Is mTOR inhibition a systemic treatment for tuberous sclerosis?

Abstract

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by the development of hamartomas in several organs. Mutations in the TSC1 and TSC2 tumor suppressor genes determin overactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for TSC patients. Everolimus has been recently approved as a pharmacotherapy option for TSC patients with subependymal giant-cell astrocytomas (SEGAs) or renal angiomyolipomas (AMLs). However, clinical evidence suggests that this treatment can benefit other TSC-associated disease manifestations, such as skin manifestations, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and epilepsy. Therefore, the positive effects that mTOR inhibition have on a wide variety of TSC disease manifestations make this a potential systemic treatment option for this genetic multifaceted disorder.

Figure 1

SEGA volume reduction during Everolimus treatment. A boy with a TSC2 mutation showed progressively growing SEGAs that caused a first acute hydrocephalus when he was 17 years old. He therefore underwent a partial resection of the lesion, with hydrocephalus resolution. However, two years later, the contralateral SEGAs determined a new episode of hydrocephalus and he underwent surgery once again. However, both lesions presented a slow regrowth after surgeries, and figure (A) shows their aspect when the boy was 24 years of age. He later presented a new episode of subacute hydrocephalus, which required an external derivation. He subsequently started Everolimus treatment, with a partial response (total lesion volume 46% of baseline) of SEGAs after 12 months of treatment (B).

Figure 2

Monthly seizure frequency in a TSC girl. A girl with a TSC2 mutation presented refractory seizures since the age of 7 years. When she was 20 years old she presented mainly secondarily generalized tonic and tonic-clonic seizures. The image shows her seizure frequency per month before and during Everolimus treatment. With everolimus seizure frequency decreased, generalized seizures stopped, and she continued to have only focal onset seizures of short duration, without drop attacks nor falling to the ground.

Figure 3

Progressive reduction of renal AMLs. A girl with a TSC2 mutation presented renal AMLs since childhood, with no impairment of renal function but with a progressivre growth both in number and in size. When she was 23 years old Everolimus was started (A, baseline), with a progressive reduction in the total volume of lesions. Figure B is the MRI after 12 weeks of treatment (76% of volume reduction), while figure C is after 144 weeks of treatment with Everolimus (85% of volume reduction).

Figure 4

Facial angiofibroma before and during Everolimus treatment. Facial angiofibroma of the same boy presented in Figure 1 at baseline (A) and after 84 weeks of treatment with Everolimus (B).