinase B; eIF-4E, eukaryotic initiation factor 4E; IGF-1R, insulin-like growth factor-1 receptor; PI3K, phosphoinositide 3-kinase; Pten, phosphatase and tensin homolog; RAS, rat sarcoma; S6K1, 40 S ribosomal S6 kinase; TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2.